Abstract
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.
Highlights
The highest, well-pronounced selectivity towards prostate cancer cells has been observed for the family of di- and trisubstituted halogen derivatives
An introduction of a small alkyl or phenyl radical to the cycle C resulted in stronger activity in treatment-resistant PC-3 cells, which has not been observed for the other types of synthesized derivatives
3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via cellular metabolism targeting
Summary
To da2t0e, more than ten methods to synthesize fas6c-aPphlysin and its derivatives and analogs have been reported [34–44]. This method was applied for the syntheses of fascaplysin and its derivatives 3 and 4 (Scheme 1). The two-step synthesis suggested by Zhu et al is the most suitable for preparation of fascaplysin derivatives from substituted tryptamines and acetophenones [42]. Chlorination, bromination and iodination of β-carboline 23b and the subsequent quaternization of obtained products enabled us to prepare fascaplysin derivatives 10–14 (Scheme 4). The introduction of the iodine instead of bromine at C-9 dramatically increases the cytotoxicity of fascaplysin derivative (7) to non-cancer cells, which resulted in a SI < 1 (Figure 2B,C). No correlations of biological activity and lipophilicity were observed for the synthesized compounds (Table S1)
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