Study of Structure–Activity Relationships of the Marine Alkaloid Fascaplysin and Its Derivatives as Potent Anticancer Agents

Autor: Maxim E. Zhidkov, Moritz Kaune, Alexey V. Kantemirov, Polina A. Smirnova, Pavel V. Spirin, Maria A. Sidorova, Sergey A. Stadnik, Elena Y. Shyrokova, Dmitry N. Kaluzhny, Oleg A. Tryapkin, Tobias Busenbender, Jessica Hauschild, Tina Rohlfing, Vladimir S. Prassolov, Carsten Bokemeyer, Markus Graefen, Gunhild von Amsberg, Sergey A. Dyshlovoy
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Marine Drugs, Vol 20, Iss 3, p 185 (2022)
Druh dokumentu: article
ISSN: 20030185
1660-3397
67330185
DOI: 10.3390/md20030185
Popis: Marine alkaloid fascaplysin and its derivatives are known to exhibit promising anticancer properties in vitro and in vivo. However, toxicity of these molecules to non-cancer cells was identified as a main limitation for their clinical use. Here, for the very first time, we synthesized a library of fascaplysin derivatives covering all possible substituent introduction sites, i.e., cycles A, C and E of the 12H-pyrido[1-2-a:3,4-b’]diindole system. Their selectivity towards human prostate cancer versus non-cancer cells, as well as the effects on cellular metabolism, membrane integrity, cell cycle progression, apoptosis induction and their ability to intercalate into DNA were investigated. A pronounced selectivity for cancer cells was observed for the family of di- and trisubstituted halogen derivatives (modification of cycles A and E), while a modification of cycle C resulted in a stronger activity in therapy-resistant PC-3 cells. Among others, 3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via the targeting of cellular metabolism. Moreover, an introduction of radical substituents at C-9, C-10 or C-10 plus C-3 resulted in a notable reduction in DNA intercalating activity and improved selectivity. Taken together, our research contributes to understanding the structure–activity relationships of fascaplysin alkaloids and defines further directions of the structural optimization.
Databáze: Directory of Open Access Journals
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