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

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

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114865. doi: 10.1016/j.ejmech.2022.114865.
Mohammed Salah Ayoup 1,  Ahmed Farag Mansour 2,  Hamida Abdel-Hamid 2,  Marwa M Abu-Serie 3,  Salma M Mohyeldin 4,  Mohamed Teleb 5
Affiliations

Affiliations

  • 1 Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt. Electronic address: [email protected].
  • 2 Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt.
  • 3 Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt.
  • 4 Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
PMID: 36335743 DOI: 10.1016/j.ejmech.2022.114865
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.

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