The most active compounds were extracted from 29 different plant families; particularly, Euphorbiaceae (69 compounds) and Lamiaceae (54 compounds) were the richest sources of active compounds. A better activity than the positive control was obtained with 33 compounds against the A549 cell line, 28 compounds against the MCF-7 cell line, 9 compounds against the HepG2 cell line, 8 compounds against the Hep3B cell line, 19 compounds against the SMMC-7721 cell line, 9 compounds against the HL-60 cell line, 24 compounds against the SW480 cell line, and 19 compounds against HeLa.Diterpenes represent a wider class of isoprenoids, with more than 18,000 isolated compounds, and are present in plants, fungi, bacteria, and animals in both terrestrial and marine environments. Here, we report on the fully characterised structures of 251 new diterpenes, isolated from higher plants and published from 2017, which are shown to have antitumoral activity. An overview on the most active compounds, showing IC The plant kingdom is the largest reservoir of secondary metabolites, due to the very large number of species present in the world, which synthesise a large variety of molecules, from the simplest ones to the most complex. Most of the secondary metabolites are unique of a single species, but some skeletons are common to different families of plants. Every year, new secondary metabolites are isolated and identified from plants, and their biological activity is evaluated. Isoprenoids represent one of the largest groups of natural products in living organisms, and they derive from the condensation of basic five-carbon units (isoprene units), namely isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The condensation of one unit of IPP with one unit of DMAPP leads to the formation of geranyl diphosphate, which will be the precursor of monoterpenes. The condensation of further IPP units will then lead to the formation of the precursors of sesquiterpenes C15) and diterpenes C20). Diterpenes represent one of the wider families of natural products, with more than 18,000 isolated compounds, which are present in plants, fungi, bacteria, and animals in both terrestrial and marine environments [5 and dit0. Diterpent” , while compounds that are specular images of the normal series belong to the series “ent” .50 values below 20 μM, thus highlighting the ones with higher cytotoxic activity, with respect to the positive control. Although diterpenes have a skeleton with 20 carbon atoms, we also reported compounds with a different number of carbon atoms in the skeleton, since they are defined as diterpenoids in the original article and derive from GGPP. Since the present review was designed to help the researchers involved in the development of new anticancer substances, three tables are provided at the end, in which, the compounds are divided by type of skeleton, cancer cells, and family plant.In the present review, we summarise the new diterpenes identified and characterised between 2017 and 31 May 2022, highlighting the cytotoxic activity against cancer cells observed for some of these compounds, in order to provide inspiration for novel drugs derived from natural products. To highlight a relation between the structure and cytotoxic activity, we decided to divide the diterpenes into two main groups: the first one containing the monocyclic diterpenes, cembrane, and diterpenes derived from cembrane, with the second one containing the diterpenes derived from the labdane-type, independently of the stereochemistry of cyclization. A second subdivision will be made according on the number of cycles present in the skeleton. Most of the review present in the literature focus on one species of plant or, sometimes, a family plant, while the present review covers all types of diterpenes isolated from different families of higher plants. For this reason, due to the large number of compounds found, we report only the chemical structures of diterpenes, which have shown significant cytotoxic activity against cancer cells, with ICIn 1 and B 2 were isolated from the stem bark and leaves of Aphanamixis polystachya  R. Parker (Meliaceae), a timber tree mainly growing in the low altitude tropical areas of Asia, such as China, India, Malaysia, and Indonesia [A. polystachya with ethanol and subsequent partitioning with petroleum ether (PE) and ethyl acetate (EtOAc). Their structures were established through comprehensive analyses of NMR spectroscopic data and high-resolution mass spectrometric (HR-ESI-MS) data, while the absolute configurations of carbon stereocenters were elucidated by circular dichroism (CD) analyses. The two compounds were tested for their potential cytotoxic effects against ACHN (human kidney cancer), HeLa , SMMC-7721 (human hepatoma cancer), and MCF-7 (human breast cancer) cell lines. Nornemoralisin A 1 showed cytotoxicity against ACHN and HeLa cell lines, with IC50 values of 13.9 and 19.3 μM, respectively, while nornemoralisin B 2 showed the cytotoxicity against all cancer cell lines used, with IC50 values ranging from 1.6 to 11.3 μM. Particularly, nornemoralisins A 1 and B 2 exhibited significant cytotoxicity on ACHN cell line, with an IC50 value better than the positive control vinblastine . Their structures were established by multiple spectroscopic methods . The in vitro cytotoxic activity was determined against a panel of four human cancer cell lines: KB , MCF-7, A549 , and HCT116 (colon carcinoma). Tagetone A 3 showed cytotoxic activity with IC50 values of 9.39, 4.68, 4.24, and 12.17 μM, respectively, while tagetone B 2 showed IC50 values of 16.20, 15.41, 8.29, and 6.30 μM, respectively. Doxorubicin was used as the positive control [Tagetones A  and B 4 , two newcis-fused, although a few examples have been found of trans-fused [Casbane-type diterpenoids possess a macrocyclic structure fused with a cyclopropane ring, and the two rings are usually ns-fused . They de5 and EBC-320 6, were isolated by ethanolic extraction and subsequent partitioning with different solvents from the stems of Australian rainforest Croton insularis (Euphorbiaceae) stems [5 and EBC-320 6 displayed significant cytotoxicity, with values of IC50 in the range of 3–6 μM, on the cancer cell lines HeLa, HT29 (colon cancer), MCF-7, MM96L (melanoma), and K562 (human erythromyeloblastoid leukemia), using the MTS color assay. No positive control was used. Cytotoxicity was observed also for NFF   stems . Their soblasts) .Daphne genkwa Sieb. et Zucc. (Thymelaeaceae) and Euphorbia fischeriana (Euphorbiaceae), with cytotoxic activity.Daphnane diterpenoids are mainly present in plants of the Thymelaeaceae and Euphorbiaceae families, and their skeleton is formed of a 5/7/6-tricyclic ring system with several hydroxyl groups. About 200 daphnane-type diterpenoids have been isolated and elucidated from these families, which were mainly described in a recent review focusing on their classification and biological activity . Here, wDaphne genkwa [7 was the most active one, with an IC50 value of 3.0 μM against SW620 cells and 6.5 μM against RKO, using 5-fluorouracil (5-FU) as the positive control and MTT assay. Moreover, further studies were performed, and it was demonstrated that compound 7 induced G0/G1 cell cycle arrest, thus leading to the induction of apoptosis in SW620 cells. It also induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound 7 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggested that compound 7 may be a suitable lead compound for further biological evaluation , using the CCK-8 assay and oxaliplatin as a positive control , HepG2, HL-60 (human erythroleukemia), K562, and HeLa, with IC50 values ranging from 5.31 to 21.46 μM, using cisplatin as a positive control (From the dry roots of  control .Hypoestes forsskaolii (Vahl) R. Br. (Acanthaceae), a perennial bushy and leafy herb widely distributed in several African countries, as well as in the high mountains of the Arabian Peninsula, by extraction with solvents of increasing polarity [50 values >20 μM for both cancer cell lines, compound 15 demonstrated an IC50 value of 18 μM in the HeLa cell line, using etoposide as positive control. Compound 15 did not show cytotoxic activity on the non-tumor human peripheral blood mononuclear cell line (PBMC) up to 100 μM , a Chinese endemic species mainly distributed in North China [2(OAc)4-induced circular dichroism (ICD), and CD exciton chirality methods. The new compounds were screened for their antiproliferative effects against HepG2, MCF-7, and DU145 (human prostate cancer) cell lines, and they all showed inhibitory effects on the cell proliferation of these three kinds of cancer cells, with IC50 in the range 6.19–29.16 μM, using the CCK-8 assay.Three ingenane-type diterpenes, named kansuingenol A–C 16–18 , have be19 was isolated by dichloromethane/acetone extraction of the aerial parts of Euphorbia erythradenia Bioss. (Euphorbiaceae) [19 was found to be cytotoxic against A375 and HMCB cells, with IC50 values of 15.37 μM and 15.62 μM, respectively, using the MTT assay. From further studies and the results obtained, the authors suggest that DANPT can inhibit proliferation of human melanoma cancer cells by promoting apoptosis and inducing cell cycle arrest; therefore, it can be a promising natural agent for the treatment of melanoma cancer (A new tetrahydroingenol diterpene (DANPT) biaceae) , one