A STUDY ON THE STRUCTURE-ACTIVITY RELATIONSHIP OF THE CARDIOTONIC STEROIDS.
According to the prevailing opinion of today about the structure-activity relationship of cardenolides and bufadienolides, the structural requirements for the characteristic cardiotonic action of these compounds can be summarized as follows: cis-fusion of the C and D rings, hydroxyl groups in positions 3β and 14β, and a five- or six-membered unsaturated lactone ring having β-configuration at C14 (1). Most of the experimental data referred to as evidences supporting this opinion have come, however, from the determination of toxic doses in the whole animal, mainly in the cat, rather than from observations of the action of these compounds in isolated hearts. It follows as a natural consequence that the compounds with a rather weak toxicity have been condemned to be inactive, even if they have a strong cardiotonic action, in spite of the fact that such a kind of compounds may actually be more important from the clinical point of view. For example, the compound like dihydrodigitoxin of which the lactone ring is saturated, and the compound like resibufogenin, which have an epoxide ring between C14 and C15 instead of C14-OH, generally believed to be inactive based on the toxicity data in the cat, have recently been found to be fairly active when tested in the isolated heart (2-3). The authors also found that, different from the above-cited opinion, the presence of 3β-OH is not indispensable for the cardiotonic action of the cardenolides ; 3-epi-digitoxigenin was found to have a definite cardiotonic action upon the isolated frog's heart (See Fig. 8). These findings seem to warrant reexamination of the problem, on the basis of the action of these compounds in the isolated heart. In recent years several adrenocortical steroids and aldosterone antagonists have been reported to be cardiotonic (4-6), despite the fact that their stereochemical structures are essentially different from those of the cardiotonic steroids. In view of these, the authors took up the problem of the cis-fusion of the C and D rings out of the several important points in the structure of cardiotonic steroids as discussed above and reexamined its importance for the specific cardiotonic action using the isolated frog's heart and the heart-lung preparation of the dog.
Bufadienolides from amphibians: A promising source of anticancer prototypes for radical innovation, apoptosis triggering and Na+/K+‐ATPase inhibition
ABSTRACT Amphibians present pharmacologically active aliphatic, aromatic and heterocyclic molecules in their skin as defense against microorganisms, predators and infections, such as steroids, alkaloids, biogenic amines, guanidine derivatives, proteins and peptides. Based on the discovered bioactive potential of bufadienolides, this work reviewed the contribution of amphibians, especially from members of Bufonidae family, as source of new cytotoxic and antitumor molecules, highlighting the mechanisms responsible for such amazing biological potentialities. Bufonidae species produce bufadienolides related to cholesterol through the mevalonate‐independent and acidic bile acid pathways as polyhydroxy steroids with 24 carbons. In vitro antitumor studies performed with skin secretions and its isolated components (specially marinobufagin, telocinobufagin, bufalin and cinobufagin) from Rhinella, Bufo and Rhaebo species have shown remarkable biological action on hematological, solid, sensitive and/or resistant human tumor cell lines. Some compounds revealed higher selectivity against neoplastic lines when compared to dividing normal cells and some molecules may biochemically associate with Na+/K+‐ATPase and there is structural similarity to the digoxin‐ and ouabain‐Na+/K+‐ATPase complexs, implying a similar mechanism of the Na+/K+‐ATPase inhibition by cardenolides and bufadienolides. Some bufadienolides also reduce levels of antiapoptotic proteins and DNA synthesis, cause morphological changes (chromatin condensation, nuclear fragmentation, cytoplasm shrinkage, cytoplasmic vacuoles, stickiness reduction and apoptotic bodies), cell cycle arrest in G2/M or S phases, mitochondrial depolarization, PARP [poly (ADPribose) polymerase] and Bid cleavages, cytochrome c release, activation of Bax and caspases (−3, −9, −8 and −10), increased expression of the Fas‐Associated protein with Death Domain (FADD), induce topoisomerase II inhibition, DNA fragmentation, cell differentiation, angiogenesis inhibition, multidrug resistance reversion, and also regulate immune responses. Then, bufadienolides isolated from amphibians, some of them at risk of extinction, emerge as a natural class of incredible chemical biodiversity, has moderate selectivity against human tumor cells and weak activity on murine cells, probably due to structural differences between subunits of human and mice Na+/K+‐ATPases. HIGHLIGHTSCardenolides and bufadienolides present similar mechanism of Na+/K+‐ATPase inhibition.Bufadienolides show moderate selectivity against human tumor cells and weak activity on murine cells.Bufalin, cinobufagin, telocinobufagin and marinobufagin exhibited remarkable antitumor potential triggered by caspase‐dependent apoptosis.Bufalin or Cinobufagin have been used in clinical therapy against advanced carcinomas of liver, lung, pancreas and bladder.
The paper chromatographic examination of the cardiac aglycones of Strophanthus seeds.
The Medical Research Council Medicinal Plants Survey in its expedition to Africa collected many specimens of the seed of Strophanthus hi8pidus P.DC. and S. sarmento8us P.DC., mostly from individual plants, in order to investigate the occurrence of sarmentogenin, a substance which forms a possible starting material for the production of cortisone. The isolation of sarmentogenin from certain of these seeds has already been reported (Callow, Meikle & Taylor, 1951). The present paper is a report on the preliminary investigation ofall the samples collected, and reveals certain interesting features about the distribution of cardiac aglycones in various Strophanthus species. As the examination of each seed sample by isolation of the constituents might take several years for completion, a method has been developed for the routine semi-micro investigation of the easily hydrolysable glycosides of the seeds. These easily hydrolysable glycosides (Reichstein, 1951), which are completely hydrolysed by refluxing for half an hour in 50% aqueous methanol which has been made 0-1N with respect to sulphuric acid, are those in which the steroidal portion of the molecule is directly attached in a glycosidic linkage to a 2deoxy sugar. Most of the best known glycosides belong to this group, which is much easier to investigate than the group in which the aglycones are directly attached to 'normal' sugars carrying a hydroxyl group at C(2), such as glucose or rhamnose, where isolation of the intact aglycone is usually difficult and has in several cases not yet been achieved. Investigation of the 'normal' glycosides in our seed samples has so far only been carried out in selected cases. The paper-chromatographic method of Zaffaroni, Burton & Keutmann (1950) (cf. Burton, Zaffaroni & Keutmann,1951)hasbeenusedbySchindler & Reichstein (1951) for separating this type of substance, but the procedure is in many ways complicated