Cytotoxic derivatives of dichloroacetic acid and some metal complexes

This study outlines a number of studies of dichloroacetic acid (DCA) and some of its derivatives. Although DCA has low cytotoxic potencies, various structural modifications are described which result in potent cytotoxins. In particular, hybrid molecules created from DCA and other bioactive molecules whose modes of action differ from DCA are particularly promising as candidate anticancer agents. Considerable emphasis in this review is placed on various series of compounds that incorporate both platinum and DCA into their structures. In addition, the importance of the formulation of some of the bioactive compounds described herein is revealed.


| INTRODUCTION
The therapeutic potential of dichloroacetate (DCA) was foreshadowed in 1960s for its interesting biological activities. [1] At that time, it was discovered that DCA can stimulate significant effects on carbohydrates and lipid metabolism in experimental diabetes [2] and soon thereafter, the historic report of its eliciting effect on the pyruvate dehydrogenase complex (PDC) was revealed. [3] These early findings led to the identification of DCA as a lipid-lowering and antidiabetic drug, [4] with the possibility of treating these diseases as well as myocardial and cerebrovascular ischemia [5] and acquired [6,7] and congenital [8,9] forms of lactic acidosis.
The anticancer properties of DCA were first discovered by Bonnet et al. They suggested that the metabolic alterations that occur in tumor cells can be manipulated to kill them. [10] Since then, more than 500 peer-reviewed publications have been published to establish DCA as a prototype of a new class of "metabolic modulators" acting to shift a cancer cell's metabolism away from cytoplasm and toward mitochondria, a consequence that, ironically, initiates the cancer cell's death. [11] To understand the interesting effects of DCA on cancer metabolism, the mechanism of action is briefly described below.
Over the last 10 years, a number of reviews have been written on DCA that provide further evidence of its potential usefulness in cancer chemotherapy. [12][13][14] Although an extensive body of literature demonstrates the antineoplastic properties of DCA, its effective clinical application for treating cancer is limited to clinical trials. [15] The clinical use of DCA is still restricted due to the existence of side effects such as neurotoxicity as well as the suspicion of carcinogenicity. [15,16] To avoid side effects that enhance drug bioavailability and efficacy, many researchers studied the synergistic effects of DCA with other potential or clinically used anticancer drugs. [17][18][19][20] In addition, over the last decade many scientists have designed and synthesized DCA derivatives that could be used as hybrids or prodrugs. A hybrid molecule is designed so that it can react at different receptor sites to increase cytotoxic potency while a prodrug is devoid of bioactivity until it releases one or more bioactive compounds. In this article, we have focused on compounds containing the DCA moiety in esters, amides, and metal complexes that showed antineoplastic properties and suggesting the employment of DCA in cancer therapy.

| MECHANISM OF ACTION OF DCA IN CANCER CELLS
Malignant cells have well-known properties including abnormal proliferation, deregulation of apoptosis, and cell cycle. Besides these properties, cancer cells also exhibit different metabolisms compared to normal cells. [21,22] In fact, to achieve increased energetic and anabolic needs, cancer cells follow reprogramming metabolic pathways for ATP, reduced coenzymes (e.g., NADPH), lipids, proteins, and nucleotides. [23] Therefore, one of the popular strategies for developing antineoplastic agents has been therapies that target the metabolic differences between cancers and normal cells. These therapeutic potentials arise from a discovery by Otto Warburg in the 1920s known as the "Warburg effect." According to the Warburg effect, for ATP production cancer cells incline to transform glucose into lactate via glycolysis even under aerobic conditions in place of the much more efficient oxidative phosphorylation (OXPHOS) pathway which is the preferred pathway for most other cells in the body. [24] Although ATP production via cytoplasmic glycolysis is 100 times faster than the mitochondrial OXPHOS, the energetic yield of glycolysis is very small since ATP production through glycolysis is 18 times lower than OXPHOS. [25] Because of this thermodynamic trade-off between the yield and rate of ATP production, cancer cells significantly increase glucose uptake by upregulating the glucose receptors in an attempt to "catch up." In fact, positron emission tomography imaging studies confirmed that most solid tumors showed markedly increased glucose uptake and metabolism, compared to noncancerous cells. [26] This bioenergetic difference between malignant and normal cells may be targeted therapeutically due to its unique importance in cancer cells. [27] Before OXPHOS can occur, pyruvate must first be converted to acetyl-CoA in a series of reactions facilitated by the PDC, named after pyruvate dehydrogenase (PDH), the first enzyme in the complex. PDC inhibition can occur if the E1α subunit of the PDH is phosphorylated by pyruvate dehydrogenase kinase-1 (PDK1), an enzyme commonly overexpressed in malignant cells. [28,29] PDC inhibition by PDK1's stops acetyl-CoA formation from pyruvate, which prevents oxidation from occurring in the TCA cycle and inhibits OXPHOS ( Figure 1).
