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Synthesis of New N 1 -Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin.
- Source :
-
Biological & pharmaceutical bulletin [Biol Pharm Bull] 2016; Vol. 39 (10), pp. 1611-1622. - Publication Year :
- 2016
-
Abstract
- A series of pyrazoline derivatives 2a-e, 3a-e and 4a-e structurally related to combretastatin A4 (CA-4) were synthesized and characterized by spectroscopic means and elemental analyses. In these compounds, the cis double bond of CA-4 was replaced with the pyrazoline ring aiming to enhance the cytotoxic effects displayed by CA-4 and to prevent the cis/trans isomerization that is associated with inactivation of CA-4. The cytotoxic activity of all new compounds was investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by the most active compounds 3d, 4a and e was evaluated. The cytotoxicity of 4e was correlated with induction of apoptosis and caspase-3 activation in vitro thus indicating the apoptotic pathway of anticancer effect of these compounds. Furthermore, in vivo evaluation of the synthesized compounds was carried out against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. Compounds 2c, 3a and e showed significant reduction in tumor weight, and about 2-4 fold increase in caspase-3 expression.
- Subjects :
- Animals
Apoptosis drug effects
Binding Sites
Carcinoma, Ehrlich Tumor drug therapy
Carcinoma, Ehrlich Tumor pathology
Caspase 3 metabolism
Colchicine chemistry
Drug Screening Assays, Antitumor
Female
HCT116 Cells
Humans
MCF-7 Cells
Mice
Models, Molecular
Polymerization drug effects
Tumor Burden drug effects
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Colchicine metabolism
Pyrazoles chemistry
Pyrazoles pharmacology
Pyrazoles therapeutic use
Tubulin metabolism
Tubulin Modulators chemistry
Tubulin Modulators pharmacology
Tubulin Modulators therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1347-5215
- Volume :
- 39
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biological & pharmaceutical bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 27725438
- Full Text :
- https://doi.org/10.1248/bpb.b16-00277