Abstract:With their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the … Show more
“…Accordingly, when the group directly attached to the ester moiety (R 3 ; Fig. 6 ) is an ortho-substituted or ortho, ortho′-disubstituted aromatic ring, the Passerini α-acyloxy carboxamides are metabolically stable to esterases 37 . Figure 6 The general structure of Passerini α-acyloxy carboxamides.…”
Section: Resultsmentioning
confidence: 99%
“…The skeleton ester is also stable toward hydrolysis when the R 1 group is a bulky substituent regardless of the nature of the R 3 substituent. The study was also pointed to the stability of the terminal aromatic ester as exemplified by experimental observation of the different hydrolytic stabilities of methyl benzoate and methyl 2,6-dimethylbenzoate toward esterases, where the former is readily hydrolyzed, while the latter is completely resistant to esterases 37 .…”
Section: Resultsmentioning
confidence: 99%
“…5). Regarding the stability of the currently studied Passerini adducts, literature review revealed a recent valuable study demonstrating that the stability of the ester in the Passerini skeleton could be influenced by other substructures present based on experiments carried on a library of more than Passerini adducts 37 . Being concerned with the medicinal chemistry applications of Passerini reaction, the study focused on investigating the metabolic stability of the scaffold towards esterases.…”
Section: Resultsmentioning
confidence: 99%
“…Accordingly, when the group directly attached to the ester moiety (R 3 ; Fig. 6) is an ortho-substituted or ortho, ortho′-disubstituted aromatic ring, the Passerini α-acyloxy carboxamides are metabolically stable to esterases 37 . This is in accordance with previous studies that generally showed that steric hindrance can reduce or suppress the hydrolytic activity of esterases, while the presence of electron-withdrawing groups on the acyl side can facilitate the enzymatic cleavage 38 .…”
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.
“…Accordingly, when the group directly attached to the ester moiety (R 3 ; Fig. 6 ) is an ortho-substituted or ortho, ortho′-disubstituted aromatic ring, the Passerini α-acyloxy carboxamides are metabolically stable to esterases 37 . Figure 6 The general structure of Passerini α-acyloxy carboxamides.…”
Section: Resultsmentioning
confidence: 99%
“…The skeleton ester is also stable toward hydrolysis when the R 1 group is a bulky substituent regardless of the nature of the R 3 substituent. The study was also pointed to the stability of the terminal aromatic ester as exemplified by experimental observation of the different hydrolytic stabilities of methyl benzoate and methyl 2,6-dimethylbenzoate toward esterases, where the former is readily hydrolyzed, while the latter is completely resistant to esterases 37 .…”
Section: Resultsmentioning
confidence: 99%
“…5). Regarding the stability of the currently studied Passerini adducts, literature review revealed a recent valuable study demonstrating that the stability of the ester in the Passerini skeleton could be influenced by other substructures present based on experiments carried on a library of more than Passerini adducts 37 . Being concerned with the medicinal chemistry applications of Passerini reaction, the study focused on investigating the metabolic stability of the scaffold towards esterases.…”
Section: Resultsmentioning
confidence: 99%
“…Accordingly, when the group directly attached to the ester moiety (R 3 ; Fig. 6) is an ortho-substituted or ortho, ortho′-disubstituted aromatic ring, the Passerini α-acyloxy carboxamides are metabolically stable to esterases 37 . This is in accordance with previous studies that generally showed that steric hindrance can reduce or suppress the hydrolytic activity of esterases, while the presence of electron-withdrawing groups on the acyl side can facilitate the enzymatic cleavage 38 .…”
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.
“…22,23 In an effort to expand the scope of the Passerini reaction, Brunelli and co-workers produced a library of 43 α-acyloxy carboxamides to evaluate the effects of substitution on the metabolic stability of the resulting ester moiety (Scheme 2). 20 Particular focus was given to the carboxylic acids and aldehydes, selecting diverse substrate models from aliphatic to substituted aromatic compounds. Assuming minimal impact of the isocyanide component due to its distance from the ester's moiety, it was decided not to alter that substitution.…”
The
generation of multiple bonds in one reaction step has attracted
massive interest in drug discovery and development. Multicomponent
reactions (MCRs) offer the advantage of combining three or more reagents
in a one-pot fashion to effectively yield a synthetic product. This
approach significantly accelerates the synthesis of relevant compounds
for biological testing. However, there is a perception that this methodology
will only produce simple chemical scaffolds with limited use in medicinal
chemistry. In this Microperspective, we want to highlight the value
of MCRs toward the synthesis of complex molecules characterized by
the presence of quaternary and chiral centers. This paper will cover
specific examples showing the impact of this technology toward the
discovery of clinical compounds and recent breakthroughs to expand
the scope of the reactions toward topologically rich molecular chemotypes.
The facile generation of the α‐acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4‐formyl‐1,4‐dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini‐derived products not previously amenable to direct aldehyde‐based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating “impossible” aldehydes.
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