A clear need is demonstrated for compounds which inhibit PDK activity since PDK inhibition can reverse the Warburg effect. A number of compounds such as DCA, a halogenated acetophenone (1), analogs of ATP, for example, adenosine 5′-[β,γ-imido]triphosphate (2), certain triterpenes such as 3 [30] and lactones, such as 4 and (R) −3,3,3-trifluoro-2-hydroxy-2-methylpropionamides such as 5 are known inhibitors that can inhibit PDK activity ( Figure 2). [28] Among these, DCA is the focus of this review. The molecular interactions between DCA and PDKs have been studied extensively. [31][32][33][34] In general, DCA appears to bind to a hydrophobic pocket in the N-terminal domain of PDK1 which promotes conformational changes at the active site and prevents phosphorylation of the E1α subunit of the PDC. [35] This frees up the PDH enzyme in the PDC and allows for full glucose oxidation through OXPHOS, inhibiting lactate fermentation (cytoplasmic glycolysis), and restoring apoptosis capability via mitochondrial depolarization ( Figure 3). [11] This cascade of events increases the interest in the use of DCA for its anticancer properties. Many different studies have shown that DCA and its derivatives reverse the glycolytic phenotype by activating a metabolic switch from aerobic glycolysis to OXPHOS; they also show suppression of tumor proliferation. [17,36,37] DCA combination with other chemotherapeutic drugs such as 5-fluorouracil or paclitaxel was more effective in killing resistant cancer cells than either chemotherapeutic drugs or DCA treatment alone. [20,38] Apoptosis capability F I G U R E 1 In the metabolic pathway preferred by cancer cells, pyruvate dehydrogenase kinase-1 (PDK1) phosphorylates a subunit of the pyruvate dehydrogenase complex (PDC) on the mitochondrial membrane and inhibits conversion of pyruvate to acetyl-CoA by blocking substrate entrance into the mitochondria is restored. DCA has also been approved as a treatment method for lactic acidosis. [9] 3 | LIMITATIONS OF THE USE OF DCA The clinical use of DCA has been related with reversible peripheral neurotoxicity, which is thought to be caused by uncompensated oxidative stress from increased reactive oxygen species (ROS) formed because of PDK inhibition by DCA. [15,39,40] In addition, it has been found that the catabolism of the amino acids phenylalanine and tyrosine and heme synthesis are interfered by the metabolism of DCA. As a result, the accumulation of reactive molecules capable of forming adducts with DNA and proteins are formed and resulted in oxidative stress. [15] Suspicion of carcinogenicity is also a restricting factor in the use of DCA and administration as an anticancer agent should be confined solely to clinical trials.
The low stability of DCA in a biological environment and also its low cellular membrane permeability are other major issues that are principally associated with the clinical use of DCA for cancer treatment. [11,41] In fact, due to its anionic charge DCA is unable to cross the cell membrane through passive diffusion and is unable to F I G U R E 2 Structures of different pyruvate dehydrogenase kinase inhibitors F I G U R E 3 Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase-1 (PDK1) from phosphorylating the pyruvate dehydrogenase complex (PDC) on the mitochondrial membrane, which promotes the conversion of pyruvate to acetyl-CoA and subsequently facilitates the entrance of the substrate into the mitochondria HOSSAIN ET AL. | 3 of 20 enter inside mitochondria by the classical mitochondrial pyruvate carrier. [42] Therefore, high dosages of DCA are required to reach therapeutic effectiveness and clinical results. [43,44]

| DERIVATIVES OF DICHLOROACETIC ACID
Because of neurotoxicity, the clinical effectiveness, and toxic properties of DCA as an antineoplastic agent need to be carefully investigated in clinical trials. Nonetheless, promising clinical and translational research suggests a wide therapeutic window for DCA, provided it can be administered with adequate tolerability and safety. Thus, there is increasing interest in the development of new strategies aimed to engineer DCA derivatives with increased tolerability and safety and that will be able to cross the cellular membranes, enabling the cellular uptake. Toward this goal over the last decade many scientists designed and synthesized derivatives of dichloroacetic acid as potent cytotoxic agents. Therefore, in this study, we have focused on various types of compounds containing the dichloroacetyl group that showed promising anticancer activity. A major emphasis is given on the structure-activity relationships of these dichloroacetic acid derivatives in this study.
