Mechanism of action of N-phenyl-N′-(2-chloroethyl)ureas in the colchicine-binding site at the interface between α- and β-tubulin

: Colchicine binding site in microtubules is among the most flourishing target for anticancer remedy. Microtubule inhibitor drugs, including combrestatin phosphate, paclitaxel and Vinca alkaloids, were formerly considered to exert their activity primarily by increasing or decreasing the cellular microtubule mass. This review describes the microtubular assembly along with the combrestatin derivatives as microtubules inhibitors, the structures of compounds known to interact with colchicines binding site, and their possible mechanism of action. Additionally, we have also discussed the utility of other heterocyclic rings and their combrestatin derivatives in treating cancer. Colchicines binding site represents a stimulating new molecular target in the design of combrestatin drugs.

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Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on β-tubulin

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(00)00068-7 ◽

2000 ◽

Vol 8 (6) ◽

pp. 1433-1441 ◽

Cited By ~ 25

Author(s):

Milton L Brown ◽

Jayson M Rieger ◽

Timothy L Macdonald

Keyword(s):

Binding Site ◽

Field Analysis ◽

Molecular Field ◽

Tubulin Polymerization ◽

Comparative Molecular Field Analysis ◽

Molecular Field Analysis ◽

Colchicine Binding Site ◽

Β Tubulin

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Butterfly Structure: A Privileged Scaffold Targeting Tubulin-Colchicine Binding Site

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620999200616132924 ◽

2020 ◽

Vol 20 (17) ◽

pp. 1505-1508

Author(s):

Yingge Wang ◽

Yongfang Yao ◽

Hai-Liang Zhu ◽

Yongtao Duan

Keyword(s):

Binding Site ◽

Heterocyclic Compounds ◽

Main Body ◽

Α Subunit ◽

Tubulin Inhibitors ◽

Colchicine Binding Site ◽

Privileged Scaffold ◽

Future Direction ◽

Novel Scaffold ◽

Β Tubulin

: Butterfly-shaped structure, as a novel scaffold with an attractive and certain shape, has been widely used in new drug discovery. Tubulin, composing of α- and β-tubulin heterodimers, plays a key role in mitosis and cell division which are regarded as an excellent target for cancer therapy. Currently, a series of butterfly shape diaryl heterocyclic compounds have been reported with strong potential against the tubulin-colchicine binding site. It is with one ring buried in the β subunit, another ring interacts with the α subunit and the main body is located in the flat pocket. Here, we firstly introduce the concept of butterfly structure for the tubulin inhibitors, focusing on the latest advancements in a variety of molecules bearing butterfly structure, and then highlight the challenges and future direction of butterfly structure- based tubulin-colchicine binding site inhibitors.

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Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1's low clinical toxicity

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010732 ◽

2019 ◽

Vol 294 (48) ◽

pp. 18099-18108 ◽

Cited By ~ 2

Author(s):

Lu Niu ◽

Jianhong Yang ◽

Wei Yan ◽

Yamei Yu ◽

Yunhua Zheng ◽

...

Keyword(s):

Binding Site ◽

Anticancer Drug ◽

Reversible Binding ◽

Colchicine Binding Site ◽

Clinical Toxicity ◽

Β Tubulin

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Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180727114216 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1194-1201 ◽

Cited By ~ 3

Author(s):

Farhad Saravani ◽

Ebrahim Saeedian Moghadam ◽

Hafezeh Salehabadi ◽

Seyednasser Ostad ◽

Morteza Pirali Hamedani ◽

...

Keyword(s):

Molecular Modeling ◽

Cytotoxic Activity ◽

Binding Site ◽

Cell Line ◽

Cell Lines ◽

Tubulin Polymerization ◽

Adenocarcinoma Cell Line ◽

Adenocarcinoma Cell ◽

Colchicine Binding Site ◽

Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

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Synthesis and tubulin interaction of thiocolchicines containing an isothiocyanato group. Synthesis of C(2)-deuterated and C(2)-14C-labeled 7-isothiocyanatodeacetamidothiocolchicine

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19912306 ◽

1991 ◽

Vol 56 (11) ◽

pp. 2306-2312 ◽

Cited By ~ 3

Author(s):

Anjum Muzaffar ◽

Ernest Hamel ◽

Rouli Bai ◽

Arnold Brossi

Keyword(s):

Binding Site ◽

Covalent Bond ◽

Tubulin Polymerization ◽

Low Concentration ◽

Covalent Interaction ◽

Isotope Label ◽

Colchicine Binding Site

Synthesis of isothiocyanato substituted thiocolchicines XI - XIV is described. Introduction of an isotope label is demonstrated with the deuterated isothiocyanate XII and the 14C-labeled analog XIII. These isothiocyanates inhibit tubulin polymerization at low concentration. In addition, the 14C-labeled XIII forms covalent bond(s) with tubulin. Unfortunately, the covalent reaction while rapid, is not inhibited by preincubation of tubulin with colchicine. The covalent interaction of XIII with tubulin thus appears to be nonspecific, limiting its use as a marker of the colchicine binding site on tubulin.

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