Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway

Song, Jian; Wang, Shenghui; Song, Chun-Hong; Zhang, Weixin; Zhu, Jiajun; Tian, Xinyi; Fu, Xiang-Jing; Xu, Yan; Jin, Cheng‐Yun; Zhang, Sai‐Yang

doi:10.1016/j.ejmech.2022.114583

Cited by 25 publications

(7 citation statements)

References 50 publications

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“…In the last decade, many trimethoxyphenyl-based structures were designed, developed, and synthesized as promising anticancer agents that could target tubulin protein, and some of these compounds reached clinical trials, or were approved by the FDA for cancer treatment [ 123 , 124 , 125 ]. Starting with CA-4P ( Figure 1 ), which was approved for thyroid cancer, many other trimethoxyphenyl-based compounds entered the clinical trials for specific cancer types including St.56 (BNC-105p; Figure 11 ), which was found to have considerable potency and an inhibitory effect against the growth of different kinds of cancer cell lines with a broader therapeutic index than CA-4P in vivo.…”

Section: Trimethoxy Phenyl Analogsmentioning

confidence: 99%

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Hawash

2022

Biomolecules

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Cancer accounts for numerous deaths each year, and it is one of the most common causes of death worldwide, despite many breakthroughs in the discovery of novel anticancer candidates. Each new year the FDA approves the use of new drugs for cancer treatments. In the last years, the biological targets of anticancer agents have started to be clearer and one of these main targets is tubulin protein; this protein plays an essential role in cell division, as well as in intracellular transportation. The inhibition of microtubule formation by targeting tubulin protein induces cell death by apoptosis. In the last years, numerous novel structures were designed and synthesized to target tubulin, and this can be achieved by inhibiting the polymerization or depolymerization of the microtubules. In this review article, recent novel compounds that have antiproliferation activities against a panel of cancer cell lines that target tubulin are explored in detail. This review article emphasizes the recent developments of tubulin inhibitors, with insights into their antiproliferative and anti-tubulin activities. A full literature review shows that tubulin inhibitors are associated with properties in the inhibition of cancer cell line viability, inducing apoptosis, and good binding interaction with the colchicine binding site of tubulin. Furthermore, some drugs, such as cabazitaxel and fosbretabulin, have been approved by FDA in the last three years as tubulin inhibitors. The design and development of efficient tubulin inhibitors is progressively becoming a credible solution in treating many species of cancers.

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Section: Trimethoxy Phenyl Analogsmentioning

confidence: 99%

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Hawash

2022

Biomolecules

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“…For example, compound 1 18 , benzamide derivative 2 19 , and N -benzylbenzamide derivative 3 20 could potently inhibit the polymerisation of tubulin and exhibit significant antiproliferative activities on several cancer cell lines. Recently, we also reported N -benzylarylamide 4 as a tubulin polymerisation inhibitor with potent antiproliferative activities in two-digit nanomolar IC 50 values 21 .…”

Section: Introductionmentioning

confidence: 91%

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity

Shi,

Jiao,

Zhang

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f ( MY-1121 ) exhibited low nanomolar IC 50 values ranging from 0.089 to 0.238 μM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC 50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f ( MY-1121 ) could bind to the colchicine binding site of β-tubulin and directly act on β-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f ( MY-1121 ) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f ( MY-1121 ) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.

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“…Compound 2a ′s increased action against HepG2 cancer cell lines may be related to its capacity to selectively inhibit COX enzymes, which have been demonstrated to be overexpressed in many cancer cell types, including HepG2 cells. Over the past decade, numerous structures based on trimethoxyphenyl have been designed, developed, and synthesized as potential anticancer agents with the ability to specifically target the tubulin protein, , and some of these compounds reached clinical trials or were approved by FDA for cancer treatment. − The trimethoxyphenyl group, which is one of the main parts of compound 2a , was present in many potent anticancer agents like combretastatin A-4 (CA-4); this moiety in CA-4 is believed to contribute to its biological activity by enhancing the compound′s lipophilicity and membrane permeability. In addition, the three methoxy groups can form hydrogen bonds with the target protein, potentially increasing the compound′s binding affinity and selectivity .…”

Section: Resultsmentioning

confidence: 99%

New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies

Hawash,

Jaradat,

Sabobeh

et al. 2023

ACS Omega

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The goal of this work was to create and test a new series of thiazole carboxamide derivatives for their cyclooxygenase (COX) suppressor and anticancer effects. The compounds were characterized using 1H, 13C NMR, and HRMS spectrum analysis, and their selectivity toward COX-1 and COX-2 was assessed using an in vitro COX inhibition assay kit. Cytotoxicity was assessed using an MTS assay against a panel of cancer and normal cell lines. The docking studies were aided by the Prime MM-GBSA method for estimating binding affinities. The density functional theory (DFT) analysis was performed to assess compound chemical reactivity, which was calculated by computing the border orbital energy of both HOMO and LUMO orbitals, as well as the HOMO−LUMO energy gap. For ADME-T analysis, the QiKProp module was employed. Furthermore, using human X-ray crystal structures, molecular docking studies were carried out to discover the probable binding patterns of these drugs within both COX-1 and COX-2 isozymes. The results demonstrated that the most effective compound against the COX-1 enzyme was 2b with an IC 50 of 0.239 μM. It also showed potent activity against COX-2 with an IC 50 value of 0.191 μM and a selectivity ratio of 1.251. The highest selectivity ratio was 2.766 for compound 2a against COX-2 with an IC 50 dose of 0.958 μM relating to the celecoxib ratio of 23.8 and its IC 50 against COX-2 of 0.002 μM. Compound 2j also showed good selectivity toward COX-2 (1.507) with an IC 50 value of 0.957 μM. All compounds showed negligible cytotoxic activity against the evaluated normal cell lines, and the IC 50 values were more than 300 μM, except for compound 2b, whose IC 50 values were 203.71 ± 1.89 and 116.96 ± 2.05 μM against LX-2 and Hek293t cell lines, respectively. Moreover, compound 2b showed moderate anticancer activity against COLO205 and B16F1 cancer cell lines with IC 50 values of 30.79 and 74.15 μM, respectively.

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Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway

Cited by 25 publications

References 50 publications

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity

New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies

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