Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

Zhu, Huajian; Li, Wenlong; Wen, Shuai; Liu, Yang; Yang, Limei; Tan, Yuchen; Zheng, Tiandong; Yao, Hong; Xu, Jinyi; Zhu, Zheying; Yang, Dong‐Hua; Chen, Zhe‐Sheng; Xu, Shengtao

doi:10.1016/j.ejmech.2021.113316

Cited by 17 publications

(13 citation statements)

References 65 publications

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“…Microtubules are directly involved in the division process, forming the division spindle and thus, are involved in tumor pathogenesis [41,42]. Reducing the formation of microtubules significantly improves the prognosis in cancer [43,44]. In addition to inhibiting polymerization, a decrease in the content of tubulin monomers can lead to a decrease in microtubule formation.…”

Section: Discussionmentioning

confidence: 99%

Organization of the Cytoskeleton in Ectopic Foci of the Endometrium with Rare Localization

Toniyan

Povorova²,

Gorbacheva³

et al. 2021

Biomedicines

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(1) Background: Endometriosis is a common pathology of the female reproductive system, often accompanied by pain and decreased fertility. However, its pathogenesis has not been sufficiently studied regarding the role of the cytoskeleton. In this study, we describe two clinical cases involving rare localization of extragenital endometriosis (umbilicus) and compare them with genital endometriosis of different localization (ovaries and uterus), as well as eutopic endometrium obtained with separate diagnostic curettage without confirmed pathology. (2) Methods: The relative content of actin and tubulin cytoskeleton proteins was determined by Western blotting, and the expression of genes encoding these proteins was determined by RT-PCR in the obtained intraoperative biopsies. The content of 5hmC was estimated by dot blot experiments, and the methylase/demethylase and acetylase/deacetylase contents were determined. (3) Results: The obtained results indicate that the content of the actin-binding protein alpha-actinin1 significantly increased (p < 0.05) in the groups with endometriosis, and this increase was most pronounced in patients with umbilical endometriosis. In addition, both the mRNA content of the ACTN1 gene and 5hmC content increased. It can be assumed that the increase in 5hmC is associated with a decrease in the TET3 demethylase content. Moreover, in the groups with extragenital endometriosis, alpha- and beta-tubulin content was decreased (p < 0.05) compared to the control levels. (4) Conclusions: In analyzing the results, further distance of ectopic endometrial foci from the eutopic localization may be associated with an increase in the content of alpha-actinin1, probably due to an increase in the expression of its gene and an increase in migration potential. In this case, a favorable prognosis can be explained by a decrease in tubulin content and, consequently, a decrease in the rate of cell division.

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Section: Discussionmentioning

confidence: 99%

Organization of the Cytoskeleton in Ectopic Foci of the Endometrium with Rare Localization

Toniyan

Povorova²,

Gorbacheva³

et al. 2021

Biomedicines

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“…The IC 50 value of TH-6 in inhibiting tubulin polymerization was further determined as shown in Figure B and Table . The results showed that TH-6 potently inhibited tubulin polymerization with an IC 50 value of 4.06 μM, which was slightly less potent than that of CA-4 (IC 50 = 1.97 μM) and TH-0 (IC 50 = 3.03 μM) . Besides, TH-6 competed with [ 3 H]-colchicine in binding to tubulin.…”

Section: Resultsmentioning

confidence: 96%

“…The chemical synthesis of N -benzylbenzamide intermediates 7a – g , 10a , and 10b was performed according to our previously reported procedures . In general, different substituted benzylamines 3a – h were obtained by reductive amination reactions with commercially available benzaldehydes.…”

Section: Resultsmentioning

confidence: 99%

“…In the dual targeting strategy, the VDAs are expected to cause tumor vascular collapse resulting in tumor core necrosis, and HDAC inhibition is expected to inhibit neovascularization at the periphery and prevent tumor regrowth, which may act as a complementary for VDAs. In the previous studies on VDAs, we reported a series of new VDAs targeting the colchicine binding site of tubulin. − Among them, the representative compound TH-0 (Figure ) produced a significant inhibition of tubulin polymerization and exhibited good performance in antitumor assays . To demonstrate the validity of the dual targeting strategy, while considering the structural simplicity and satisfactory physicochemical properties, TH-0 was selected as the lead compound to design a series of novel multifunctional agents.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects

Zhu

Tan

et al. 2022

J. Med. Chem.

Self Cite

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Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor TH-0 as the lead compound. Among them, compound TH-6 exhibited the most potent antiproliferative activity (IC50 = 18–30 nM) against a panel of cancer cell lines. As expected, TH-6 inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further in vivo antitumor assay displayed that TH-6 effectively inhibited tumor growth with no apparent toxicity. More importantly, TH-6 disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, TH-6 deserves to be further investigated for the new approach to clinical cancer therapy.

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“…Some recent studies show that chalcone-amide derivatives have strong inhibitory effects against tubulin polymerization and thus show anti-tumor effects [ 31 ]. However, some well-known tubulin polymerization inhibitors such as shikonin also have recently been identified as interesting SARS-CoV-2 inhibitors [ [32] , [33] , [34] ].…”

Section: Antiviral Activity Of Chalcone-amide-based Structuresmentioning

confidence: 99%

Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors

Valipour

2022

European Journal of Medicinal Chemistry

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Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

Cited by 17 publications

References 65 publications

Organization of the Cytoskeleton in Ectopic Foci of the Endometrium with Rare Localization

Organization of the Cytoskeleton in Ectopic Foci of the Endometrium with Rare Localization

Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects

Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors

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