Different compounds are grouped together as derivatives of natural, synthetic organic and metal complexes, and their potencies as anticancer agents are discussed.

| DCA derivatives of natural compounds
Historically natural products and their derivatives play a significant role in drug development, especially in the area of cancer therapy.
A diverse source of new medicinal leads have been obtained from natural products and their derivatives. [45] Among them, triterpenes are a significant class of compounds for their anticancer properties.
Recently, a dichloroacetamide (6b) of a triterpenoid saponin albiziabioside A (6a) (Figure 4) was reported to show selective cytotoxicity against PDK-medium and PDK-high-expressed human cancer cells. [46] Previously, it was found that albiziabioside A (isolated from Albizia inundata) could induce apoptosis in A375 cells by adjusting mitochondrial function, involving a caspase cascade with an IC 50 value of 5.47 μM. [47] When the dichloroacetyl moiety was attached to albiziabioside A (6a) as an amide, the resultant compound 6b displayed greater cytotoxicity compared with 6a and DCA alone against all tested cancer cells (MCF-7, HCT116, A375, and 4T1). [46] Most importantly, the dichloroacetamide 6b exhibited the best cytotoxicity against the PDK-high-expressed human breast cancer cells (MCF-7) with IC 50 value 0.43 μM, which is enhanced 47.5-fold compared to albiziabioside A. This enhanced activity can be attributed to the more efficient PDK inhibition capacity of 6b.
The compound 6b could inhibit PDK activity and impact the energy metabolism reprogramming of tumor cells and turn cellular metabolism away from aerobic glycolysis to OXPHOS. [46] It was also reported that compound 6b induced a significant increase in intracellular ROS and reduced the accumulation of lactic acid in the tumor microenvironment (TME). Importantly, compound 6b caused apoptosis via a caspase dependent pathway, inhibited the glutathione peroxidase IV (GPX4) pathway and induced ferroptosis by the accumulation of lipid peroxidation. Additionally, in an antitumor experiment on nude mice containing MCF-7 tumors, compound 6b was found to be an effective and safe agent. It was also reported that 6b could inhibit both primary and distal tumor progression in a dual-4T1 tumor model in female BALB/c mice by remolding the tumor immunosuppression microenvironment via eliminating M2-TAMs (tumor-associated macrophages). [46] Tormentic acid (7a) (Figure 4), a triterpenoid, can be isolated from different plants including Myrianthus serratus, Perilla frutescens, Cotoneaster simsonsii, and Rubus sieboldii. [48] Tormentic acid (7a) possesses many biological activities such as in vitro inhibition of platelet aggregation, reduction of vascular smooth muscle cell proliferation, anti-inflammatory activity, and inhibition of αand β-DNA polymerases. Although only a weak cytotoxic activity has been established against different cancer cell lines for 7a, the F I G U R E 4 Structures of compounds 6 and 7 derivatives 7b-7d containing monochloroacetyl groups showed excellent cytotoxic activities against 518A2 (melanoma), 8505C (anaplastic thyroid), A253 (head), A2780 (ovarian), A549 (lung), DLD1 (colon), MCF7 (mamma). [48] Among all the tormentic acid derivatives, compound 7b exhibited excellent antitumor activity with IC 50 values ranging 1.1-1.6 μM and this anticancer property was found due to the induction of an apoptosis pathway. Doxorubicin (8a) ( Figure 5) is a natural compound isolated from a soil born bacteria, Streptomyces peucetius. It has been used as an efficient chemotherapeutic drug for many cancers, including bladder cancer, Kaposi's sarcoma, breast cancer, lymphoma, and acute lymphocytic leukemia. [49] However, because of several side effects such as vomiting and nausea, hepatotoxicity, cardiotoxicity, and myelosuppression, its clinical application is limited. To reduce side effects, enhance antitumor efficiency, and increase drug loading content, Yang et al. synthesized the amide 8b by coupling doxorubicin (8a) and DCA. [50] It was reported that compound 8b can be easily self-assembled into NPs with a small amount of PEGylated lipid DSPE- cancer cell lines. [51] To increase the potency of these compounds, Omran et al. developed a codrug of 14-hydroxytylophorine and dichloroacetic acid by combining the two molecules through an ester linkage. [52] The resultant DCA esters 9 ( Figure 5) were evaluated against two reference cell lines: human embryonic kidney cells (HEK293) and Chinese hamster ovary cells (HEK293) and against four cancer cell lines: neuroblastoma (SK-N-DZ), Burkitt's lymphoma, [53] hepatocarcinoma (HepG2), and colorectal adenocarcinoma (DLD-1).
