Nature-inspired new isoindole-based Passerini adducts as efficient tumor-selective apoptotic inducers via caspase-3/7
Mohammed Salah Ayoup1, Ahmed Farag Mansour1, Hamida Abdel-Hamid1
1Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt.
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.
Insights
New isoindole-based compounds activate caspase-3/7, inducing cancer cell apoptosis. These novel therapeutics show high potency and selectivity against lung, colorectal, and breast cancers, offering a promising anticancer strategy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Selective tumor elimination is crucial in oncology.
- Caspase activation, particularly caspase-3, is an emerging personalized anticancer strategy.
- Previous research utilized Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers.
Purpose of the Study:
- To design and synthesize novel isoindole-based Passerini adducts as potent caspase-3/7 activators.
- To evaluate the antiproliferative and apoptotic activities of these compounds against various cancer cell lines.
- To elucidate the mechanism of action, including caspase-dependent apoptosis and receptor binding.
Main Methods:
- Scaffold hopping design inspired by Lion's Mane mushroom alkaloids.
- One-pot synthesis of isoindole-based Passerini adducts.
- MTT assay for antiproliferative screening, apoptosis assays, AIF1 quantification, and molecular docking simulations.
Main Results:
- Several derivatives exhibited superior antiproliferative activity compared to 5-fluorouracil.
- Compound 8a showed the highest potency (IC50 = 0.04-0.11 μM) and selectivity (SI = 42.59-125.53).
- The most potent compounds induced apoptosis via caspase-3/7 activation, with no caspase-independent AIF1 pathway involvement, and demonstrated favorable drug-like properties.
Conclusions:
- The novel isoindole-based Passerini adducts are effective caspase-3/7 activators and potent anticancer agents.
- These compounds represent a promising new class of therapeutics for selective tumor elimination.
- Further development is warranted based on their high efficacy, selectivity, and favorable drug-like profiles.
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