Nature-inspired new isoindole-based Passerini adducts as efficient tumor-selective apoptotic inducers via caspase-3/7 activation

Abstract

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC₅₀ = 0.04-0.11 μM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like.

Keywords: 4-(2′-phthalimido)phenylisonitrile; Apoptosis; Cancer; Caspase-3/7 activator; Isoindole alkaloids; Passerini.