of a cancer .20, a highly modified ingenane diterpenoid incorporating a large (C24) appendage forming an additional 5/6/19 ring system (Euphorbia kansuensis (Euphorbiaceae). Compound 20 was screened for cytotoxicity against the HepG2, HepG2/DOX (doxorubicin resistant human liver hepatocellular carcinoma), HCT-15 (human colon cancer), HCT-15/5-FU , A549, A549/CDDP , A375, RKO, and MDA-MB-231 (human breast cancer) cell lines. The results showed that euphorkanlide A 20 inhibited most cancer cell lines at a micromolar level, with IC50 values less than 5 μM for the cell lines of HCT-15/5-FU, A375, and RKO. A mechanistic study of 20 on the 5-fluorouracil resistant cell line, HCT-15/5-FU, was further carried out [Euphorkanlide A g system , was isoried out .21, together with two new latyrane-type diterpenoids (see Euphorbia stracheyi Boiss (Euphorbiaceae), a perennial herb distributed in the Sichuan, Yunan, Tibet, Qinghai, and Gansu provinces of China [21 was cytotoxic against the MV4-11 (lymphoblast from human biphenotypic B myelomonocytic leukemia) cancer cell line, with an IC50 value of 5.92 μM, using the MTT assay and taxol as a positive control , an endemic spurge from Greece, it was possible to isolate several diterpenes, and three of them proved to be cytotoxic against HeLa cancer cell lines [22, obtained by methanolic extraction, showed an IC50 value of 9.8 μM using the MTT assay and partenolide as a positive control , collected in Serbia, by extraction with 96% ethanol and subsequent fractionation by column chromatography [23 inhibited cell growth of non-small cell lung carcinoma cell line NCI-H460, as well as glioblastoma cell lines U87 and U87-TxR (resistant glioblastoma), with IC50 values between 10 μM and 20 μM, using the MTT assay , together with euphodeflexin L 22 . Their structures, as well as the stereochemistry, were assigned , a multipurpose shrub commonly found in Africa, Asia, and Latin America, which is used in traditional medicine for various diseases, such as antimicrobial and anti-insect [29 exhibited significant cytotoxic effects against Saos-2 and MG-63, with IC50 values of 8.08 and 14.64 μM, respectively, lower than the IC50 values for the positive control 5-FU. Morphological features of apoptosis activities were evaluated in compound 29-treated Saos-2 cells, and the results confirmed apoptosis in a dose-dependent manner , an ornamental shrub mainly distributed in South America and South China, it was possible to isolate the new jatromultones A-I. Extraction was performed with 95% ethanol and subsequent partitioning with EtOAc and their structures, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, and chemical evidence. They were screened for antiproliferative activity against a panel of five different cancer cell lines , and four of them showed cytotoxic activity. Among them, jatromultone G 30 had an IC50 < 20 μM against A549 and HeLa, while jatromultone I 31 had an IC50 < 20 μM against only A549. The MTT assay was used, with doxorubicin as a positive control [From the air-dried powder of the trunks of Euphorbia fischeriana, whose structures were elucidated by spectroscopic analysis [32 exhibited significant cytotoxicity against the C4-2B (human prostate cancer) cell line, with an IC50 value of 11.3 μM, using doxorubicin as positive control. Compound 32 represents a rare example of a lathyrane diterpenoid featuring a 15-p-coumaroyl moiety.Two new lathyrane diterpenoids, euphofischers A and B, were isolated by EtOAc extraction from the roots of analysis . Only eu33 and B 34 were isolated by methanolic extraction and subsequent partitioning in EtOAc from the roots of Euphorbia stracheyi Boiss [33 and B 34 showed moderate cytotoxicity against the MV4-11 cell line, with IC50 values of 12.29 and 14.80 μM, respectively, using the MTT assay and taxol as a positive control . Cytotoxicity assays showed that compound 35 exhibited stronger cytotoxicity against the MCF-7 cell line (IC50 9.43 μM) than classic anticancer drug cisplatin, as well as significant cytotoxicity against HepG2 cell line (IC50 13.22 μM), indicating that esterification at C-3 with α-configuration and substituting with heterocyclic ester group would improve the cytotoxicity of the lathyrane-type diterpene [Euphorbia factor Lt at C-3 , was isoiterpene .Euphorbia paralias in 1998, are rare 5/6/5/5 tetracyclic systems that are probably formed through a transannular ring-closing reaction of the jatrophane diterpene (a jatropha-6(l7),12-diene), thus resulting in a 5/6/5/5-ring system. The introduction of primary alcohol on gem-dimethyl, followed by a complete cycle expansion, results in the formation of the pepluane skeleton (5/6/5/6) [Both pepluane and paraliane diterpenes are based on a fused tetracyclic core originated from further rearrangements of a proper jatrophane skeleton. The paraliane skeletons, isolated for the first time from 5/6/5/6)   (China) [38 showed remarkable activity, with IC50 values less than 10 μM, against five different cancer cell lines , while compound 37 had cytotoxic activity against A549, MDA-MB-231, HepG2, and HepG2-DOX, with IC50 values in the range of 2.69–6.44 μM. Doxorubicin as a positive control and the MTT assay were used  . Compounere used .Tigliane diterpenoids are based on a 5/7/6/3 tetracyclic ring system, and the skeleton derives from the cyclization of lathyrane diterpenoids  Scheme .39, crodamoid C 40, crodamoid D 41, crodamoid H 42, and crodamoid I 43 (Croton damayeshu (Euphorbiaceae), which is mainly distributed in Yunnan Province, China. The structural elucidation of these compounds was conducted by comprehensive analyses of the NMR, single-crystal X-ray crystallography, and ECD data. Cytotoxic tests revealed that compounds 42 and 43 exhibited significant activities against the A549 and HL-60 cell lines (IC50 0.9–2.4 μM). Particularly, compound 42 displays a selective activity comparable to adriamycin against the A549 cell line. Compound 39 showed activity against A549, with IC50 value of 3.7 μM, while compounds 40 and 41 showed activities against both the tested cancer cell lines, with IC50 values ranging from 4.1 to 22.7 μM [New tigliane diterpenoids, crodamoid A oid I 43 , were is 22.7 μM . The pre44 and crotonol B 45 were isolated from the leaves of Croton tiglium (Euphorbiaceae), and crotonol B 45 represents the first example of a 13,14-seco-tigliane diterpenoid  cell lines, with paclitaxel as a positive control. Compounds 44 and 45 showed strong cytotoxic activities , better than paclitaxel, towards the K562 cell line, while exhibiting low cytotoxicity in the MCF-7 and SGC-7901 cancer cell lines [Crotonol A erpenoid . Crotonoll lines .Taxus wallichiana (Taxaceae) by extraction with dichloromethane [46, which is a representative of the rare abeo-taxoid class, showed cytotoxic activity with IC50 value of 4.9 μM, although paclitaxel, which was used as the positive control, has an IC50 value of 0.0014 μM. Note that the two known compounds 7-epi-taxol and 7-epi-10-deacetyltaxol, which were also isolated, showed IC50 values of 0.05 and 0.085 nM, respectively, against the HeLa cells  families, while clerodanes with a 5:10 cis ring junction are more commonly found in the Euphorbiaceae, Flacourtiaceae , and Menispermaceae families. A description of the clerodane structure and nomenclature can be found in the review of Lee et al. published in 2016 [The clerodane skeleton contains a decalin ring mojety that can have a g fusion . Cleroda in 2016 .Laetia corymbulosa  with CH3OH–CH2Cl2 (1:1), which provided five new clerodane diterpenes, designated as corymbulosins D–H [47–49 exhibited antiproliferative activity, with IC50 values of around 5 μM, using paclitaxel as a positive control  [50 values ranging between 6.4 and 11.4 μM, using paclitaxel as a positive control.16-Hydroxy-pentandralactone miaceae)   led to the isolation of the new clerodane diterpene, which was named caseargrewiin M 51 [1H and 13C) and 2D NMR  techniques. Cytotoxic activity of caseargrewiin M 51 was determined towards Hep-G2, SW-620, Chago-K1 (undifferentiated lung carcinoma), KATO-III (gastric carcinoma), and BT474  cell lines, using the MTT colorimetric method and doxorubicin as a positive control. It exhibited significant cytotoxicity, with IC50 values of 12.84 μM for BT474, 12.43 μM for Chago-K1, 9.46 μM for Hep-G2, 11.21 μM for KATO-III, and 11.21 μM for SW-620.Methanolic extraction and subsequent partitioning with EtOAc of the fresh ripe fruits of iin M 51  , an herb widely distributed in mainland China, Korea, India, and other Asian countries [52 showed cytotoxic activity against A549 and HL-60, with IC50 values of 10.4 and 15.3 μM, respectively, using the MTT and SRB methods and cisplatin as a positive control (Six new ountries . Their s control .Croton crassifolius (Euphorbiaceae), a monecious undershrub widely distributed throughout south and southeast China, Thailand, Vietnam, and Laos [13C NMR chemical shifts. The cytotoxic activity of the new compounds was tested against human liver cancer cell lines (HepG2 and Hep3B). Among them, crassifolius A 53 exhibited good cytotoxicity, with IC50 value of 17.91 μM against human liver cancer cells Hep3B, using MTT assay and 5-FU as a positive control  [54 and caseakurzin J 55 exhibited significant inhibitory activity, with IC50 values of 4.4 and 4.6 μΜ, respectively , the apoptosis rate increased from 