Three-component synthesis of β-aminoxy amides

Zeng, Lieguang; Xu, Shuheng; Cui, Sunliang; Zhang, Fengzhi

doi:10.1039/d2qo00631f

Cited by 2 publications

(2 citation statements)

References 64 publications

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“…Mario Passerini performed the first IMCR by combining three components (an isocyanide, carboxylic acid, and oxo-compound) to form α-acyloxy carboxamides. Passerini products are scaffolds that have been used for synthesizing large libraries of bioactive drugs 32,33 .…”

Section: Resultsmentioning

confidence: 99%

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Ayoup

Wahby

Hamid

et al. 2022

Sci Rep

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Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like.

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Section: Resultsmentioning

confidence: 99%

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Ayoup

Wahby

Hamid

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…77 Meanwhile, by adopting the ynamide hydroacyloxylation strategy, Cui and co-workers realized the rapid assembly of β-amino amides 47 via BF 3 •Et 2 O-catalyzed four-component coupling of terminal ynamides, carboxylic acids, aldehydes, and amines (Scheme 37). 78,79 This process includes synα-hydroacyloxylation of the ynamide, enamide addition to the imine intermediate, and the Mumm rearrangement. More recently, Tan's group accomplished an asymmetric version by employing the chiral strong Brønsted acid N-triflylphosphoramide (R)-48 as the catalyst.…”

Section: C-o Bond Formationmentioning

confidence: 99%