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.
Socially responsible enterprise in Cuba: a positive role model for Corporate Social Responsibility?’
This article examines the unique institutional environment of socialist Cuba, where currently a process of controlled marketization and expansion of private enterprise is taking place. The article investigates business behaviour in Cuba with particular reference to implicit assumptions relating to socially responsible enterprise, or Corporate Social Responsibility (CSR) as the term is understood in Western Liberal Democracies. It draws upon a series of interviews with business practitioners and business commentators (both Cuban and non-Cuban residents on the island). The interviews focused on the participants’ awareness of business ethics and socially responsible enterprise, and the cultural differences in assumptions and expectations relating to the concept of CSR between the Cuban and non-Cuban interviewees. We find that Cuba at this early stage of tentative marketization presents a positive role model of socially responsible enterprise. Both the highly regulated State economy and the embedded norms and values of social equity that have emerged as a consequence of Cuba’s socialist revolution facilitate business social responsibility. The relevance of this research to current debates in relation to CSR is discussed and it is argued that capitalist economies may similarly benefit from tighter regulatory control and by cultivating more pro-social business norms that prioritise ethical over economic concerns.