The cytotoxic data of esters 9 were compared with the parent 14-hydroxytylophorine and with the reference chemotherapeutic drug, doxorubicin. Although the developed codrugs 9 maintained the cytotoxicity of the parent alkaloids, the codrug strategy did not improve their potency or selectivity. antioxidative, and antibacterial activities. [54] Recently, honokiol (10a) has also been found as a promising anticancer agent in preclinical studies because of its nontoxic properties. [55] However, honokiol has poor solubility and bioavailability. [56] To increase its cellular uptake and lipophilicity, honokiol (10a) was transformed into the corresponding bis-DCA ester derivative (10b). It was reported that both honokiol (10a) and its DCA derivative 10b could inhibit androgen receptor (AR) activity in prostate cancer cells, [57] showed in vivo activity against vemurafenib-resistant melanoma, [58] and are selective allosteric inhibitors of the mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1). [59] Both honokiol (10a) and its DCA derivative 10b were reported to inhibit the growth of an androgen-responsive prostate cancer cell line with wildtype p53 (LNCaP) and its androgen-independent variant (C4-2) in a time and dose-dependent manner. [57] The bis-DCA ester 10b was more potent than the parent compound 10a and other tested analogs. Like the cell viability data, compound 10b was relatively more efficient in reducing AR protein level than the parent compound 10a in prostate cancer cells. It was also reported that both proteasomal degradation and transcriptional repression mechanisms likely cause honokiol-mediated downregulation of the AR protein expression. In addition, the reasons for showing different effects of 10 on mRNA and AR protein between LNCaP and C4-2 cells were not yet clear.
Honokiol bis-DCA (10b) and a hexafluoro analog 11 ( Figure 6) were studied against aggressive melanoma such as LM36R and A375, and less aggressive LM36 cells in vivo. [58] Both 10b and 11 showed activity against A375 melanoma in vivo, but compound 10b was more effective. Honokiol 10b exhibited activity against LM36R (vemurafenib resistant) in vivo but not toward parental LM36. Both 10b and 11 inhibited the phosphorylation of dynamin-related protein 1 (DRP1), which stimulates a phenotype suggesting respiration via mitochondrial normalization. It was suggested that 10b possibly acts in vemurafenib-resistant melanomas by increasing both respiration and ROS production, which leads to show its activity against aggressive melanoma in vivo.
Honokiol bis-DCA (10b) was also found to display allosteric inhibition of TRAP1 chaperone activity which makes it a potential lead compound for a new generation of antineoplastic agents. [59] The molecular chaperones TRAP1 are the mitochondrial paralog of the heat shock protein 90 (Hsp90). It is necessary for tumor growth found in several tumor cell models. TRAP1 induces bioenergetic rewiring, maintenance of redox homeostasis, and orchestration of a hypoxia-inducible factor 1-alpha (HIF1α)-mediated pseudohypoxic program by inhibiting succinate dehydrogenase (SDH) activity. It was reported that compound 10b can bind to the allosteric site in TRAP1, which inhibited TRAP1 but not Hsp90 ATPase activity. In neoplastic cells, 10b was able to revert TRAP1-dependent downregulation of SDH, decrease proliferation rate, increase mitochondrial superoxide levels, and abolish tumorigenic growth. [59] A series of new DCA derivatives of phenstatin were reported recently that focused on the use of a single compound acting on two different biological targets thereby enhancing potency and lowering the toxicity of the chemotherapeutic agent. [60] The first point of action was inhibition of the tubulin which is involved in cell proliferation due to its ability to polymerize and form microtubules polymerization inhibitor, with mono-, di-and tri-chloroacetate groups targeting PDK1. Based on biological studies, all the synthesized compounds were grouped as: (i) inhibitors of tubulin polymerization, classic cytotoxic agents, for example, compounds 12a, 12b, 12d, 12e; (ii) inhibitors of PDK1, which are cytostatic, such as compounds 12f, 12g, 12h; (iii) dual inhibitors of tubulin/PDK1, for example, compounds 12c and 13; (iv) highly cytotoxic compounds. To efficiently deliver compound 16 inside the mitochondria in cancer cells, a biodegradable nanoparticle (NP) was constructed from poly-(lactic-co-glycolic acid) (PLGA)-block(b)-polyethylene glycol (PEG) functionalized using a terminal TPP cation. [63] The NP formulation of compound 16 was reported to reduce glycolysis by targeting PDK1 only in cancer cells, not affecting the immune cells. A syngeneic tumor model was used that stimulates pathways to instruct inhibitory effects on multiple immune checkpoint proteins while improving cytotoxic T cell infiltration.