13.57% to 46.14%. The results showed that compounds 54 and 55 arrested the cell cycle at the G2/M and S phases, respectively, and induced apoptosis of the A549 cells.Ten clerodane diterpenoids, caseakurzins A–J, were isolated by ethanolic extraction and subsequent partitioning from the twigs and leaves of tiaceae) . The strectively . MoreoveCasearia kurzii [50 values > 60 μM), while kurzipene A 56 and kurzipene B 57 showed promising activities, with IC50 values ranging from 5.3 to 19.0 μM, compared to the positive control etoposide. Compound 57, with an IC50 value of 5.3 μM, was particularly cytotoxic against HeLa cells , a deciduous tree distributed principally in Yunnan Province of mainland China, northern Myanmar, and India [63 was shown to be the most potent, with an IC50 value of 1.9 μM against A549 cells and IC50 value of 4.6 μM against HepG2 cells, using homoharringtonine as a positive control  roots, which were mixed with diatomite and then eluted with different solvents, such as petroleum ether, CHCl3, and EtOAc [64 showed an IC50 value lower than 20 μM against the T24 cell line (human urinary bladder cancer), using the CCK-8 method and gemcitabine as the positive control  distributed in northeast, southwest, and central-south of China , and A549 cell lines. Compounds 65 and 66 exhibited broad-spectrum and moderate to potent cytotoxicity, with IC50 values below 10.0 μM; compound 67 exhibited more selective activity against the PANC-1 cell line (IC50 9.8 μM) than against the A549 and HeLa cell lines , using etoposide as a positive control [Sheareria A–C of China . Compoun control .Sheareria nana S. Moore, and its structure was elucidated by spectroscopic data [68 exhibited excellent cytotoxicity against human endometrial carcinoma cells (ECC-1), with IC50 values of 5.6 and 2.2 μM for 24 and 48 h, respectively, and it showed no cytotoxicity against normal cells. The MTT assay was used    and show control .70, a neo-clerodane diterpenoid, was isolated from the whole herbs of Ajuga decumbens (Labiatae). Compound 70 showed cytotoxic activity against HepG2 cell line (IC50 19.7 μM), using doxorubicin as a positive control [Ajugacumbin N  control   inhibitory activity, were isolated from the stems of Tinospora crispa (Menispermaceae)  cell line, respectively. The results suggested a STAT3-specific inhibition. The compounds were also tested against a non-tumor lung fibroblast cell line, WI-38, but did not show any toxicity at the highest concentration (100 μM) tested. A molecular modeling study was carried out to better understand the molecular mechanism of actions of 71 and 72 [Two new rmaceae) . Compoun1 and 72 .73–80 were isolated from the bark of Laetia corymbulosa   . The abs81 was isolated from the aqueous alcoholic extract of Tinospora cordifolia (Menispermaceae) stems , using mitomycin-C as a positive control, and 14.8 μM against the melanoma cancer cell line (MDA-MB-435). It was demonstrated that the new clerodane diterpenoid 81 induced apoptosis of HCT-116 cells mainly by triggering ROS (reactive oxygen species) production [A new clerodane furano diterpene glycoside TC-2 e) stems . The strThe halimane skeleton derives from a methyl migration of the labdane skeleton and is present within a diverse number of species of the plant, animal, and bacteria kingdoms.Croton crassifolius Geisel (Euphorbiaceae) roots, which is primarily distributed in southern China, Laos, Thailand, and Vietnam [82 exhibited selective cytotoxicity against the A549 cells (IC50 5.2 μM), compared with the HL-60 cells (IC50 11.8 μM), using the MTT and SRB methods and cisplatin as the positive control , widely cultivated in China, India, and Southeast Asian countries, such as Thailand, Indonesia, and the Philippines, it was possible to isolate three new labdane-type diterpenes, named galangalditerpenes A–C 83–85, by 80% aqueous acetone extraction, and their stereostructures were elucidated on the basis of their spectroscopic properties [50 values of 4.4, 8.6, and 4.6 μM, respectively, better than the positive control arbutin (174 μM).From the dried fruit of operties  , it was possible to isolate four new labdane diterpenes, which were unambiguously identified by applying extensive 1D and 2D NMR spectroscopic studies, as well as HR-ESI-MS [86–88, revealed significant cytotoxic activity against the mouse lymphoma L5178Y cell line, with IC50 values ranging from 1.4 to 12.9 μM, using kahalalide F as a positive control.From the methanolic extract of leaves from R-ESI-MS   [R,13E)-ent-labd-13-ene-3α,8,15-triol 15-O-β-D-glucopyranoside by chemical and spectroscopic methods, including 1D and 2D NMR. It showed cytotoxic activity against the mouse leukemia p388D1 cancer cells, with an IC50 value of 17.7 μM, using taxol as the positive control.One diterpenoid glycoside labdane type, named phocantoside A idaceae)   were isolated by methanolic extraction and subsequent partitioning in different solvents from the leaves and twigs of Amentotaxus argotaenia (Taxaceae), a coniferous species endemic to China [90 and T 91 showed cytotoxic activity against the MDA-MB-231 cell line, with IC50 values of 1.6 and 1.5 μM, respectively, using paclitaxel as the positive control (Four to China . Their s control .Phlomoides betonicoides (Diels) Kamelin and Makhm (Lamiaceae), a perennial herb present in China [13C NMR. Only phlomoideside A 92 showed an IC50 value of 7.5 μM against the MCF-7 cell line, better than the positive control cisplatin  (China). Its structure and absolute configuration were unequivocally established by a combination of spectroscopic data and X-ray single-crystal diffractions. Hedychins B 93 was cytotoxic against the HepG2 and XWLC-05 (lung adenocarcinoma) cell lines, with IC50 values of 8.0 and 19.7 μM, respectively [Hedychin B 93 , an unprectively .ent-labda-5,13-dien-15-oic acid 94, was isolated from the oleoresin obtained from the trunk of Copaifera trapezifolia L. (Fabaceae), a large tree present in Brazil [1H and 13C NMR, correlation 1H-1H (COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple bond correlation (HMBC), and HR-ESIMS analyses. Compound 94 displayed relevant cytotoxic effect against the ACP01 (gastric cancer) and A549 cell lines, with IC50 values of 11.7 μM (3.57 μg mL−1) and 17.6 μM (5.35 μg mL−1), respectively, using doxorubicin as a positive control and the sulforhodamine B (SRB) assay  assay .Croton sublyratus Kurz (Euphorbiaceae) by ethanolic extraction and subsequent partitioning with EtOAc [95 displayed cytotoxic activity against the HL-60 cell line, with an IC50 value of 2.8 μM, using the sulforhodamine B (SRB) and cell counting kit-8 (CCK-8) assays and adriamycin as the positive control  rhizomes, present in alpine grassland, grassy hillsides, and stony slopes of central to eastern Himalaya from Uttarakhand to north-east states, led to the identification of the new labdanes coronarin K and coronarin L [96 showed cytotoxic potential against A549 cell line, with an IC50 value of 13.49 µM, using the MTT assay and paclitaxel as a positive control (Purification of the chloroform soluble fraction from the methanol extract of onarin L . Particu control .Euphorbia pekinensis Rupr. (Euphorbiaceae), by ethanolic extraction and subsequent partitioning with EtOAc, it was possible to isolate a new labdane-type diterpenoid, named euphodane A 97, with cytotoxic activity against the U-937 (human monoblastic leukemia) cell line, with an IC50 value of 5.92 μM, using the cell counting kit-8 and paclitaxel as a positive control [From the roots of  control  , a dispersed herb or subshrub now growing in most tropical areas of the world [n-BuOH, while structure determination was performed using spectroscopic techniques, including MS, NMR, and ECD. The two compounds are epimers at C-14, and both showed cytotoxicity against the MCF-7, MDA-MB231, and A549 cancer cell lines in the IC50 range of 7.63–18.2 μM, using the MTS assay and suberoylanilide hydroxamic acid (SAHA) as a positive control.Two formerly undescribed labdane-type diterpenoids, scoparicols C he world   [100 showed significant cytotoxicity against the A2780 (human ovarian) and HepG2 cell lines, with IC50 values of 5.88 and 11.74 μM, respectively, using taxol as the positive control (Triregelins A–K were isolated by methanolic extraction and subsequent partitioning with traceae) . Their s control .Perovskia atriplicifolia (Labiatae) [101 was cytotoxic against the HepG2, NB4 (human acute promyelocytic leukemia cell), HeLa, MCF-7, and HL-60 cell lines, with IC50 values in the range of 0.23–8.72 μM, while perovskiaditerpenoside C 102 had significant cytotoxic activity against the NB4, HeLa, K562, MCF-7, and HL-60 cell lines, with IC50 values in the range of 0.35–5.17 μM, using cisplatin as the positive control (Perovskiaditerpenosides A–D were isolated from the BuOH extract of the whole plant of abiatae) . Their s control .ent-abietane diterpenoids were isolated by extraction with 70% aqueous acetone from the aerial parts of Isodon serra (Maxim.) Hara (Lamiaceae), a periennal herb used as a Chinese folk medicine for the treatment of jaundice hepatitis, acute cholecystitis, and enteritis [103, named serrin K, showed cytotoxicity towards the HL-60, SMMC-7721, A549, MCF-7, and SW480 cell lines, with IC50 values ranging from 9.4 to 20.4 μM. The IC50 value was calculated by Reed and Muench’s method, using cisplatin