Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

Marigorta, Eduardo Martı́nez de; Santos, Jesús M. de los; Retana, Ana M. Ochoa de; Vicario, Javier; Palacios, Francisco

doi:10.3762/bjoc.15.104

Cited by 44 publications

(13 citation statements)

References 114 publications

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“…Multi-component reaction (MCR) is attracting the attention of chemists for the construction of diverse heterocyclic scaffolds. MCR is a powerful synthetic methodology in which three or more reactive substrates are mixed in one reaction flask to form a new product employing all substrates with minimized by-products and good yields (Paprocki et al, 2018;de Marigorta et al, 2019;Zhi et al, 2019;Kappe, 2020).…”

Section: Introductionmentioning

confidence: 99%

Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches

et al. 2021

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A series of bis-thiazoles 5a–g were synthesized from bis-thiosemicarbazone 3 with hydrazonoyl chlorides 4a–g. Reaction of 3 with two equivalents of α-halocarbonyl compounds 6–8, 10, and 12a–d afforded the corresponding bis-thiazolidines 9, 11, and 13a–d, respectively. Condensation of bis-thiazolidin-4-one 9 with different aromatic aldehydes furnished bis-thiazolidin-4-ones 14a–d. Compounds 5a–g, 9, and 13a,c,d were screened in vitro for their cytotoxic activities in a panel of cancer cell lines. Compounds 5a–c, 5f–g, and 9 exhibited remarkable cytotoxic activities, especially compound 5c with potent IC50 value 0.6 nM (against cervical cancer, Hela cell line) and compound 5f with high IC50 value 6 nM (against ovarian cancer, KF-28 cell line). Compound 5f–induced appreciated apoptotic cell death was measured as 82.76% associated with cell cycle arrest at the G1 phase. The apoptotic pathways activated in KF-28 cells treated with 5a, 5b, and 5f were further investigated. The upregulation of some pro-apoptotic genes, bax and puma, and the downregulation of some anti-apoptotic genes including the Bcl-2 gene were observed, indicating activation of the mitochondrial-dependent apoptosis. Together with the molecular docking studies of compounds 5a and 5b, our data revealed potential Pim-1 kinase inhibition through their high binding affinities indicated by inhibition of phosphorylated C-myc as a downstream target for Pim-1 kinase. Our study introduces a set of bis-thiazoles with potent anti-cancer activities, in vitro.

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Section: Introductionmentioning

confidence: 99%

Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches

et al. 2021

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“…Due to the high degree of molecular diversity achieved in MCRs, they are now an essential tool in diversity-oriented synthesis [3,4], with huge potential in the field of medicinal chemistry [5,6]. Considering the relevance of the γ-lactam ring I (Figure 1) [7] and the increasing demand of potentially active compounds in medicinal sciences, MCR protocols were extensively used during the last decades for the synthesis of a wide number of densely functionalized γ-lactam derivatives [8,9]. In particular, 1,5-dihydro-2 H -pyrrol-2-ones II (Figure 1) are conjugated unsaturated γ-lactam substrates with huge potential as intermediates in synthetic chemistry that also show assorted pharmacological activities [10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

et al. 2019

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Brønsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized γ-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.

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“…A wide range of bioactive natural products or clinically used drugs and pharmaceuticals embody the γ-lactam scaffold as a part of their complex molecular architecture [ 1 , 2 ]. Thus, tremendous efforts have been devoted during the last decades towards the efficient synthesis of functionalized γ-lactam derivatives [ 3 , 4 , 5 , 6 , 7 ]. In particular, 3-pyrrolin-2-ones (also named as 1,5-dihydropyrrol-2-ones), closely related to γ-lactams, are not only useful building blocks in chemical synthesis [ 8 , 9 ], but also core structures of bioactive natural products and pharmaceuticals [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

et al. 2022

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A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.

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Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

Cited by 44 publications

References 114 publications

Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches

Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches

A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

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