Synthesis and Evaluation of Indole-Based Chalcones as Inducers of Methuosis, a Novel Type of Nonapoptotic Cell Death

Abstract

Methuosis is a novel caspase-independent form of cell death in which massive accumulation of vacuoles derived from macropinosomes ultimately causes cells to detach from the substratum and rupture. We recently described a chalcone-like compound, 3-(2-methyl-1H indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e. MIPP), which can induce methuosis in glioblastoma and other types of cancer cells. Herein we describe the synthesis and structure-activity relationships of a directed library of related compounds, providing insights into the contributions of the two aryl ring systems and highlighting a potent derivative, 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e. MOMIPP) that can induce methuosis at low μM concentrations. We have also generated biologically active azide derivatives that may be useful for future studies aimed at identifying the protein targets of MOMIPP by photoaffinity labeling techniques. The potential significance of these studies is underscored by the finding that MOMIPP effectively reduces the growth and viability of temozolomide-resistant glioblastoma and doxorubicin-resistant breast cancer cells. Thus, it may serve as a prototype for drugs that could be used to trigger death by methuosis in cancers that are resistant to conventional forms of cell death (e.g. apoptosis).

Novel indolyl-chalcones target stathmin to induce cancer cell death

“…In total, we synthesized and tested 23 CIT compounds that are structurally distinct from known chalcones with anticancer and anti-inflammatory activities. 5,[25][26][27][28] The discussions of structure-activity relationship (SAR) as well as the identifications of lead compounds, including CIT-026, will be reported separately.…”

“…26 Details of reaction conditions, isolations, and characterization data of CIT-026, 214, and 223 are provided in the supplementary material online. All new compounds were characterized by 1 H NMR and mass spectra and their purity was >90% by reverse phase HPLC analyses.…”

Aerobic C–H Olefination of Indoles via a Cross-Dehydrogenative Coupling in Continuous Flow

“…16 Their pioneering studies involved the coupling between olefins and benzene in the presence of stoichiometric amounts of PdCl 2 . In 1999, Fujiwara described a highly efficient dehydrogenative Heck reaction of heterocycles, including (NH)-indole substrates, with olefins using catalytic amounts of Pd(OAc) 2 and tBuOOH as a terminal oxidant. 17 Inspired by the work of Fujiwara, several other research groups continued developing selective C-3 crossdehydrogenative Heck reactions for (NH)-indoles, utilizing a variety of oxidants.…”

Catastrophic vacuolization

“…[5][6][7][8] The nonapoptotic cell death pathway described in those papers "appears similar if not identical to what is described by the Karolinska team, " noted Roth.…”