as positive control (Four new nteritis . Their s control .Caryopteris nepetaefolia (Benth.) Maxim. (Verbenaceae), a folk medicine used to treat inflammatory diseases in eastern China [104 and 105, namely nepetaefolin F and nepetaefolin G, showed higher cytotoxicity than paclitaxel (IC50 11.2 μM) in one non-small-cell lung cancer (LUPF045) patient-derived xenograft (PDX) model, when tested using PDX models and the adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA) (Nepetaefolins A–J were isolated from 95% EtOH extraction of the whole plant of rn China . Their sATP-TCA) .Salvia plebeian R. Br. (Lamiaceae), an annual or biennial herb, which has been used in folk medicine for the treatment of cough, hepatitis, and haemorrhoids [106 and 107 showed anti-proliferative activity against the CaCo2  cell line, with IC50 values of 9.65 μM for Compound 106 and 17.86 μM for Compound 107. Adriamycin was used as the positive control , a perennial herb mainly distributed in northeastern China [ent-abietane diterpenoid, fischeriabietane A 112 [50 value < 20 μM against the C4-2B and C4-2B/ENZR  cell lines, while compound 108 showed cytotoxicity also against the HCT-15 and RKO cell lines, with compound 112 against the HCT-15 cell line. Doxorubicin was used as the positive control. Biological activity was ascribed to the presence of the α,β-unsaturated carbonyl moiety . Fischerianoid A 113, and fischerianoid B 114 showed selective cytotoxicity against the MM-231 (breast cancer) and Hep3B cell lines, with IC50 values of 12.10 and 15.95 μM for compound 113, respectively, with 9.12 and 8.50 μM, respectively, for compound 114. Cisplatin was used as the positive control, and no obvious cytotoxicity was observed for the normal cell NCM460 [Fischerianoids A–C were also isolated and identified from the ethyl acetate extracts of roots of l NCM460  4 induced CD spectrum, and ECD calculations [115 was only active against HeLa cells, with an IC50 value of 15.47 μM, while difischenoid B 116 was more potent than cisplatin against the HeLa and MCF-7 cells, with IC50 values of 3.75 and 9.31 μM, respectively, using the MTT assay. Difischenoid B 116 shows a modified abietane skeleton, probably due to a cycloreversion reaction of ring A, which formed a seco-diterpenoid skeleton , and Namalwa (Burkitt lymphoma) cell lines, with IC50 values of 4.6, 11.5, and 16.4 μM, respectively, while euphorfischerin B 118 provided comparable IC50 values of 9.5, 17.4, and 13.3 μM against the three cancer cell lines, respectively, using the cell counting kit-8 assay and doxorubicin as a positive control , a perennial herb widely distributed at altitudes of 2650–3300 m in northwest of Yunnan Province and southwest of Sichuan Province, People’s Republic of China [119 showed equivalent cytotoxic activity with cisplatin to the SW480 (human colon cancer) cell line, while isoforrethins D 120 exhibited significant cytotoxic activity against SMMC-7721, A549, MCF-7, and SW480 , which is naturally distributed throughout East Asia. Tripterregeline A 121 was evaluated for its cytotoxicity against the HL-60, SMMC-7721, A549, MCF-7, and SW480 cell lines and showed stronger inhibitory activities than those of cisplatin, with IC50 values ranging from 0.58 to 5.82 μM [Tripterregeline A  5.82 μM  , which is widely distributed in the tropical and subtropical regions of Asia. Trigohowimine A 122 showed significant cell growth inhibitory activities against the HL-60, SMMC-7721, A54, MCF-7, and SW480 cell lines, with IC50 values of 0.82, 2.65, 5.64, 6.26, and 8.53 μM, respectively, better than the positive control cisplatin [Trigohowimine A isplatin   led to the isolation of 14 highly oxygenated new ent-abietane diterpenoids, euphelionolides A–N [123 and L 124 had significant cytotoxic activity against the MCF-7  and PANC-1  cells. However, compounds analogues of 123 and 124 did not exhibit significant cytotoxic effects; the structure–activity relations of the Euphorbia diterpenoids results are still unclear , which is distributed in China, India, Indonesia, the Philippines, and Australia. Spiroscutelone B 125 exhibited the most potent cytotoxicity against the MCF-7 cell line, with an IC50 value of 17.9 μM, while it had low cytotoxicity against the normal cell line (WI-38) [Three new abietane-type diterpenoids possessing a spiro-cyclopropane moiety, named spiroscutelones A–C, were isolated from the leaves of  (WI-38)   HOOK. (Taxodiaceae), an evergreen arbor mainly distributed in the regions south to the Yangtze River of China [126, named cuceolatin D, showed significant cytotoxicity against the MDA-MB-231, MCF-7, and HeLa cell lines, with IC50 values all below 5 μM, using the MTT method and doxorubicin as a positive control (One new abietane-type diterpene was isolated from the leaves of of China . The new control .Metasequoia glyptostroboides (Taxodiaceae), thirteen previously undescribed diterpenoids (metaglyptins A–M) were isolated by ethanolic extraction, and their cytotoxicity was evaluated against the HeLa, AGS (gastric cancer), and MDA-MB-231 cancer cell lines using the MMT assay [127 exhibited moderate cytotoxicity against the MDA-MB-231 cell line, with an IC50 value of 20.02 μM, using cisplatin as a positive control , a biennial lemon-scented herb that grows widely in Iran, Anatolia, Afghanistan, and the northern parts of Iraq and Transcaucasia [128 showed an IC50 value of 7.9 against MOLT-4, using cisplatin as a positive control.Two previously undescribed rearranged abietanes, named ceratol and ceratodiol caucasia  , an endemic medicinal plant in the west region of China [129 suppressed the A549 cell proliferation, with an IC50 value of 10.79 μM, and induced cell apoptosis through the SHP2/ERK1/2 and SHP2/AKT pathways.A new abietane diterpenoid, named 3-acetoxylteuvincenone G of China  , a perennial plant mainly distributed in the northern Xinjiang, China [13C NMRDP4+ analysis, calculated ECD, and Mo2(OAc)4-induced ECD. They were evaluated for their antiproliferative activities against the A-549, SMMC-7721, SW480, MCF-7, and HL-60 cancer cell lines and a normal epithelial cell line, BEAS-2B, in vitro. Salvidesertone E 130 and salvidesertone F 131 showed more potent antiproliferative effect against A549 than the positive control cisplatin, with IC50 values of 5.89 and 6.94 μM, respectively, while IC50 values of >40 and 35.48 μM were reported for normal epithelial cell line BEAS-2B, respectively , a medicinal plant abundant in central Kunming, Yunnan Province, P.R. China, together with the new ent-kaurene diterpene rabdokunmin F  [133 and 134 demonstrated cytotoxic activities against the HL-60 (IC50 21.22 and 10.91 μM) and A549 (IC50 13.71 and 18.42 μM) cell lines, respectively  . Their sectively .Clerodendrum chinense var. simplex (Verbenaceae), an ethnomedicinal plant of the Dai minority in China [135 and D 136 showed IC50 values of 10.75 and 10.58 μM against HL-60 cancer cell lines, respectively, while clerodenoids E 137 and F 138 showed a strong antiproliferative activity against HL-60 and A549, with IC50 values ranging from 1.00 to 5.03 μM, using the sulforhodamine B (SRB) assay and adriamycin as a positive control. Compound 136 belongs to the rearranged abietane skeletons of 17 (15 → 16)-abeo-abietane, while compounds 137 and 138 belong to the 17 (15 → 16),18 (4 → 3)-diabeo-abietane , a poisonous plant mainly distributed in tropical and subtropical regions of Asia, it was possible to isolate thirteen undescribed diterpenoids by ethanolic extraction and subsequent partitioning with EtOAc [50 range values of 2.5–9.9 μM against the A549 and HL-60 cancer cells, using the sulforhodamine B (SRB) and cell counting kit-8 (CCK-8) methods and adriamycin as the positive control. Compounds 139, 140, and 141, named phorneroids A-C, are ent-abietane, while phorneroid H is an ent-atisane-type  Hutch. (Celastraceae), a plant present in China, it was possible to isolate two new compounds with cytotoxic activity against the SW1990 (human pancreatic cancer) cell line [142 and 143, named hypoglicin R and 18-acetyl-triptobenzene A, respectively, were obtained after extraction with 90% EtOH of T. hypoglaucum stem and subsequent partitioning with EtOAc. Their structures were elucidated by HRESIMS, 1D NMR, and 2D NMR spectroscopic analysis. The IC50 values for 142 and 143 were 19.28 and 9.91 μM, respectively, using the MTT assay and paclitaxel as a positive control (From ell line . Compoun control .Plectranthus scutellarioides (Lamiaceae) led to the isolation and characterization of the abietane diterpene 6-acetylfredericone B 144  cells, using bortezomib as a positive control [Chemical investigation of the dichloromethane extract of the aerial parts of ne B 144 . Compoun control .145  roots. A plausible biosynthetic pathway for salviyunnanone A 145 was also described. Compound 145 showed significant toxicity against the HL-60, SMMC-7721, A549, MCF-7, and SW480 cell lines, with IC50 values of 2.63, 2.52, 4.84, 1.18, and 3.23 μM, respectively, using cisplatin as a positive control [Salviyunnanone A 145 , a cytot control .146 (Lycopodium complanatum (Lycopodiaceae) whole herbs. A plausible biogenetic pathway of abietane diterpenoid 146 was also proposed. Compound 146 inhibited the MSTO-211H cell line (human lung cancer), with an IC50 value of 17.34 μM, using staurosporine as a positive control [Complanatin D 146  was isol