3,5-Bis(benzylidene)−4-piperidones are known to possess promising cytotoxic potencies. These compounds were designed to undergo sequential interactions with cellular thiols leading to greater toxicity to tumors than normal cells. [22,64] To enhance tumorselective cytotoxicity of this piperidone scaffold, the dichloroacetyl group was attached to the cytotoxic warheads, 3,5-bis(benzylidene) −4-piperidones, to create a series of 15 novel hybrid molecules having the general structure 17 [65] (Figure 10). In general, these new was lower than that of 18b. It was suggested that the orthocompound may block the interaction between the pharmacophore and the receptor as the ortho-substituent is close to the pharmacophore (2,2-dichloroacetyl). The best potencies to inhibit A549 cells was found to be the meta-substituted structures, followed by the ones with para-substituents. For example, the IC 50

| Metal complexes of DCA
Metal complexes have been used in cancer chemotherapy for many years. Because of their unique molecular geometries as well as their catalytic, ligand exchange, photophysical, and redox reactions, metal complexes have the ability to react and interact with biomolecules in distinctive ways and by unique mechanisms of action. [72] Since the discovery of cisplatin as an anticancer drug in 1967 by Rosenberg, platinum-based metal complexes particularly have played an important role in chemotherapy. [73] Since then, more than 30 platinum- formation of DNA lesions leading to cell death. [75,76] Passive diffusion and/or active transport are the two predominant mechanisms known for cellular uptake for cisplatin and related compounds. [77] After cellular uptake, a ligand substitution event occurs in the cytoplasm in which a chloride ligand is replaced by a water molecule in cisplatin to form cis-[Pt(NH 3 ) 2 Cl(H 2 O)] + , known as aquation or activation. [76] Due to the positive charge on the platinum complex, it can be attracted to the negatively charged nuclear DNA, and subsequently coordinatively interact with DNA to form DNA adducts. The N-7 atoms of the purine residues of guanine and adenine are the most nucleophilic sites of DNA, and these are preferentially coordinated with the cis-[Pt(R-NH 2 ) 2 Cl] fragment.
Following this event, the remaining chloride ligand is substituted for a second guanine base, forming either an intrastrand or interstrand DNA cross-links. The formation of cross-link adducts distort the structure of DNA in a substantial manner leading to an impairment of DNA expression and stability of G quadruplexes, which are thought to be the crucial lesion for its biological effectiveness as an antitumor agent. [73,78,79] Besides platinum-based metal complexes, complexes with other metals such as Cu, Ru, Os, and Rh are also known in the literature that can act as anticancer agents.

| Platinum complexes of dichloroacetic acid
Although platinum-based complexes have entered clinical trials, the poor selectivity, severe side effects, drug resistance, and systemic toxicity have restricted the application to clinical use of these drugs. Therefore, a considerable amount of effort has been dedicated for developing new platinum-based antineoplastic agents having equal or higher antitumor activity but lower toxicity. [73] To obtain novel have been reported to be potential dual-targeting anticancer agents. [83] These four complexes exhibited potent anticancer activity against  Figure 15) containing DCA and biotin moiety as axial ligands. [80] It  [86] Cell lines that were used include cervical (A431), breast (MCF-7), lung (A549), pancreatic (BxPC3), and colon (HCT-15) cancers, as well as melanoma (A375).
