ABSTRACT
Title
Structure Activity Relation of rigid analogues of Combretastatin A4, a tubulin depolymerizing agent with antutumoral activity
Authors
A. Caldarelli, S. Theeramunkong, A. Massarotti, D. Caprioglio, A. Teruggi, Tr. Pirali, PL. Canonico, G.C. Tron and AA. Genazzani
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
Università degli Studi del Piemonte Orientale “A. Avogadro”, Via Bovio 6, 28100
Novara, Italy.
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
Università degli Studi del Piemonte Orientale “A. Avogadro”, Via Bovio 6, 28100
Novara, Italy.
Abstract
Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent, able to inhibit tumour growth and with anti-angiogenic effects (Tron et al, 2006). Although it is in clinical trials, the search for novel analogues that may display better/different features is still ongoing. We present the synthesis of novel constrained analogues of CA-4 obtained in only two synthetic steps exploiting a regioselective Suzuki coupling of dihalogenated heteroaromatic and alyclic compounds (Handy et al. 2006). We generated a library of 32 molecules, using different pentatomic rings (furan, thiophene and cyclopentan) to replace the double bound bridge of CA-4.
In neuroblastoma SHSY-5Y and cervical cancer HeLa cells we evaluated cytotoxycity through an MTT assay, DNA content, cell cycle progression. The polymerization state of tubulin was evaluated both in immunofluorescence and in Western blotting.
The rigidified analogues displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to CA-4. The most potent chemical presented a similar structure to original CA-4 with a furan replacing the double bound. Furthermore, the different rings appeared to elicit some selectivity for cell type. Molecular docking investigations appeared to correlate with the activity found in the cytotoxicity assays. This synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins.
Tron et al (2006) J Med Chem 49:5372-6
Handy et al. (2006) Chem Comm. 299-301
In neuroblastoma SHSY-5Y and cervical cancer HeLa cells we evaluated cytotoxycity through an MTT assay, DNA content, cell cycle progression. The polymerization state of tubulin was evaluated both in immunofluorescence and in Western blotting.
The rigidified analogues displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to CA-4. The most potent chemical presented a similar structure to original CA-4 with a furan replacing the double bound. Furthermore, the different rings appeared to elicit some selectivity for cell type. Molecular docking investigations appeared to correlate with the activity found in the cytotoxicity assays. This synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins.
Tron et al (2006) J Med Chem 49:5372-6
Handy et al. (2006) Chem Comm. 299-301