control .Salvia leriifolia (Lamiaceae) resulted in the isolation of leriifolione 147, an unprecedented nor-abietane isoprenoid possessing a rare five-membered C-ring   and CEM/ADR5000 (its multidrug resistant P-glycoprotein-overexpressing subline) cell lines (treated once per week with 5000 ng/mL doxorubicin), respectively [Salvimulticanol abiatae) . Structuectively .Caesalpinia genus, and their skeleton seems to derive from the pimarane skeleton, due to a migration of the methyl group [Cassane diterpenoids have been isolated in recent years from different species of medicinal plants belonging to the yl group  (Scheme 149 and B 150 were isolated from the bark of Erythrophleum fordii Oliver (Fabaceae), a species with both medicinal and poisonous properties, which is widely distributed throughout China, Vietnam, and Taiwan  cells, with an IC50 value of 3.2 μM, using the MTT assay and doxorubicin as a positive control. A simple mechanistic study revealed that 152 could induce cell cycle arrest at G0/G1 phase and apoptosis in HEL cells  present in China, mainly in Hainan Island. The absolute configuration of tagalene I 153 was established by single-crystal X-ray diffraction analyses by Zhang and Coll [153 displayed potent cytotoxic effects against the MDA-MB-453, MDA-MB-231, SK-BR-3 (human breast cancer), and MT-1 (human contaminated breast cancer) cell lines, with IC50 values of 8.97, 8.97, 4.62, and 3.93 μM, respectively, whereas tagalene K 154  exhibited selective cytotoxicity against MT-1 cell line, with an IC50 value of 8.07 μM [Tagalenes G–I  and tagaand Coll . Tagalen 8.07 μM .155, the first C22 skeletal dolabrane, with an unprecedented 5/6/6/6-fused tetracyclic core, was also isolated from the Chinese mangrove Ceriops tagal (Rhizophoraceae) stems and twigs  cell lines, with IC50 values of 1.73, 8.12, 2.45, 12.03, 3.75, and 1.97 μM, respectively. Cisplatin was used as the positive control. Investigation of the mechanisms on MD-MBA-453 cells revealed that tagalide A 155 induces ROS-mediated apoptosis and cell-cycle arrest at the G2/M phase [Tagalide A nd twigs . A biosy/M phase .Salvia ballotiflora (Lamiaceae), a new icetexane, derivative 156, was isolated  allowed for the establishment of the absolute configuration. The natural product 156 showed cytotoxicity against U-251 (human glioblastoma) and SKLU-1 (human lung adenocarcinoma), with IC50 values of 1.4 and 0.82 μM, respectively, while it was non-toxic to FGH . Adriamycin at 0.5 μM was used as the positive control [From the aerial parts of isolated . The rel control .Salvia deserta (Lamiaceae) by ethanolic extraction and subsequent partitioning with petroleum ether [13C chemical shift calculations with DP4+ probability analysis and ECD calculations), and single-crystal X-ray diffraction analysis. Only salviadenone A 157 showed moderate cytotoxicity against the HL-60 cell line, with an IC50 value of 17.70 μM, using the MTS method and cisplatin as a positive control.Four new icetexane diterpenoids, salviadenones A–D, together with two highly modified spirocyclic diterpenoids see , were isum ether . Their sent-pimarane, and isopimarane are reported in The skeletons of pimarane, Ceriops tagal (Rhizophoraceae) stems and twigs [Tagalon A, an isopimarane diterpene and tagalons B and C, two 16-nor-pimaranes, were isolated from the Chinese mangrove nd twigs .158 exhibited selective cytotoxicity against MT-1 cells, with IC50 value of 3.75 μM, using cisplatin as a positive control  aerial parts, widely distributed in China [159 showed superior inhibitory activities, in comparison with the positive control drug (2-morpholin-4-yl-8-phenylchromen-4-one) with an IC50 value of 0.27 μM . All the isolated compounds were evaluated for their cytotoxic activity against five human cancer cell lines, but only euonymusisopimaric acid B 160 exhibited cytotoxicity against A549 cell line growth, with an IC50 value of 2.6 μM [Euonymusisopimaric acids A–F and euonymusone A were isolated from the stems of f 2.6 μM  ,15-diene 162, were isolated by ethanolic extraction and subsequent partitioning with petroleum ether, EtOAc and n-BuOH, from the air-dried branches and leaves of Salacia cochinchinensis (Celastraceae), a perennial shrub mainly distributed in countries in south-east Asia, such as China, Vietnam, and Cambodia [50 values ranging from 0.23 to 4.29 μM, using cisplatin as a positive control . A plausible biosynthetic pathway for the new compound 163 was also proposed. Alatavnol A 163 showed potential cytotoxic activities, with IC50 values of 14.327 and 12.033 μM, against the MCF-7 and A549 cell lines respectively, using doxorubicin as a positive control [Alatavnol A iterpene , was iso control .Podocarpane diterpenoids usually possess a backbone of seventeen carbons arranged in a tricyclohexane system close to abietane and pimarane.164, a new podocarpane diterpenoid, was isolated from aerial parts of Anemone hupehensis (Ranunculaceae). Compound 164 showed moderate activity against SW480 cell line with IC50 value of 13.2 μM, using cisplatin as a positive control [Anemhupehin A  control  , isopimarane-type diterpenoids can be formed by the both protonation-initiated cyclization and ionization-dependent cylization of GGPP. With the possible catalyzation of cytochrome P-450, the isopimarane-type diterpenoids acted as a precursor, which can be transformed into staminane-type diterpenoids through the migration of the vinylic group from C-13 to C-12 .165 and C 166, which were isolated from the aerial parts of Clerodendranthus spicatus (Lamiaceae). C. spicatus is one of the oldest popular herbs distributed in Southeast Asia, and it is extensively used as a traditional medicine for the treatment of many disorders, especially for kidney diseases [50 values in the range of 5.62–36.60 μM, using cisplatin and taxol as positive controls.This is the proposed biosynthetic mechanism for the formation of the two new diterpenoids spicatusenes, B diseases   aerial parts, together with ent-abietane-type diterpenoids  Fée (Sinoptiridaceae), which is distributed in most parts of China [168 was tested on the MCF-7 and SKOV3 cell lines using the MTT method. The IC50 values of the inhibition ratio were calculated by the Reed and Muench’s method. Aleuritopsis A 168 showed inhibitory activities against SKOV3 cells, with an IC50 value of 11.1 μM, using cisplatin as a positive control  by extraction with EtOH/H2O (95:5) and subsequent partitioning in EtOAc and petroleum ether [(169–171) showed significant inhibitory activities against both cell lines, with IC50 values ranging from 1.0 to 9.8 μM, using adriamycin as the positive control. The tropone ring seems to be essential for the anticancer activity, since compounds lacking the tropone ring were inactive . Compound 172 exhibited cytotoxic activities against HL60 and A549 cells, with IC50 values of 0.77 and 1.129 μM, respectively, using doxorubicin as a positive control [A new cephalotaxus troponoid , 20-oxoh control .Cephalotaxus fortunei var. alpina and C. lanceolata (Taxaceae) leaves and twigs. The cytotoxic activities of the tested compounds 173–181 were evaluated against the HeLa, SGC7901, and A549 cell lines. In particular, cephinoids H 175 and I 176 exhibited excellent inhibitory effects, with IC50 values ranging from 0.1 to 0.71 μM, using cisplatin as a positive control. The IC50 values were calculated by the Reed and Muench method [The Cephalotaxus tropone analogues, cephinoids A-S , were idh method .Coffea arabica (arabica) and Coffea canephora (var. Robusta), have been extensively studied. Among the many compounds identified, there are three important diterpenes, such as cafestol, 16-O-methylcafestol and kahweol, which belong to the kaurene family [O-methylcafestol is considered a marker of the species Coffea canephora [Isodon. A large number of reports describe the anticancer potential and mechanism of action of ent-kaurane compounds in a series of cancer cell lines [Diterpenes of the kaurane family  are prese family , that hae family ,116. In anephora . Since tll lines .Ligularia fischeri (Ledeb.) Turcz (Compositae), a perennial leafy edible plant distributed in wet shady regions of Europe and Asia that has been used to treat jaundice, hepatic problems, scarlet fever, coughs, and hepatic diseases [182 showed moderate inhibitory activity against human B lymphoblast HMy2.CIR cells in a dose-dependent manner at concentrations of 2.5–40 μM. It showed an IC50 value of 13.3 μM using the sulforhodamine B (SRB) method (Six new diterpenoids were isolated by methanolic extraction and susequent partitioning in EtOAc from the whole plant of diseases . Among t) method . Its strent-kauranes, 3-epi-isodopharicin A 183 and scopariusol C 184, with cytotoxic activity were isolated by extraction with 70% aqueous acetone and subsequently partitioned in water-EtOAc from the aerial parts of Isodon scoparius (Lamiaceae) present in China [183 showed significant cytotoxic activity against all the cancer cell lines, with IC50 values of 1.0, 1.5, 4.4, 2.9, and 0.9 μM, respectively, better than cisplatin, while compound 184 showed IC50 values of 7.0, 4.7, 19.6, 11.0, and 2.5 μM, respectively, with a stronger effect than cisplatin for the cell lines SMMC-7721, MCF-7, and SW-480.Two C-13-oxygenated in China  , a perennial herb widely distributed in the Yellow River Basin and southern area of China, by