Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

Cai, Mao; Hu, Jie; Tian, Jilai; Huang, Yan; Zheng, Chenguo; Hu, Wanle

doi:10.1016/j.cclet.2015.03.015

Cited by 26 publications

(3 citation statements)

References 27 publications

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“…In the synthesis of amidoximes both mono-12, 14, 16 and 19 and their bis-amidoxime analogues 13, 15, 17 and 20 were obtained (Scheme 2). Nitrile derivatives 3a-3i were subsequently used as precursors for the synthesis of amidine-(4-11) and amidoxime-substituted (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) heterocycles (Schemes 2 and 3). Amidines were synthesized according to the Pinner method [39].…”

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Thus, indole scaffold, found to be widely distributed in natural products and bioactive molecules, was linked to 1,2,3-triazole and yielded new hybrids with potent anticancer activity [11]. For example, in order to obtain histone deacetylases (HDAC) inhibitors with lower side effects, indole-derived N-hydroxyarylamide I with the triazole ring as a linker was obtained and showed the positive effects of 5-methoxy group and the one-carbon-bridge between triazole and the indole ring on antiproliferative activity (Figure 1) [16]. Bis-1,2,3-triazole-indole hybrids were further synthesized and evaluated for their in vitro and in vivo anticancer activity, among which compound II caused DNA cleavage and displayed significant activity against breast cancer (MCF-7), cervical carcinoma (HeLa) and embryonic kidney (HEK 293) cell lines, as compared with cisplatin [17].…”

Section: Introductionmentioning

confidence: 99%

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Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding

et al. 2021

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The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4–11 and amidoxime 12–22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding

et al. 2021

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N‐Substituted 1,2,3‐Triazolyl‐Appended Indole‐Chalcone Hybrids as Potential DNA Intercalators Endowed with Antioxidant and Anticancer Properties

et al. 2018

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Despite the fact that many small molecule inhibitors have been approved for cancer therapy, we still have a mighty long road to traverse in the field of targeted therapy against cancer. In order to overcome the challenges of chemo resistance and selectivity, we designed and synthesized 1,2,3-triazole appended indole-chalcone derivatives (4 a-q) and evaluated their antioxidant, anticancer and DNA binding properties. Among all the analogs, compounds with o-chloro (4b), o-fluoro (4h) and p-fluoro (4j) substitution exhibited potent antioxidant activity and the potency of 4 b was comparable to the standard ascorbic acid. In a cell based screen, compound 4 b inhibited the growth of human cervical cancer (SiHa) and colorectal epithelial carcinoma (SW620) cancer cell lines with an IC 50 values of 67.99 and 48.96 mg mL À1 , respectively without showing any significant cytotoxicity in human embryonic kidney cells (HEK293) at the similar concentration. To gain insight into the DNA-binding ability, various spectroscopic techniques such as UV-visible, fluorescence, circular dichroism, viscosity and cyclic voltametric studies were performed. These studies exposed that compounds 4 b, 4 h and 4 j act via noncovalent intercalative mode of binding to DNA causing their antiproliferative activity, supported by molecular docking studies. Our study revealed the non-toxic nature and potent activity of compound 4 b makes it a suitable candidate for further optimization and pharmacological studies.

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Futuristic Approaches Towards Designing of Isozyme-Selective Histone Deacetylase Inhibitors Against Zinc-Dependent Histone Deacetylases

Ganai¹

2020

Histone Deacetylase Inhibitors in Combinatorial Anticancer Therapy

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Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

Cited by 26 publications

References 27 publications

Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding

Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding

N‐Substituted 1,2,3‐Triazolyl‐Appended Indole‐Chalcone Hybrids as Potential DNA Intercalators Endowed with Antioxidant and Anticancer Properties

Futuristic Approaches Towards Designing of Isozyme-Selective Histone Deacetylase Inhibitors Against Zinc-Dependent Histone Deacetylases

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