Design, Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

Hu, Meng-Jin; Zhang, Bei; Yang, Hai‐Kui; Liu, Yang; Chen, Yurong; Ma, Tianzhu; Lu, Lanlan; Wang, You; Zhao, Pei‐Liang

doi:10.1111/cbdd.12616

Cited by 40 publications

(6 citation statements)

References 28 publications

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“…Agents containing the indole moiety exhibited various biological activities including enzyme inhibition [14,15], tubulin polymerization inhibition [16] and anticancer activity in human HCT116 colon and HepG2 liver carcinoma cells [17]. In particular, pyrimido[5,4- b ]indoles were reported to act as the selective α 1 -AR subtypes antagonists [18,19].…”

Section: Introductionmentioning

confidence: 99%

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists

et al. 2015

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Indole-arylpiperazine derivatives have exhibited good selectivity for the α 1A -adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α 1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H¨¨¨π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α 1A -adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α 1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α 1A antagonists with high selectivity.

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Section: Introductionmentioning

confidence: 99%

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists

et al. 2015

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“…A new tool for searching new potent anticancer agents is docking studies. Some years ago it became possible to study new compounds of possible biological activity by new technical methods like molecular modeling and docking studies [37,[86][87][88][89][90].…”

Section: Docking Studiesmentioning

confidence: 99%

Cytotoxic Colchicine Alkaloids: From Plants to Drugs

Kurek¹

2018

Cytotoxicity

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Plants produce and store many organic compounds like amino acids, proteins, carbohydrates, fats, and alkaloids, which are usually treated as secondary metabolites. Many alkaloids are biologically active for humans. For thousand years, extracts from plants containing alkaloids had medicinal use as drugs and they owe their powerful effects thanks to presence of alkaloids. Alkaloids have anti-inflammatory, antibacterial, analgesic, local anesthetic, hypnotic, psychotropic, antimitotic, and antitumor activity. Nowadays, alkaloids from plants are still of great interest to organic chemists, pharmacologists, biologists, biochemists, and pharmacists. Plants of Liliaceae family contain colchicine as the main alkaloid, which has cytotoxic activity. Colchicine has limited pharmacological application because of its toxicity, but many derivatives have been synthesized and their cytotoxic activity and tubulin-binding properties have been tested. Many of the synthetic derivatives showed good cytotoxic activity.

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“…As shown in the SAR analysis, the pyridine D-ring moiety of IIP provided some benefits toward metabolic stability in HLM. Hu et al synthesized novel hybrids of an indole-pyrimidine containing a piperazine moiety [74]. The majority of these compounds possessed significant cytotoxicity.…”

Section: Compounds With An Indole Nucleusmentioning

confidence: 99%

Novel Natural Product- and Privileged Scaffold-Based Tubulin Inhibitors Targeting the Colchicine Binding Site

et al. 2016

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Tubulin inhibitors are effective anticancer agents, however, there are many limitations to the use of available tubulin inhibitors in the clinic, such as multidrug resistance, severe side-effects, and generally poor bioavailability. Thus, there is a constant need to search for novel tubulin inhibitors that can overcome these limitations. Natural product and privileged structures targeting tubulin have promoted the discovery and optimization of tubulin inhibitors. This review will focus on novel tubulin inhibitors derived from natural products and privileged structures targeting the colchicine binding site on tubulin.

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Design, Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

Cited by 40 publications

References 28 publications

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists

Cytotoxic Colchicine Alkaloids: From Plants to Drugs

Novel Natural Product- and Privileged Scaffold-Based Tubulin Inhibitors Targeting the Colchicine Binding Site

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