Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

Qu, Bingxue; Xu, Yongjin; Yang, Lǜ; Zhuang, Wenhua; Jin, Xinxin; Shi, Qiu-Qiu; Yan, Shuo; Guo, Yu; Shen, Zheyuan; Che, Jinxin; Wu, Yize; Tong, Lexian; Dong, Xiaowu; Yang, Haiyan

doi:10.1016/j.ejmech.2022.114257

Cited by 7 publications

(3 citation statements)

References 43 publications

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“…N -(4-Bromopyridin-2-yl)acetamide ( 10 ), N -(4-bromopyridin-2-yl)cyclopropanecarboxamide ( 12 ), N -(4-bromopyridin-2-yl)cyclobutanecarboxamide ( 15 ), N -(4-bromopyridin-2-yl)cyclohexanecarboxamide ( 16 ), N -(4-bromopyridin-2-yl)benzamide ( 17 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide ( 24 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclopropanecarboxamide ( 26 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide ( 29 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclohexanecarboxamide ( 30 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzamide ( 31 ) [ 57 ]; N -(4-bromopyridin-2-yl)isobutyramide ( 11 ), N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isobutyramide ( 25 ) [ 58 , 59 ]; N -(3-bromophenyl)cyclopropanecarboxamide ( 13 ), N -(3-bromophenyl)ethanesulfonamide ( 20 ), N -(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide ( 27 ), N -(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide ( 34 ) [ 60 ]; N -(4-bromopyridin-2-yl)methanesulfonamide ( 18 ) [ 61 ]; 1-((3-bromophenyl)sulfonyl)piperidine ( 23 ), 1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine ( 37 ) [ 62 ]; 4-bromo- N -(cyclopropylmethyl)pyridin-2-amine ( 21 ), N -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine ( 35 ) [ 63 ]; N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methanesulfonamide ( 32 ) [ 64 , 65 ]; N -(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanesulfonamide ( 36 ) [ 66 ]; 6-bromo-2,2-dimethyl-2,3-dihydrothieno [3,2- d ]pyrimidin-4(1 H )-one ( 6 ) [ 50 ]; 5-Bromo-3-ureidothiophene-2-carboxamide ( 5 ) [ 67 ]; and 6′-bromo-1′ H -spiro[cyclopentane-1,2′-thieno [3,2- d ]pyrimidin]-4′(3′ H )-one ( 7 ) [ 68 ].…”

Section: Methodsmentioning

confidence: 99%

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

Góral,

Wichur,

Sługocka

et al. 2024

Molecules

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GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer’s disease due to their involvement in the misfolding and accumulation of amyloid β (Aβ) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3β plays the most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive GSK-3β inhibitor (IC50 = 8 nM, Ki = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC50 = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound 62 effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility.

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Section: Methodsmentioning

confidence: 99%

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

Góral,

Wichur,

Sługocka

et al. 2024

Molecules

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“…Except for NCI-1, all reported CRM1 inhibitors covalently bind to cysteine 528 (C528) in the NES-binding groove (or NES groove in short), thereby directly inhibiting the function of CRM1 (Scheme ). − We previously proposed that noncovalent CRM1 inhibitors may be less toxic, more effective, and resistant to C528 mutations . However, it is challenging to target CRM1 by noncovalent inhibitors because of the large interfaces and high affinities of this protein–protein interaction …”

Section: Introductionmentioning

confidence: 99%

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

et al. 2023

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Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets. In this work, we virtually screened a library of marketed drugs and identified zafirlukast as a new CRM1 inhibitor. Biochemical and structural analysis revealed that zafirlukast was a noncovalent CRM1 inhibitor that bound to four subpockets in the nuclear-export-signal (NES) groove. Methylation of the sulfonamide group rendered zafirlukast completely inactive against CRM1. Zafirlukast inhibited the growth of a variety of cancer cells and worked synergistically with the drug doxorubicin. Taken together, these works laid a solid foundation for reshaping zafirlukast as a valuable lead compound for further design of noncovalent, specific, and potent CRM1 inhibitors toward the treatment of various cancers.

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“…Although using a high concentration of MEL in myeloablative therapy in preparation for hematopoietic cell transplantation remains the standard of care for MM patients [4], relapses are still common, with periods of remission becoming shorter and shorter. Therefore, new approaches are urgently needed for patients who are resistant to existing therapies [12].…”

Section: Introductionmentioning

confidence: 99%

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells

Poczta

Krzeczyński²,

Йонов³

et al. 2022

IJMS

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Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan.

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Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

Cited by 7 publications

References 43 publications

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells

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