Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors

Wan, Yicong; Wang, Junhua; Sun, Feng’e; Chen, Minglu; Hou, Xuben; Fang, Hao

doi:10.1016/j.bmc.2015.11.014

Cited by 24 publications

(6 citation statements)

References 19 publications

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“…Starting from (2 S ,4 R )-4-hydroxyproline, Wan et al [ 66 ] designed and synthesized a new series of pyrrolidine derivatives based on compound 87 , which was described as potent inhibitor of myeloid cell leukemia-1 (Mcl-1) protein ( K i = 8.4 µM) (Fig. 19 ).…”

Section: Pyrrolidine Derivatives From Commercial Building Blocksmentioning

confidence: 99%

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

et al. 2021

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The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

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Section: Pyrrolidine Derivatives From Commercial Building Blocksmentioning

confidence: 99%

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

et al. 2021

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“…Meanwhile, continued structural elaboration of Fesik’s indoles has led to the discovery of the acylsulfonamide derivative 50 which inhibits Mcl-1 with a K i of 1 nM and exhibits 3 orders of magnitude selectivity over Bcl-x L . Fang’s group have reported some other acylsulfonamides as pan-Bcl-2 inhibitors, including 51 , based on an imidazolidine-2,4-dione core, and compounds derived from pyrrolidine (e.g., 52 ) that demonstrate up to 15-fold selectivity for Mcl-1 over Bcl-x L …”

Section: Updatementioning

confidence: 99%

“…99 Fang's group have reported some other acylsulfonamides as pan-Bcl-2 inhibitors, including 51, based on an imidazolidine-2,4-dione core, 100 and compounds derived from pyrrolidine (e.g., 52) that demonstrate up to 15-fold selectivity for Mcl-1 over Bcl-x L . 101 Covalent inhibition of proteins is experiencing a renaissance, particularly through a more targeted strategy, and, in this regard, Mcl-1 has not been neglected. Walensky and colleagues have discovered the covalent inhibitor 53 (Figure 24) that binds Mcl-1 allosterically and selectively through chemical modification of Cys286.…”

Section: ■ Stapled Helicesmentioning

confidence: 99%

Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules

et al. 2016

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A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.

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“…Both molecular targets VEGFR2 and Topoisomerase II were previously investigated for many benzene‐sulphonamide derivatives; Benzene sulfonamide‐based derivatives, pazopanib, and compounds ( I–IV ) exhibited potent anticancer though VEGFR2 inhibition, [17–20] and ( II, IV–V ) exhibited potent topoisomerase II inhibition [20–24] . Various representative inhibitors of anti‐apoptotic B‐cell lymphoma‐2 (Bcl‐2) proteins containing the sulfonamide moiety were identified [25–28] . Halawa et al , reported new heterocyclic compounds containing derived sulfonamides with pyrone, benzofuran, oxazole rings; the proposed structures exhibited potent antiproliferative activity as topoisomerase I and II inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

Albujuq,

Althumayri,

Alharbi

et al. 2023

ChemistrySelect

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Novel hybrid series of benzenesulfonamide coupled with piperidine, morpholine, and N,N‐dimethylethanamine moieties at sulfonyl group were designed through pharmacophore hybridization, synthesized, and evaluated for cancer treatment. Benzenesulfonamide‐based derivatives had been synthesized, structurally elucidated, and biologically evaluated as potent VEGFR2 kinase and topoisomerase II inhibitors with cytotoxicity against MCF‐7 and HepG2 cells. Interestingly, the most cytotoxic compound against MCF‐7 and HepG2 cells exhibited promising IC50 values of 0.08 and 0.186 μM, respectively, compared to Doxorubicin as the reference drug with IC50 values of 7.67 and 8.28 μM. It exhibited promising dual enzyme inhibition VEGFR2 and Topoisomerase II with IC50 values of 13.24 nM and 8.3 μM compared to Sorafenib and Doxorubicin as standard drugs. It significantly stimulated total apoptotic breast cancer cell death by 55.25‐fold (34.26 % compared to 0.62 for the control), arresting the cell cycle at S‐phase, which affected the apoptosis‐mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the anti‐apoptotic gene Bcl‐2. A molecular docking study was conducted to confirm the binding affinity of the designed compounds towards VEGFR2 and Topoisomerase II proteins with good binding energy and interactive modes as their co‐crystallized ligands.

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Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors

Cited by 24 publications

References 19 publications

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

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