Synthesis and Biological Evaluation of Novel Bufalin Derivatives

Abstract

Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawa’s reagent resulted in the production of two novel bufalin derivatives: bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na+, K+-ATPase activity of the brain microsomal fraction to induce cytotoxic activity against the NCI-60 human tumor cell line panel and non-cancer human cells, and to increase the force of contraction of quail embryonic heart muscle cells in culture. The two steroids exhibited biological activities similar to those of other CS in the tested experimental systems, but with reduced cytotoxicity, advocating their development as drugs for the treatment of heart failure and arrhythmias.

Toad venom-derived bufadienolides and their therapeutic application in prostate cancers: Current status and future directions

“…By far, this research area is extremely undeveloped. Very few studies have been published, and most of them are focusing on the modification of hydroxyl groups at different positions ( Sampath et al, 2022 ). Further and varied structural modification at other positions and functional groups are necessary.…”

“…While several TVAs derivatives also exhibited promising anticancer effects in PCa and other cancer types ( Yuan et al, 2014 ; Meng et al, 2021 ; Sampath et al, 2022 ), their application remains to be fully exploited. It’s also noteworthy that except for bufalin, arenobufagin, and cinobufagin, very few studies of bufotalin and resibufogenin in PCa have been reported in the past decade.…”

Toad venom bufadienolides and bufotoxins: An updated review

“…Sampath et al (2022) recently synthesized new bufalin derivatives 6 and 7 using Ishikawa's reagent (Scheme 4). In general, Ishikawa's reagent is applied to convert alcohols into alkyl fluorides or carboxylic acid groups into acyl fluorides.…”

“…The authors demonstrated that acetyl bufalin (5) could be a new CDK9 inhibitor for cancer treatment as a single agent or in combination with other drugs to improve efficacy. However, deeper investigations will be needed Sampath et al (2022). recently synthesized new bufalin derivatives 6 and 7 using Ishikawa's reagent (Scheme 4).…”

Histological Study of Glandular Variability in the Skin of the Natterjack Toad—Epidalea calamita (Laurenti, 1768)—Used in Spanish Historical Ethnoveterinary Medicine and Ethnomedicine

“…It can be stated that the compounds synthesised by amphibians are quite numerous and diverse in chemical composition, but most of them include biogenic amines (adrenaline, noradrenaline, bradykinin, or histamine), steroids (bufadienolides and bufotoxins), alkaloids (batrachotoxin or tetrodotoxin, mostly in the Dendrobatidae family), peptides, and proteins [59]. In recent years, pharmacological and chemical studies on amphibians are still relevant, and can be considered a hot topic due to the interest in traditional Asian medicines or from regions such as Central and South America [26,34,64]. However, the contributions on the medicinal use of amphibians in specific European popular medicine and/or EVM are occasional.…”