Title : Original Synthesis of natural acetogenins, fattyacids and lembehynes as a potential drugs for treatment of cancer and neurodegenerative diseases
The report discusses the latest achievements of the authors in developing original methods for stereoselective synthesis of natural acetogenins, higher bis-methylene-separated(interrupted) di- and trienoic acids, lembehynes that are of interest as low-toxic target antitumor drugs, as well as compounds with neritogenic activity for treating neurodegenerative diseases.
The synthetic approaches to the above listed natural compounds are based on the use at the key stage of the synthesis, of new organometallic reactions, such as Ti-catalyzed homo- and cross-cyclomagnesiation of 1,2-dienes, discovered in the Laboratory of Catalytic Synthesis of the IPC RAS, involving available Grignard reagents.
The studies of the synthesized compounds for their antitumor and neuritogenic activities in vitro were performed withthe use of unique equipment in “Centre for Molecular Design and Biological Screening of Candidate Substances for the Pharmaceutical Industry” at the Institute of Petrochemistry and Catalysis of RAS using modern methods such as flow cytofluorometry, fluorescence microscopy, Luminex MagPlex magnetic microsphere technology and western blotting.
In silico studies into regularities of the structural influence of the synthesized compounds on their antitumor activity were fulfilled with the use of molecular docking and molecular dynamics experiments.
For compounds that showed the greatest activity, in vivo tests were performed for linear mice with grafted malignant Lewis carcinoma.
This work was financially supported by the Russian Science Foundation (Grants 16-13-10172, 18-73-10030), Russian Foundation for Basic Research (Grants 17-43-020502, 18-33-20058, 18-29-09068, 19-03-00603) and Grant of the RF President for the support of leading scientific schools(NS-5240.2018.3). The research has been carried out in accordance with the approved plans for research projects at the IPC RAS State Registration No. AAAA-A19-119022290007-9, AAAA-A19-119022290008-6 (2019-2021).
Audience take away:
• Author’s original methods for stereoselective synthesis of natural acetogenins, di- and trienoic acids, lembehynes.
• The studies of the synthesized compounds for their antitumor and neuritogenic activities in vitro, in silico and in vivo.
• Studies on the induction of apoptosis, the effect of the synthesized compounds on the cell cycle, biological effects on mitochondria, histones and topoisomerases using modern methods such as flow cytofluorometry, fluorescence microscopy, Luminex MagPlex magnetic microsphere technology and western blotting.