extraction with 70% aqueous acetone [185, C 186, and E 187 exhibited potent active effects against all cell lines, with IC50 values in the range 0.8–8.6 μM, using cisplatin and paclitaxel as reference compounds  present in Korea , and HCT15 cell lines, with IC50 values of 5.92, 15.31, and 17.27 μM, respectively, using etoposide as a positive control [Pharboside H in Korea . Pharbos control .189–190 (Wedelia prostrata (Asteraceae) herbs present in China and exhibited cytotoxic activity against HepG2 cells, with IC50 values of 16.94 and 12.38 μM, respectively, using the MTT assay and cisplatin as a positive control [Compounds 189–190  were iso control .ent-kaurane-type diterpenoid, named aleuritopsis B 191, together with the new beyerene-type diterpenoid aleuritopsis A 168 (see Aleuritopteris argentea (Gmél.) Fée (Sinoptiridaceae), which is distributed in most parts of China [191 was tested on MCF-7 and SKOV3 cell lines using the MTT method, and the IC50 values of the inhibition ratios were calculated by Reed and Muench’s method. Aleuritopsis B 191 showed inhibitory activities against the SKOV3 and MCF-7 cell lines, with IC50 values of 8.7 and 11.3 μM, respectively, using cisplatin as a positive control.One new  168 see , were exof China   [192 was tested against the growth of the Hep3B and A549 cell lines by the MTT assay. In the cytotoxic assays on the Hep3B cell line, 192 showed an IC50 value of 8.1 μM, which was stronger than the positive control, 5-FU.A similar compound, biaceae) , a plantent-kaurane-type diterpenoids (amentotaxins C-M) were isolated, by methanolic extraction and subsequent partitioning in different solvents, from the leaves and twigs of Amentotaxus argotaenia (Taxaceae), a coniferous species endemic to China [193 showed cytotoxic activity against all six cell lines, with IC50 values ranging from 1.9 to 9.8 μM, using paclitaxel as the positive control. Compound 193 is a rare 18-nor-ent-kaurane-type diterpenoid featuring a 4β,19-epoxy ring (Eleven to China . Their soxy ring .ent-kaurane diterpenes were isolated from Annona squamosa L. (Annonaceae) pericarp, and they were evaluated for their cytotoxic activities against the SMMC-7721 and HepG2 cell lines, among which, 4β,17-dihydroxy-16α-acetoxy-18-nor-ent-kaurane 194 displayed powerful anti-tumor capacity against the SMMC-7721 and HepG2 cell lines, with IC50 values of 17.28 and 11.56 μM, respectively [Five new ectively  , which is primarily distributed in the northwest district of Sichuan Province and the southern district of Tibetan Region [195–200 were evaluated for the in vitro growth inhibitory effects against HL-60, SMMC-7721, A549, MCF-7, and SW-480 cell lines, with cisplatin and paclitaxel as the positive controls. Compound 199 exhibited significant inhibitory effects against all five human tumor cell lines, with IC50 values ranging from 2.20 to 5.61 μM, whereas compounds 195, 197, and 198 showed some cytotoxic potency, indicating that the α,β-unsaturated ketone group is structurally required for cytotoxicity. Compound 196 also contained this motif, but almost showed no cytotoxicity, possibly due to the hydroxy group substitution at C-14. Despite having no α,β-unsaturated ketone group, compound 200 exhibited significant inhibitory activities against all five human tumor cell lines, with IC50 values ranging from 2.58 to 6.03 μM, suggesting that an improvement of the lipid solubility might aid in promoting the cytotoxic potency.in F 200  were ison Region . Compounseco-ent-kaurane diterpenoids, kongeniods A–C 201–203 (Croton kongensis (Euphorbiaceae). Compounds 201–203 were evaluated in vitro against the HL-60 and A549 cell lines, with adriamycin as the positive control. Kongeniods A–C 201–203 exhibited strong cytotoxicity against the HL-60 cell line, with IC50 values of 1.27, 0.47, and 0.58 μM, respectively; compounds 201 and 202 showed moderate inhibition against the A549 cell line, with IC50 values of 5.74 and 3.24 μM, respectively [Three new 8,9- 201–203 , were isectively .ent-kaur-16- en-15-one 204 was isolated from the aerial parts of Isodon excisoides (Lamiaceae) using an orientational preparation method based on a UPLC-LTQ-Orbitrap-MS [human gastric cancer), NCI-H1650 , and A2780 cell lines, and it showed cytotoxic activity, with IC50 values of 1.34, 1.07, 3.60, 2.35, and 2.53 µM, respectively, using cisplatin as the positive control.The novel compound 1α-acetoxy-7α, 14β, 20α-trihydroxy-itrap-MS   by 70% EtOH extraction and subsequent partitioning with petroleum ether, EtOH, and n-BuOH [205 was active against the SNU638 and HCT116 cell lines, with IC50 values of 19.5 and 19.6 μM, respectively, while maizediterpene B 206 was more active then etoposide, with IC50 values of 15.18 and 1.99 μM against MDA-MB-231 and HCT116, respectively, but was also active on SK-Hep-1 and SNU638, although to a minor extent  leaves, together with kunminolide A 132  whole plant, a traditional Chinese herb, it was possible to isolate seven new ent-kauranes, named mesonols A–G, by methanolic extraction and subsequent partitioning with n-hexane and CH2Cl2 [208–211 showed potential antiproliferative activities against A549, Hep3B, PC3, HT29, and U937 cancer cells, with IC50 values ranging from 1.97 to 19.86 μM, using the cell counting Kit-8 and CPT-11 as positive controls. Further investigations on cell cycle progression, apoptosis, and ROS generation in U937 human leukemia cancer cells showed that compounds 208 and 209 are potent and promising anticancer agents -abeo-6,7-seco-ent-kaurane skeleton, was isolated from Isodon oresbius (W. W. Smith) Kudo (Labiatae), a small shrub distributed on dry hillside rocks or shrubs in China [I. oresbius and subsequent partitioning with EtOAc and H2O. Compound 212 showed cytotoxicity against the HeLa, SK-OV-3, SK-HEP-1, Caco2, MDA-MB-231, PC-3, SW480, and A549/Taxol (taxol resistant lung cancer) cell lines, with IC50 values in the 2.07–14.60 μM range, using the MTS assay, cisplatin, and taxol as positive controls.Isoresbin A in China   by ethanolic extraction and subsequent partitioning with EtOAc and n-BuOH [213 is an 8,9-seco-ent-kaurane diterpenoid, while compound 214 is a 7,20-epoxy-ent-kaurane diterpenoid. Compounds 213 and 214 inhibited cell proliferation and viability in a dose- and time-dependent manner, whereas both induced the cleavage of either caspase-3 or PARP-1 in the SW480 cell line. Both compounds had IC50 values <20 μM against the HeLa and SW480 cell lines, while compound 213 was also cytotoxic against the A549 and ACHN cell lines, using cisdiaminedichloroplatinum (CDDP) as a positive control.Croyanhuins A d n-BuOH  . Structurally, the isolates were characterised as 7α,20-epoxy-ent-kaurane diterpenoids. Preliminary structure—activity relationship studies were evaluated, in terms of their in vitro cytotoxic activities against the HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cell lines. Pharicins D, M, Q and R 215–218 displayed inhibitory activities, with IC50 values in the range of 1.23–18.04 μM, using cisplatin and paclitaxel as positive controls [Pharicin D in R 218  were isocontrols .219 (Scapania carinthiaca J.B. Jack ex Lindb. (Scapaniaceae) whole plant. Scapanacin A 219 showed significant inhibitory effects against the MCF-7, A549, and PC-3 cell lines, with IC50 values of 6.6, 2.3, and 11.5 μM, respectively, using adriamycin as a positive control [Scapanacin A 219  was isol control .Epi-11-O-acetylangustifolin 220 and 11-O-acetylangustifolin 221, two 6,7-seco-spiro-lacton-ent-kauranoids, were isolated from the branches and leaves of Isodon rubescens (Lamiaceae)  . The 11-ectively .222, a new glycoside based on ent-kaurane-type diterpenoid, was isolated from the leaves of Diospyros maritima (Ebenaceae)  . Diosmar control .223 (Isodon scoparius (Lamiaceae), and its absolute configuration was established by a single crystal diffraction analysis using Cu Kα radiation. The new ent-kaurane diterpenoid 223 showed stronger cytotoxicity than cisplatin, with respective IC50 values of 2.8, 3.4, 3.6, 4.0, and 2.6 μM against the HL-60, SMMC-7721, A549, MCF-7, and SW-480 cell lines [Scopariusol L 223  was isolll lines .224, an ent-kaurene diterpenoid isolated from Isodon rubescens (Lamiaceae) leaves, proved to possess strong anti-proliferative activities on the esophageal cancer (EC) cell line . The cytotoxicity of 224 was determined on the human esophageal cancer cell lines EC109, EC9706, KYSE-450, and human immortalised normal esophageal epithelial cell HET-1A and it showed IC50 values of 8.6, 9.4, 26.2, and 36.1 μM, respectively, using the natural product adenanthin as positive control. Furthermore, JDA-202 showed inhibitory activity against SHG-44 (human glioblastoma) and MCF-7 cell lines with IC50 values of 2.4 and 4.2 μM, respectively [JDA-202 ell line . JDA-202ectively .225 (IsoA) (ent-kaurane isolated from the leaves of Isodon forrestii (Lamiaceae), significantly inhibited Thioredoxin 1 (Trx1) activity and mediated anticancer effects in multiple preclinical settings. IsoA 225 displayed antiproliferative activity with IC50 values < 20μM against HepG2, Caco2, U2OS (human osteosarcoma), and MDA-MB-231 cell lines, while it was not cytotoxic to non-malignant human hepatic cells (IC50 113μM). Of all the tested cancer cell lines, HepG2 cells were the most sensitive to IsoA 225, with an IC50 value of 15.83 μM. Thus, this cancer cell line