Periplogenin, isolated from Lagenaria siceraria, ameliorates L-T4-induced hyperthyroidism and associated cardiovascular problems.

The importance of glycoside in the regulation of thyroid dysfunction is not well understood. In the present investigation, effects of periplogenin-3- O-D-glucopyranosyl (1→6)(1→4)-D-cymaropyranoside, isolated from the vegetable, LAGENARIA SICERARIA, in L-thyroxine (L-T4)-induced hyperthyroidism and in related cardiovascular abnormalities have been revealed in Wistar albino rats. L-T4 (500 µg/kg, s. c./d) administration for 12 days significantly increased serum concentrations of thyroxine (T4), triidothyronine (T3), and hepatic 5'-deiodinase I (5'-DI) activity with a parallel increase in lipid peroxidation (LPO) in different organs such as heart, liver and kidney; serum glucose and insulin concentrations and a decrease in cardiac Na (+)-K (+)-ATPase activity as well as serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides. Most of these adverse effects were reversed following the administration of isolated periplogenin. However, out of its 3 different concentrations (5.0, 10, and 25 mg/kg), 5 mg/kg appeared to be the most effective one as it could nearly normalize the level of T3, glucose, insulin, Na (+)-K (+)-ATPase activity, tissue LPO and different serum lipids suggesting the protective role of periplogenin against thyrotoxicosis and associated cardiovascular problems. It appears that the periplogenin actions are mediated through its direct antithyroidal and/or LPO inhibiting properties.

A cardiac glucoside with in vitro anti-HIV activity isolated from Elaeodendron croceum.

Human immunodeficiency virus (HIV) affects more than 40 million people worldwide and more than 5 million in South Africa alone. There is no cure for the disease yet, and novel effective drugs need to be discovered to make any progress in combating the disease. Twelve extracts from indigenous South African plants were analysed, of which Elaeodendron croceum showed potent inhibition of transcription factors and a recombinant HIV strain in an MT-2 VSV-pseudotyped recombinant virus assay at 100 ng mL(-1). Bioassay guided isolation of an ethanolic extract of E. croceum yielded a well-known digitoxigenin-glucoside as the only active compound. It showed significant inhibition (90%) at 0.2 µM. The in vitro toxicity of digitoxigenin-glucoside proved to be quite low, and its therapeutic index was 250. This observation indicates that digitoxigenin-glucoside could represent a potential pharmacophore for the treatment of HIV from natural sources.

Periplogenin-3-O- -D-glucopyranosyl -(1-->6)- -D-glucopyaranosyl- -(1-->4) -D-cymaropyranoside, isolated from Aegle marmelos protects doxorubicin induced cardiovascular problems and hepatotoxicity in rats.

Doxorubicin is a common chemotherapeutic anticancer drug. Its use is associated with adverse effects including cardiotoxicity. Several therapeutics interventions have been attempted to reduce the toxicity and to improve the efficacy of the drug. However, on phytochemicals very few investigations have been made. In the present study we have evaluated the potential of a cardenolide, periplogenin, isolated from the leaves of Aegle marmelos in protecting the doxorubicin induced cardiotoxicity and lipid peroxidation (LPO) in rats. Doxorubicin induced cardiac and hepatotoxicity were characterized by marked biochemical changes including an increase in serum creatine kinase-MB (CK-MB), glutamate-pyruvate transaminase (SGPT), and tissue LPO, with a decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). It also increased the levels of different serum lipids, but decreased the amount of high-density lipoprotein (HDL). Cotherapy of the test cardenolide and doxorubicin for 4 weeks reversed all these adverse effects. However, out of three different concentrations (12.5, 25, and 50 mg/kg p.o.) of the test periplogenin, 25 mg/kg appeared to be most effective. When its efficacy was compared with that of vitamin E (alpha-tocopherol) the isolated compound exhibited a better therapeutic potential. The isolated periplogenin from the leaves of A. marmelos could potentially inhibit doxorubicin-induced cardiovascular problems in rats. However, its moderate dose was found to be most effective.

Efficient synthesis of 3-aminodigoxigenin and 3-aminodigitoxigenin probes.

