Bicyclic Basic Merbarone Analogues as Antiproliferative Agents
| Autor: | Aldo Profumo, Matteo Lusardi, Chiara Caneva, Marco Ponassi, Andrea Spallarossa, Camillo Rosano |
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| Rok vydání: | 2021 |
| Předmět: |
Antiproliferative agents
Docking simulation Pyrimido-pyrimidine derivatives Structure activity relationships (SAR) study Stereochemistry Substituent Pharmaceutical Science 01 natural sciences Article Analytical Chemistry lcsh:QD241-441 antiproliferative agents 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry docking simulation Drug Discovery Side chain Moiety Physical and Theoretical Chemistry 030304 developmental biology chemistry.chemical_classification 0303 health sciences Bicyclic molecule biology Topoisomerase Organic Chemistry Ligand (biochemistry) 0104 chemical sciences structure activity relationships (SAR) study 010404 medicinal & biomolecular chemistry Enzyme chemistry Chemistry (miscellaneous) Docking (molecular) pyrimido-pyrimidine derivatives biology.protein Molecular Medicine |
| Zdroj: | Molecules Volume 26 Issue 3 Molecules, Vol 26, Iss 557, p 557 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26030557 |
| Popis: | Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase II&alpha To further extend the structure&ndash activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3&ndash 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&ndash 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 II&alpha 5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation. |
| Databáze: | OpenAIRE |
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