Bicyclic Basic Merbarone Analogues as Antiproliferative Agents

Andrea Spallarossa, Matteo Lusardi, Chiara Caneva, Aldo Profumo, Camillo Rosano, Marco Ponassi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)557
JournalMolecules (Basel, Switzerland)
Issue number3
Publication statusPublished - Jan 21 2021


  • antiproliferative agents
  • docking simulation
  • pyrimido-pyrimidine derivatives
  • structure activity relationships (SAR) study

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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