Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

Abstract

Certain indolyl-pyridinyl-propenone analogues kill glioblastoma cells that have become resistant to conventional therapeutic drugs. Some of these analogues induce a novel form of non-apoptotic cell death called methuosis, while others primarily cause microtubule disruption. Ready access to 5-indole substitution has allowed characterization of this position to be important for both types of mechanisms when a simple methoxy group is present. We now report the syntheses and biological effects of isomeric methoxy substitutions on the indole ring. Additionally, analogues containing a trimethoxyphenyl group in place of the pyridinyl moiety were evaluated for anticancer activity. The results demonstrate that the location of the methoxy group can alter both the potency and the mechanism of cell death. Remarkably, changing the methoxy from the 5-position to the 6-position switched the biological activity from induction of methuosis to disruption of microtubules. The latter may therefore represent a prototype for a new class of mitotic inhibitors with potential therapeutic utility.

6-MOMIPP, a novel brain-penetrant anti-mitotic indolyl-chalcone, inhibits glioblastoma growth and viability

“…In a previous study, we found that indolyl pyridinyl propenones related to 6-MOMMIP caused cell rounding, surface blebbing and tubulin depolymerization within 4 h [27]. Likewise, we found that cell rounding and blebbing are early effects of 6-MOMIPP [28]. These features are consistent with the effects of direct microtubule depolymerizing agents.…”

Indolyl-Pyridinyl-Propenone-Induced Methuosis through the Inhibition of PIKFYVE

“…Follow-up structure–activity relationship (SAR) studies defined key features associated with three phenotypic classifications, namely, the induction of methuosis, vacuolization without cell death, 6 and disruption of microtubules leading to apoptosis. 7 Selected substitutions on the indole at position 2 or moving the methoxy group from position 5 to 6 8 redirected the mode of cytotoxicity from distinctive methuosis to microtubule disruption with little observable effect on vacuoles. However, the protein target(s) of the compounds that prompt the methuosis phenotype have not been identified.…”

Hydropic anthelmintics against parasitic nematodes

“…It is reported that para positioning of nitrogen in the pyridinyl moiety of chalcones is vital for vacuolization, which is abolished when the nitrogen was at the meta position [6]. In addition, positioning of the methoxy group at the fifth position of indole in indolyl-pyridinyl-propenone analogs induced methuosis, while shifting the methoxy group to the sixth position abolished methuosis and disrupted microtubules in GBM cells [16]. Similarly, 2 of the iodoindoles (5-iodoindole and 7-iodoindole) have elicited vacuoles in nematodes.…”