title: Synthesis of New N1-Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin.
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.
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University.
authors.forename: Salwa
authors.initials: S
authors.lastname: Elmeligie
authors.forename: Nadia Abdalla
authors.initials: NA
authors.lastname: Khalil
authors.forename: Eman Mohamed
authors.initials: EM
authors.lastname: Ahmed
authors.forename: Soha Hussein
authors.initials: SH
authors.lastname: Emam
authors.forename: Sawsan Abo-Bakr
authors.initials: SA
authors.lastname: Zaitone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D003078:Colchicine / Q000737:chemistry / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008958:Models, Molecular; D058105:Polymerization / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D014404:Tubulin; D050257:Tubulin Modulators; D053148:Caspase 3; D003078:Colchicine