Both compounds 32 and 33 displayed a better cytotoxicity toward neoplastic cells in comparison to nontumor cells. In particular, compound 32 exhibited the best cytotoxicity against human pancreatic carcinoma cells (BxPC3) among all the tested cells.
Generally, the presence of oxalate leaving ligand appears to decrease the cytotoxicity of kiteplatin derivatives. It was reported that the most active Pt(IV) complex 32 underwent very rapid hydrolysis in a solution at pH = 7.4 to release the axial DCA ligands. In addition, both complexes underwent rapid reduction (half times of minutes) by ascorbic acid to form the Pt(II) complex (kiteplatin). As a result, DNA-platination was observed due to the presence of Pt(II) and a significant increase of ROS generation, inhibition of OXPHOS, hypopolarization of the mitochondrial membrane, and caspase-3/7mediated apoptotic cell death were also observed due to the presence of DCA which was released by the Pt(IV) compounds. Finally, complex 32 was able to reduce the tumor mass of murine LLC solid tumor found in an in vivo study which was similar to that of cisplatin but it is less cytotoxic.
A series of novel Pt(IV) prodrugs with triple action capacity has been developed and synthesized by Petruzzella et al. for evaluating the hypothesis that compounds with multi-action capacity may have more cytotoxic effect than a single action compound for killing cancer cells. [87] The rationale behind this hypothesis was based on the assumption that different bioactive moieties may interact with different cellular processes. Thus, they developed Pt(IV) derivatives of cisplatin with "triple action" ability where they introduced PDK, inhibitors of cyclooxygenase, [25] or histone deacetylase (HDAC). were investigated against both Pt sensitive A2780 and Pt resistant SKOV-3 human cancer cell lines. [90] The amine complexes 42-43 were slightly more active against Pt sensitive A2780 cells than the showed the ability to overcome the resistance of cancer cells found with cisplatin. In addition, it was expected that complexes 48a-48b may cross the cell membrane more easily to enter the cells because of better lipophilicity of the molecules and increase the uptake of DCA into cells as compared to free DCA alone.

| Other metal complexes of dichloroacetic acid
Beside platinum, osmium and ruthenium complexes have been studied extensively as potential anticancer agents. [94,95] Their mechanisms of actions are different than the platinum-based drugs.
Therefore, their cytotoxicity profiles are different and they have the potency to overcome both the intrinsic and acquired resistance of various tumors against platinum-based drugs. Two half-sandwich complexes of Ru (60a) and Os (60b) ( Figure 23) containing a releasable DCA ligand have been reported to show good in vitro anticancer property against A2780 human ovarian carcinoma cells with IC 50 = 3.5 and 2.6 μM respectively, slightly higher than that of the clinically used platinum-based drug cisplatin (IC 50 = 5.9 μM). [96] However, they were much less toxic toward healthy human hepatocytes. Upon hydrolysis, the complexes 60a and 60b released the DCA ligand which is probably the reason for this cytotoxicity at (SKBR-3 and MCF-7). [97] Importantly, 60b displayed remarkable submicromolar cytotoxicity for killing CSCs, which is considerably more efficient than that of its Ru analog 60a and salinomycin, known for one of the most selective CSC-targeting compounds. Additionally, Os complex 60b has been reported to reduce the size, formation, and existence of three-dimensional mammospheres which is more closely related to the tumor microenvironment than cells in traditional two-dimensional cultures. Complex 60b can kill human breast CSCs primarily by a programmed form of necrosis, known as necroptosis. In contrast, Ru(II) complex 60a and salinomycin displayed different modes of action which involved blocking of both apoptosis and necroptosis in CSCs. Os complex 60b undergoes hydrolysis slower than the Ru complex 60a, therefore, it is possible that 60b has better ability to carry the biologically active DCA into the cell as compared to the Ru(II) complex and salinomycin, and thereby, they have differences in their biological effects.
A multifunctional rhenium (Re) complex 61a ( Figure 23) containing DCA has been developed and synthesized as an anticancer agent. [98] Complex 61a can alter cancer cell metabolism from glycolysis to glucose oxidation because of its ability to efficiently diffuse into cancer

ACKNOWLEDGMENT
There is no one to acknowledge for writing this review article.
Open Access Funding provided by Big Ten Academic Alliance hybrid -Indiana University Kokomo.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.