Marine Drugs (Mar 2022)

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

  • 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

DOI
https://doi.org/10.3390/md20030185
Journal volume & issue
Vol. 20, no. 3
p. 185

Abstract

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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.

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