Synthesis, antiproliferative, anti-tubulin activity, and docking study of new 1,2,4-triazoles as potential combretastatin analogues

被引：57

作者：

Mustafa, Muhamad ^{[1
,2
]}

Abdelhamid, Dalia ^{[1
]}

Abdelhafez, ElShimaa M. N. ^{[1
]}

Ibrahim, Mahmoud A. A. ^{[3
]}

Gamal-Eldeen, Amira M. ^{[4
]}

Aly, Omar M. ^{[1
]}

机构：

[1] Minia Univ, Med Chem Dept, Fac Pharm, Al Minya 61519, Egypt

[2] Deraya Univ, Pharmaceut Chem Dept, Fac Pharm, Al Minya, Egypt

[3] Minia Univ, Chem Dept, Computat Chem Lab, Fac Sci, Al Minya, Egypt

[4] Natl Res Ctr, Canc Biol Lab, Ctr Excellence Adv Sci, Cairo, Egypt

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 141卷

关键词：

Combretastatin A4; Antiproliferation; 1,2,4-Triazole; Tubulin; Molecular docking; TUBULIN POLYMERIZATION; ANTINEOPLASTIC AGENTS; ANTIMITOTIC AGENTS; A4; PHOSPHATE; A-4; ANALOGS; IN-VITRO; COLCHICINE; INHIBITION; SCHEDULE; ACCURACY;

D O I：

10.1016/j.ejmech.2017.09.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Combretastatin A4 (CA4) is a natural product characterized by a powerful inhibition of tubulin polymerization and a potential anticancer activity. However, therapeutic application of CA4 is substantially hindered due to geometric isomerization. In the current study, new cis-restricted Combretastatin A4 analogues containing 1,2,4-triazle in place of the olefinic bond were designed and synthesized. The synthesized compounds were evaluated for their in vitro antiproliferative activity in human hepatocellular carcinoma HepG2 and leukemia HL-60 cell lines using MTT assay. Moreover, fourteen compounds were selected and tested for their antiproliferative activity by the National Cancer Institute. Some of the tested compounds showed moderate activity against sixty cell lines. In vitro tubulin polymerization inhibitory activity was evaluated on HepG2 cells. The assay revealed that 6a showed a remarkable tubulin inhibition compared to CA4. Moreover, the cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 6c in HepG2 cells. Molecular docking combined with AMBER-based molecular mechanical minimization results showed several noncovalent interactions, including van der Waals and hydrogen-bonding with several amino acids within the colchicine binding site of beta-subunit of tubulin. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：293 / 305

页数：13

共 37 条

[1] In vitro metabolism study of combretastatin A-4 in rat and human liver Microsomes [J].

Aprile, Silvio ;

Del Grosso, Erika ;

Tron, Gian Cesare ;

Grosa, Giorgio .

DRUG METABOLISM AND DISPOSITION, 2007, 35 (12) :2252-2261

[2] Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability [J].

Ashraf, Md. ;

Shaik, Thokhir B. ;

Malik, M. Shaheer ;

Syed, Riyaz ;

Mallipeddi, Prema L. ;

Vardhan, M. V. P. S. Vishnu ;

Kamal, Ahmed .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (18) :4527-4535

[3] A-Ring Dihalogenation Increases the Cellular Activity of Combretastatin-Templated Tetrazoles [J].

Beale, Thomas M. ;

Allwood, Daniel M. ;

Bender, Andreas ;

Bond, Peter J. ;

Brenton, James D. ;

Charnock-Jones, D. Stephen ;

Ley, Steven V. ;

Myers, Rebecca M. ;

Shearman, James W. ;

Temple, Jill ;

Unger, Jessica ;

Watts, Ciorsdaidh A. ;

Xian, Jian .

ACS MEDICINAL CHEMISTRY LETTERS, 2012, 3 (03) :177-181

[4] In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4 [J].

Blanch, Nuria Mur ;

Chabot, Guy G. ;

Quentin, Lionel ;

Scherman, Daniel ;

Bourg, Stephane ;

Dauzonne, Daniel .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 54 :22-32

[5] Fluorine in medicinal chemistry [J].

Böhm, HJ ;

Banner, D ;

Bendels, S ;

Kansy, M ;

Kuhn, B ;

Müller, K ;

Obst-Sander, U ;

Stahl, M .

CHEMBIOCHEM, 2004, 5 (05) :637-643

[6] Design and synthesis of 3,5-disubstituted boron-containing 1,2,4-oxadiazoles as potential combretastatin A-4 (CA-4) analogs [J].

Das, Bhaskar C. ;

Tang, Xiang-Ying ;

Rogler, Patrick ;

Evans, Todd .

TETRAHEDRON LETTERS, 2012, 53 (31) :3947-3950

[7]

Dowlati A, 2002, CANCER RES, V62, P3408

[8] Computational protein-ligand docking and virtual drug screening with the AutoDock suite [J].

Forli, Stefano ;

Huey, Ruth ;

Pique, Michael E. ;

Sanner, Michel F. ;

Goodsell, David S. ;

Olson, Arthur J. .

NATURE PROTOCOLS, 2016, 11 (05) :905-919

[9]

Frisch M.J., 2016, Gaussian, V16

[10] Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit? [J].

Gaukroger, K ;

Hadfield, JA ;

Lawrence, NJ ;

Nolan, S ;

McGown, AT .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2003, 1 (17) :3033-3037

← 1 2 3 4 →