was chosen as a model to further investigate the anticancer activity and underlying mechanisms of IsoA 225 [Isoforretin A 5 (IsoA) , a novelIsoA 225 .ent-kauranoid-type diterpenoids 226 and 227 (Rabdosia japonica (Lamiaceae). Their chemical structures were established by 1D and 2D NMR techniques and mass spectrometry. They were tested for their cytotoxic effects against the A549, HCT116, CCRF-CEM, and HL-60 cell lines. Compounds 226 and 227 showed significant inhibitory activities toward the four human cancer cell lines, with IC50 values in the range 3.01–15.45 μM, using doxorubicin as a positive control [Two new  and 227  were obt control .ent-kaurene diterpenoid, Jaridon 6 228 (Rabdosia rubescens (Lamiaceae). The results of the MTT assay showed that Jaridon 6 228 treatment had an obvious cytotoxic effect in EC109 cells, with an IC50 of 15.59 μM, whereas the cytotoxic effect on normal HET-1A cells was minimal. Cell viability and apoptosis results, obtained by flow cytometry, confirmed the tumor inhibitory effect of Jaridon 6 228 in esophageal cancer cells [A novel on 6 228 , was isoer cells .229 (Pteris semipinnata (Pteridaceae) aerial parts showed significant cytotoxicity against the HCT116 cell line in a dose- and time-dependent manner, with IC50 values of 4.07 μM after 72 h, using a CCK-8 assay and TBE test. The effects of pteisolic acid G 229 on the cell cycle and apoptosis in HCT116 cells were investigated [Pteisolic acid G 229  was isolstigated .Dysoxylum [230 and lonimacranthoidin D, were isolated from the roots of Lonicera macranthoides (Caprifoliaceae), which is mainly distributed in the southwest of China . Only lonimacranthoidin C 230 showed moderate antiproliferative activity against the HeLa cell lines, with an IC50 value of 13.8 μM, using etoposide as positive control, while no cytotoxicity was observed for the normal cells HASMC.Prenyleudesmanes are a rare class of diterpenes that were originally isolated from marine algae and mollusks, fungi, and plants of the genus ysoxylum . Two preof China . Their sPodocarpus nagi (Thunb.) Pilg. Herein (Podocarpaceae) [231 and 2β-hydroxynagilactone L 232 displayed cytotoxicity against A2780 and HEY cancer cells. Compound 232 showed the highest potential, with IC50 values of less than 2.5 μM on the two cell lines. Compound 231 showed IC50 values of 3.8 μM against A2780 cells and 6.4 μM against HEY cells, respectively (Nine new norditerpenoids were isolated from a 95% ethanolic extract of the seeds of rpaceae) . The strectively .epi-austrobuxusins B, G, and H, were isolated from the EtOAc fruit extract of the species Austrobuxus carunculatus (Baill.) Airy Shaw (Picrodendraceae), a plant endemic to New Caledonia [233 and austrobuxusin L 234 showed IC50 values of 5.8 μM for the A549 cell line and 0.7 μM for the U87-MG cell line, respectively. Doxorubicin was used as a positive control   . The strll lines .Viburnum and liverwort Odontoschisma denudatum. Their plausible biogenetic pathway starts from GGPP, which cyclise to form a 11-membered ring, as described in a recent review [Vibsane-type diterpenoids are rare 6–11 membered ring polysubstituted macrocyclic diterpenoids, and their natural occurrence is confined to the genus t review .237, 15-hydroperoxyvibsanol A 238, 14-hydroperoxyvibsanol B 239, and 15-O-methylvibsanin U 240 (Viburnum odoratissimum (Viburnaceae). Their structures have been elucidated by spectroscopic analyses and the chemical derivatization method. All the compounds showed different levels of cytotoxicity against the cell lines HL-60, A-549, SMMC-7721, MCF-7, and SW480, with IC50 values in the range of 2.56–27.06 μM, with cisplatin and taxol as positive controls [Four new eleven-membered vibsane-type diterpenoids, vibsanol I in U 240  were isocontrols .Viburnum odoratissimum in 2021, using small molecule accurate recognition technology (SMART). Their structures were elucidated by means of comprehensive analyses of spectroscopic data, as well as comparison of the experimental and calculated ECD spectra. The cytotoxic activity was evaluated against A549 and HepG2 cells via MTT assay, using taxol and sorafenib as positive controls. Among them, vibsanolid B 241 and C 242 resulted active against both cell lines; particularly, vibsanolid B had a significant cytotoxic activity against A549 cells, with an IC50 value of 1.11 μM. Further staining experiments indicated that 241 could promote apoptosis induction, enhance reactive oxygen species (ROS) level, and attenuate mitochondrial membrane potential (MMP) in A549 cells [Further, seven new diterpenoids, named vibsanolid A–G, were isolated from the crude extracts of the leaves of 49 cells   [243 showed significant activity for HL-60 cells, with an IC50 value of 2.6 μM, using mitomycin C as a positive control.Prattinin A miaceae)  , an annual to perennial herb widely used for treatment of human tuberculosis, infectious hepatitis, thyroid gland swell, hypertension, and bacillary dysentery, as well as high blood pressure [244 demonstrated modest cytotoxic activity against the A549 cell line, with IC50 values of 18.0 μM, using the MTT method and 5-FU as the positive control  aerial parts [245 exhibited significant cytotoxicity against the HL-60 and A549 cell lines, with IC50 values of 1.24 and 1.92 μM, respectively  C. Y. Wu (Verbenaceae) (whole plant) [246 exhibited significant cytotoxic activity against the PC-9, H1650, and A549 cell lines, with IC50 values of 8.2, 5.4, and 10.4 μM respectively, using 5-FU as the positive control. Structurally, aureoglandulosin A 246 is a highly oxygenated abietane diterpenoid, with an unprecedented 7/6/6/5-ring system (Seven new diterpenoids were isolated by ethanolic extraction and subsequent partitioning in CHe plant) . These dg system .247, was isolated from the roots of Euphorbia fischeriana (Euphorbiaceae), which is widely distributed in northeast China. Fischeriana A 247 possesses an unusual heptacyclic ring system (6/6/5/5/5/6/6), featuring a modified ent-abietane diterpene, combined with a phloroglucinol moiety by direct carbon–carbon linkage  roots, together with three clerodane diterpenoids  calculations), and single-crystal X-ray diffraction analysis. The two spirodesertols 249 and 250 exhibited cytotoxicity against the five cancer cell lines considered , with IC50 values in the range of 6.60–21.65 μM; particularly, spirodesertol 249 was more cytotoxic than the positive control, cisplatin. The MTS method was used for cytotoxic analysis.Two highly modified spirocyclic diterpenoids, with an unprecedented 6-isopropyl-3 A–D see , were is deserta  , an endemic plant of Iran, led to the isolation of tebesinone B 251 , and type of document (article and communication). Since the present review regards diterpenes from plants with cytotoxic activity, they were further refined using the keyword “cytotoxic or cancer” and excluding marine, coral, fungi, alkaloid, and dimer. Finally, due to the large number of articles obtained, only articles reporting the isolation of new compounds, with their complete characterization and demonstrating cytotoxic activity, were selected. SciFinder provided the larger number of articles, while web of science and scopus provided comparable results. To highlight the most potent compounds with cytotoxic activity, only compounds with IC < 20 μM .Euphorbia species, for which less than 5% has been studied until now [50 < 20 μM have been described. These compounds could be further studied, in order to evaluate their use as potential anticancer drugs. The main skeletons that showed cytotoxic activity were: kaurane (29 compounds), abietane (17 compounds), clerodane (17 compounds), and labdane (8 compounds). The most active compounds were extracted from 29 different plant families; particularly, Euphorbiaceae (69 compounds) and Lamiaceae (54 compounds) were the richest sources of active compounds. Cytotoxicity of the compounds was verified on several cancer cell lines, especially against the most common cancer diseases, such as human non-small-cell lung carcinoma (A549 cell line), breast cancer (MCF-7 cell line), promyelocytic leukemia (HL-60 cell line), cervical carcinoma (HeLa cell line), colon cancer (SW480), and liver carcinoma . A better activity than the positive control was obtained with 33 compounds against the A549 cell line, 28 compounds against the MCF-7 cell line, 9 compounds against the HepG2 cell line, 8 compounds against the Hep3B cell line, 19 compounds against the SMMC-7721 cell line, 9 compounds against the HL-60 cell line, 24 compounds against the SW480 cell line, and 19 compounds against HeLa. In general, the structure–activity relations still remain unclear, and it seems very difficult to find a correlation between the diterpene structures and cytotoxicity against a specific cancer cell line.The isolation and characterization of new diterpenes compounds from higher plants has increased constantly from 1970, with a higher number of published articles in the years 2000–2017. Although, in the present review, we have observed a decreasing number of published articles from 2017, plants represent one of the most promising reservoir of compounds, often structurally complex, that could be useful in the treatment of cancer disease. In fact, many plant species are still unexplored—for example, the During our bibliographic research, we observed that many new discovered