Oxidation of digoxigenin and digitoxigenin to the 3-ketones followed by reductive amination produced a mixture of amine epimers. The inability to separate the epimeric mixtures of chemiluminescent digoxigenin probes derived by conjugation to the acridinium label prompted us to develop an HPLC method to separate the amines. Labeling of the pure amines resulted in good yields of the isomerically pure probes.

Na+,K+-ATPase inhibitors in rat urine: origins and physiological significance.

To identify the origins and structures of mammalian tissue-derived Na+,K+-ATPase inhibitors, we investigated the tissue distribution of inhibitors in rats. Among many tissues tested, urine was found to contain high levels of many inhibitors. The structures of the two major inhibitors were identified as neoconvalloside and periplogenin monorhamnoside, which are derivatives of strophanthidin. Urinary levels of these inhibitors, however, decreased considerably after changing the diet from the regular diet to purified synthetic diet, suggesting that the majority of the urinary inhibitors are of dietary origin. Investigation of the ingredients of the diet further revealed that alfalfa meal and ground oats are the major sources of these cardiac glycosides. As to the physiological relevance of the cardiac glycosides, a low concentration (1-50 nM) of ouabain dose-dependently enhanced aldosterone secretion from adrenal glomerulosa cells by an increase in local renin release. Ouabain was also found to be involved in AT2 receptor-specific expression in rat PC12W cells through an increment in intracellular Na+. These results suggest that Na+,K+-ATPase inhibitors, regardless of the source, are involved in the regulation of blood pressure.

Cytotoxic principles of a Bangladeshi crude drug, akond mul (roots of Calotropis gigantea L.).

Three cardenolide glycosides, calotropin (1), frugoside (2), and 4'-O-beta-D-glucopyranosylfrugoside (3), were obtained as the cytotoxic principles of "akond mul" (roots of Calotropis gigantea L.). The cytotoxicity of these compounds against various cell lines of human and mouse origin was tested. They showed similar cell line selectivity to those of cardiac glycosides such as digoxin and ouabain: they are toxic to cell lines of human origin, but not to those from mouse at 2 micrograms/ml.

Cytotoxic cardenolides from woods of Euonymus alata.

Three cytotoxic cardenolides, acovenosigenin A 3-O-alpha-L-ramnopyranoside (1), euonymoside A (2) and euonymusoside A (3), were isolated from the woods of Euonymus alata (Celastraceae). The chemical structure of a new cardenolide, euonymusoside A (3) has been elucidated on the basis of extensive spectral analysis and enzymic hydrolysis to be acovenosigenin A (1 beta, 3 beta, 14 beta-trihydroxy-5 beta-cardenolide) 3-O-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosyl(1-->4)-alpha-L-rhamnopyranoside. All three showed potent cytotoxic activity against some neoplastic cell lines.

Euonymoside A: a new cytotoxic cardenolide glycoside from the bark of Euonymus sieboldianus.

A new cytotoxic cardenolide glycoside, euonymoside A (1), was isolated from the bark of Euonymus sieboldianus. The structure of 1 was elucidated as acovenosigenin A-3-O-beta-D-glucopyranosyl (1-->2)-alpha-L-rhamnopyranoside. The IC50 values of 1 against A549 (human lung carcinoma) and SK-OV-3 (human ovary adenocarcinoma) were 0.06 and 0.4 micrograms/ml, respectively.

Cardiac glycosides of Beaumontia brevituba and B. murtonii.

Cardiac glycosides from Beaumontia brevituba and B. murtonii were examined. Gentiobiosyl-beta-D-cymaroside and gentiobiosyl-alpha-L-cymaroside of digitoxigenin were isolated from the seeds, unripe fruits, and leaves of B. brevituba, and the leaves of B. murtonii. Oleandrigenin and/or delta 16-digitoxigenin glycosides having the same sugar moieties were not isolated from the leaves of B. brevituba but from the leaves of B. murtonii as well as the seeds of B. brevituba.

Behaviour of cardiac glycosides and cardenolides related to digitoxigenin on sephadex LH-20.

The behaviour of six cardenolides and eight cardiac glycosides related to digitoxigenin during column chromatography on Sephadex LH-20 gel has been investigated. Complete resolution was obtained for mixtures of digitoxigenin, gitoxigenin and digoxigenin, but not for those of the 3-epimeric cardenolides. It was possible to achieve a group separation of cardenolides and their glycosides of the digitoxigenin series from those of the digoxigenin or gitoxigenin series.