Bicyclic Basic Merbarone Analogues as Antiproliferative Agents.
Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure-activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3-6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure-activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.
['Spallarossa|Andrea|A|', 'Lusardi|Matteo|M|', 'Caneva|Chiara|C|', 'Profumo|Aldo|A|', 'Rosano|Camillo|C|0000-0003-2949-9215', 'Ponassi|Marco|M|']
D000970:Antineoplastic Agents D049109:Cell Proliferation D004250:DNA Topoisomerases, Type II D005260:Female D006801:Humans D061986:MCF-7 Cells D062105:Molecular Docking Simulation D009363:Neoplasm Proteins D009369:Neoplasms D000075223:Poly-ADP-Ribose Binding Proteins D013858:Thiobarbiturates D059005:Topoisomerase II Inhibitors
antiproliferative agents pyrimido-pyrimidine derivatives docking simulation structure activity relationships (SAR) study