title: New insights into the structural requirements for pro-apoptotic agents based on 2,4-diaminoquinazoline, 2,4-diaminopyrido[2,3-d]pyrimidine and 2,4-diaminopyrimidine derivatives.
abstract: As a continuation of our work on new anti-tumoral derivatives with selective pro-apoptotic activity in cancer cells, we describe the synthesis and the preliminary evaluation of the cytotoxic and pro-apoptotic activities of a series of pyrimidin-2,4-diamine derivatives that are structurally related to quinazolin-2,4-diamine and pyrido[2,3-d]pyrimidin-2,4-diamine derivatives. We also describe the structure-activity relationship studies carried out on four series' of quinazolin-2,4-diamine, 2-(alkylsulfanyl)-N-alkyl- and 2-(alkylsulfanyl)-N-alkylarylpyrido[2,3-d]pyrimidine and pyrimidin-2,4-diamine derivatives. The proposed preliminary pharmacophore consists of a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine, with two equivalent alkylarylamine chains, preferably N-benzyl- or N-ethylphenylamine, located in positions 2 and 4 of the ring, and with a preferred ALogP in the range 4.5-5.5. The nitrogen present in the central ring can act as hydrogen bond acceptors (HBA) whereas the amino group in the 4-position can act as a donor (HBD) or an HBA and the amino group in the 2-position can act as an HBD. On the basis of the analyzed structural profiles, different mechanisms of action can be suggested for the quinazolin-2,4-diamine, the 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidin-4-amine and the pyrido[2,3-d]pyrimidin-2,4-diamine derivatives.
authors.affiliation: Sección de Modelización Molecular, Dpto de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Irunlarrea 1, E-31008 Pamplona, Spain. mfont@unav.es
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.forename: Álvaro
authors.initials: Á
authors.lastname: González
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; C017205:2,4-diaminopyrimidine; C013474:2,4-diaminoquinazoline