Vladimir A. D'yakonov

The facile synthesis of the 5Z,9Z-dienoic acids and their topoisomerase I inhibitory activity

An original, effective approach to the synthesis of natural and synthetic 5Z,9Z-dienoic acids in high yields (61-67%) and with high selectivity (>98%) was developed. The approach is based on the use of the new intermolecular catalytic cross cyclomagnesiation of terminal aliphatic and oxygenated 1,2-dienes upon treatment with Grignard reagents in the presence of the Cp2TiCl2 catalyst. High activity of (5Z,9Z)-5,9-eicosadienoic acid as a human topoisomerase I inhibitor at concentrations above 0.1 μM was elucidated.

Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors

Abstract The search for new, effective, and low-toxic anticancer agents is one of the most important tasks of modern medicinal chemistry. In general, the solution to this problem comes down to finding new compounds that would act on molecular targets, the targets that play an important role in carcinogenesis. Numerous studies in this field have shown that topoisomerases I and II are one of the main molecular targets in the development of modern anticancer agents. A large number of compounds belonging to different classes are known as capable of inhibiting topoisomerases, including the ones isolated from the natural objects; for example, camptothecin, podophyllotoxin, anthracyclines, polyene acids, and many others. However, along with their efficacy, some of these compounds have a number of substantial disadvantages; chief among these are high toxicity and low solubility, low selectivity of action against malignant tumors, and development of multidrug resistance. The way of overcoming these shortcomings is to create anticancer drugs with improved properties and to study the mechanism of their action within the cell. Therefore numerous groups of researchers carry out an intensive search and selection of natural topoisomerase inhibitors, as well as work on the creation of new synthetic analogs and semisynthetic derivatives of known anticancer compounds capable of altering catalytic activity of ferment by stabilizing the covalent DNA-protein complexes. The present review summarizes the achievements of the past 5–10 years in finding new natural compounds, effective topoisomerase inhibitors, their modification aimed at improving the properties, the study of mechanisms of action, and antitumor activity.

Novel Hybrid Molecules on the Basis of Steroids and (5Z,9Z)-Tetradeca-5,9-dienoic Acid: Synthesis, Anti-Cancer Studies and Human Topoisomerase I Inhibitory Activity

Novel steroid derivatives of 5Z,9Z-dienoic acids were prepared by the DCC/DMAP-catalyzed esterification of (5Z,9Z)-tetradeca-5,9-dienoic acid with hydroxy steroids. High cytotoxicity towards the HEK293, Jurkat, K562 cancer cell lines and human topoisomerase I (hTop1) inhibitory activity in vitro were found for the synthesized acids. A probable mechanism of topoisomerase I inhibition was hypothesized on the basis of in silico studies resorting to docking.

Catalytic cyclometallation in steroid chemistry V: Synthesis of hybrid molecules based on steroid oximes and (5Z,9Z)-tetradeca-5,9-dienedioic acid as potential anticancer agents

Graphical abstract Figure. No Caption available. HighlightsSynthesis of steroid containing 5Z,9Z‐dienoic acids have been developed.New molecules are efficient apoptosis inducers in cancer cells.The structures of all novel compounds were confirmed by NMR measurements. ABSTRACT Synthetic analogues of natural 5Z,9Z‐dienoic acids ‐ hybrid molecules based on the oximes of cholesterol, pregnenolone, and androsterone with 1,14‐tetradeca‐5Z,9Z‐dienedicarboxylic acid ‐ were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of O‐containing 1,2‐dienes with Grignard reagent in the presence of Cp2TiCl2 as the key step. Using flow cytometry, it was shown for the first time that the new molecules are efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562.

Catalytic cyclometallation in steroid chemistry VI: Targeted synthesis of hybrid molecules based on steroids and tetradeca-5Z,9Z-diene-1,14-dicarboxylic acid and study of their antitumor activity

Graphical abstract Figure. No Caption available. HighlightsSynthesis of steroid containing 5Z,9Z‐dienoic acids have been developed.New molecules are efficient apoptosis inducers in cancer cells.The structures of all novel compounds were confirmed by NMR measurements. ABSTRACT Hybrid molecules based on a number of steroids (cholesterol, pregnenolone, androsterone) and 1,14‐tetradeca‐5Z,9Z‐dienedicarboxylic acid linked via mono‐ and diethylene glycol spacers were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of oxygenated 1,2‐dienes with Grignard reagent in the presence of Cp2TiCl2 as the key synthetic step. Using flow cytometry, the new molecules were shown for the first time to be efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell cultures and to have dose‐dependent effect on the S and G2 phases of the cell cycle.