title: Pyrazolopyrimidines: synthesis, effect on histamine release from rat peritoneal mast cells and cytotoxic activity.
abstract: A series of 1H-pyrazolo[3,4-d]pyrimidines (3--6) substituted at positions 1 (R(1)=Ph, H, tert-butyl and ribosetribenzoate), 4 (R(2)=chlorine, nitrogen and oxygen nucleophiles), and 6 (dimethylamino) have been synthesized and their effect on the release of histamine from rat peritoneal mast cells measured. After chemical stimulation, (polymer 48/80), several compounds (i.e. 3b, 4a, 4b, 4d, 4g, 5a), produce inhibition two to three times higher (40--60%) than DSCG but this action is lower after preincubation. 4b (R(1)=Ph, R(2)=NHCH(2)Ph; 50--70% inhibition) and 5a (R(1)=H, R(2)=OMe; 50--55% inhibition) are the most active ones in both experiments. With ovoalbumin as stimulus, several pyrazolopyrimidines show inhibition similar to DSCG, the most active compounds being 6a--d (IC(50)=12--16 microM; R(1)=ribosetribenzoate, R(2)=methoxy and amino). Compounds 4e (R(1)=t-butyl, R(2)=OMe) and 4g (R(1)=t-butyl, R(2)=piperidino) are inducers of the release of histamine (60 and 150% increase). Compounds 4b and 4c showed cytotoxic activity (IC(50)=1 microg/mL) to HT-29 human colon cancer cells.
authors.affiliation: Departamento de Química Fundamental e Industrial, Facultad de Ciencias, Universidad de La Coruña, La Coruña E-15071, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Quintela
authors.forename: C
authors.initials: C
authors.lastname: Peinador
authors.forename: M J
authors.initials: MJ
authors.lastname: Moreira
authors.forename: A
authors.initials: A
authors.lastname: Alfonso
authors.forename: L M
authors.initials: LM
authors.lastname: Botana
authors.forename: R
authors.initials: R
authors.lastname: Riguera
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010533:Peritoneal Lavage; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D018927:Anti-Asthmatic Agents; D006634:Histamine H1 Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; C031280:pyrazole; D006632:Histamine; D010047:Ovalbumin; D004205:Cromolyn Sodium