Synthesis, Antitubulin and Antimitotic Activity, and Cytotoxicity of Analogs of 2-Methoxyestradiol, an Endogenous Mammalian Metabolite of Estradiol That Inhibits Tubulin Polymerization by Binding to the Colchicine Binding Site

1995 ◽  
Vol 38 (12) ◽  
pp. 2041-2049 ◽  
Author(s):  
Mark Cushman ◽  
Hu-Ming He ◽  
John A. Katzenellenbogen ◽  
Chii M. Lin ◽  
Ernest Hamel
Keyword(s):  
Binding Site ◽  
Tubulin Polymerization ◽  
Antimitotic Activity ◽  
Colchicine Binding Site

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

2019 ◽  
Vol 16 (11) ◽  
pp. 1194-1201 ◽  
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.

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

1991 ◽  
Vol 56 (11) ◽  
pp. 2306-2312 ◽  
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.

scholarly journals Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site

RSC Advances ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 2791-2811 ◽  
Author(s):  
Abeer M. El-Naggar ◽  
Ibrahim H. Eissa ◽  
Amany Belal ◽  
Amira A. El-Sayed
Keyword(s):  
Molecular Modeling ◽  
Cancer Treatment ◽  
Binding Site ◽  
Therapeutic Approach ◽  
Tubulin Polymerization ◽  
Colchicine Binding Site ◽  
Tubulin Polymerization Inhibitors

In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment.

The Structure of MT189-Tubulin Complex Provides Insights into Drug Design

2019 ◽  
Vol 16 (9) ◽  
pp. 1069-1073
Author(s):  
Zhongping Li ◽  
Lingling Ma ◽  
Chengyong Wu ◽  
Tao Meng ◽  
Lanping Ma ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Binding Site ◽  
Complex Structure ◽  
Microtubule Assembly ◽  
Tubulin Polymerization ◽  
Colchicine Binding Site ◽  
Structure Activity ◽  
Tubulin Tyrosine Ligase ◽  
Tubulin Polymerization Inhibitors

Background: Drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Microtubules are composed of αβ-tubulin heterodimers, and the colchicine binding site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However, these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction approach to obtain a new derivative MT189, which showed in vivo anticancer activity. Methods: We crystallized a protein complex including two tubulins, one stathmin-like domain of RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the diffraction data and determined the tubulin-MT189 structure to 2.8 Å. Results: Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous results of the structure-activity-relationship studies. Conclusion: The tubulin-MT189 complex structure reveals the interactions between this agent and tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.

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