diterpenes have not been tested for their biological activities, sometimes for the low amount available, and were not considered in the present review. Not all the papers cited in the present review reported the cytotoxic activity against normal cell lines that we consider important to determine the selectivity against cancer cells. Moreover, the positive controls used were not the same, and values of cytotoxic activity better than the positive control cannot be completely compared. It should be useful, in our opinion, to define a protocol for anticancer activity, with a list of the most common cancer cell lines to be tested, as well as a definition of the positive control and assay to be used .Although the number of papers published on new natural products isolation and characterization has decreased in the last few years, we think that this kind of work remains a very important topic to focus on, since cancer disease represents one of the major health problems in our society. Plants are able to synthesise complex structures that are difficult to obtain in the laboratory by chemical synthesis; so, plants are a good source for the development of new drugs. Moreover, a large amount of plants still remains unexplored and represents a reservoir of potentially active substances. One limit on this research may be the low amount of secondary metabolites that are usually isolated and the complex separation processes needed. Anyway, biotechnological techniques could overcome this problem and help to direct secondary metabolite biosynthesis towards the target product.


PLK1 expression is inversely correlated with the overall survival of NB patients. Additionally, we found that PLK1 strongly correlates with NB disease and stage progression. HMN-214 significantly inhibited NB proliferation and colony formation in both MYCN-amplified and -nonamplified cell lines in a dose-dependent manner. Furthermore, HMN-214 induces apoptosis and significantly obstructs the cell cycle at the G2/M phase in NB cells by inhibiting multiple cell-cycle-related genes, such as PLK1, WEE1, CDK1, CDK2, Cyclin B1, CHK1, and CHK2. HMN-214 significantly inhibits cell cycle regulator CDK1 and the phosphorylation and activation of PLK1 in NB. In the NB 3D spheroid tumor model, HMN-214 significantly and in a dose-dependent manner inhibits spheroid tumor mass and growth. Overall, our study highlights that targeting PLK1 using HMN-214 is a novel therapeutic approach for NB.Polo-like kinase 1 (PLK1) is an essential cell cycle mitotic kinase component that plays an important role in cell cycle progression and has been reported to be involved in various cancers, including neuroblastoma (NB). PLK1 also regulates G2/M transition, chromosomal segregation, spindle assembly maturation, and mitotic exit. NB is an early embryonic-stage heterogeneous solid tumor and accounts for 15% of all pediatric cancer-related deaths. Therefore, we aimed to develop a targeting strategy for PLK1 by repurposing HMN-214 in NB. HMN-214 is a prodrug of HMN-176 and is known to selectively interfere with PLK1 function. In the present study, we performed the transcriptomic analysis of a large cohort of primary NB patient samples and revealed that  Neuroblastoma (NB) is the most prevalent heterogeneous solid tumor that develops during the early embryonic stage from the sympathetic nervous system . NB accoTumorigenesis mainly depends on the activation of oncogenes and the inactivation of tumor suppressor genes . Most ofIn the present study, we evaluated the effects of a small-molecule PLK1 inhibitor HMN-214 on NB growth ,18. HMN-PLK1 gene expression in NB progression, we investigated the transcriptional data of 1235 NB primary patient samples, including the Versteeg dataset (n = 88), Kocak dataset (n = 649), and SEQC dataset (n = 498). Kaplan–Meier survival analysis revealed that PLK1 expression inversely correlates with the poor overall survival of NB patients. Higher expression of the PLK1 gene leads to poor overall survival of NB patients . These findings from primary NB patient samples suggest that PLK1 is a critical prognostic factor for NB disease and stage progression.To determine the role of Furthermore, we used a specific small-molecule PLK1 inhibitor, HMN-214, and performed proliferation assays using differentrent NB cell lines. Cytotoxic assays using three MYCN-amplified , three MYCN-non-amplified NB cell lines , and three control fibroblast cell lines  showed that HMN-214 significantly and dose-dependently inhibits NB cell proliferation . Both MYHMN-214 is known to inhibit the cell cycle progression of various cancer cells, including breast, colon, and esophageal cancer [We further evaluated the anti-proliferative effect of HMN-214 in NB 3D spheroid tumor models that mimic the physiological growth patterns of in vivo solid tumor growth. We developed 3D spheroid tumors using both MYCN-non-amplified (SH-SY5Y) , and MYCPLK1 pathway genes, such as PLK1, CCNB1 (Cyclin-B1), and CDK1; proto-oncogenes, such as MYC and MDM2; and cell cycle regulator genes, such as WEE1, CDK2, CHEK1 (CHK1), and CHEK2 (CHK2) in a dose-dependent manner in contrast to controls , Kocak dataset (n = 649), and SEQC dataset (n = 498)), using the publicly available R2: Genomic Analysis and Visualization Platform. This dataset includes microarray profiles of unique primary tumors and supports multi-parametric analysis of NB patient outcomes with gene expression data.Six human NB cell lines—including both MYCN-amplified  and MYCN-non-amplified  cell lines and three normal fibroblast control cell lines —were routinely cultured and maintained as described previously . All the4 cells per well were seeded into a 96-well plate and treated with different concentrations of HMN-214 for 72 h and developed as per the manufacturer’s instructions. Clonogenic assays were performed as described previously [50 values.Cell viability assays were performed using MTT cell proliferation dye -2,5-Diphenyltetrazolium Bromide) . Briefly, 1 × 10eviously . Colonie6 NB cells per well were seeded in a six-well plate followed by treatment with different doses of HMN-214 for 16 h. Apoptosis assays were performed using Muse flow cytometer (Luminex) and cell cycle assays were performed using Attune Nxt Flow Cytometer (ThermoFisher Scientific). Data were analyzed using Muse and Flow Jo software version 10 (BD Biosciences).Apoptosis assays were performed using Muse Annexin V & Dead Cell Kit , and cell cycle assays were performed using Click-iT™ Plus EdU Alexa Fluor™ 488 Flow Cytometry Assay Kit  and FxCycle™ PI/RNase Staining Solution  according to the manufacturer’s instructions and as described previously . BrieflyThree-dimensional spheroidal 96-well microplates  were used to perform 3D spheroidal tumor assays as described previously . Briefly6 NB cells per well were seeded into a 6-well plate and treated with the different concentrations of HMN-214 for 12 h. Total RNA was extracted using RNeasy plus mini kit  according to manufactures instructions and as described previously [p values were calculated by Student’s t-test for expression fold difference of individual genes. Primers used in this study are as follows.Gene expression analysis was performed using the RT-qPCR analysis as described previously . Briefly6 NB cells were seeded in a 10 mm petri dish and treated with increasing concentrations of HMN-214 for 12 h. Cell pellets were collected and lysed with RIPA extraction buffer cocktail and the extracted protein was quantified using Bradford assay . Protein samples were loaded and separated on 12% SDS-PAGE gel and transferred to the PVDF membrane, blocked with 5% BSA solution and then probed with corresponding primary and secondary antibodies. Clarity ECL Western substrate (Bio-Rad) and ChemiDoc XRS Plus system (Bio-Rad) was used to develop, visualize, and document the blots. Protein bands were quantified using the ImageJ software. CyclophilinB (CyPB) was used as a loading and normalizing control.Western blots were performed as described previously . Brieflyt-test was used to determine the statistical significance among drug treatment groups. p < 0.05 was considered statistically significant. Patient survival analyses were performed using the Kaplan–Meier method and two-sided log-rank tests.All the assays performed in the present study were repeated at least three times with three technical replicates. All values are presented as the mean ± standard deviation (SD). A two-tailed Student’s In conclusion, our study demonstrates the importance of PLK1 in regulating NB progression and growth and highlights PLK1 as a target for developing effective NB therapeutic approaches. We also demonstrate that the repurposing of HMN-214 to inhibit PLK1 in NB is a novel therapeutic approach. HMN-214 significantly inhibits NB proliferation, induces apoptosis, inhibits cell cycle regulators, inhibits NB 3D spheroid tumor growth, and directly inhibits the phosphorylation and activation of PLK1 in NB to block the cell cycle progression at the G2/M phase. In our future efforts, we will determine the effects of other PLK1 inhibitors to further confirm the findings of the present study and to establish the role of PLK1 in NB. Overall, our preclinical data suggest repurposing of HMN-214 and combining it with current therapies to develop effective therapeutic approaches for children battling NB.