title: Synthesis and evaluation of 3-phenylpyrazolo[3,4-d]pyrimidine-peptide conjugates as Src kinase inhibitors.
abstract: 3-Phenylpyrazolo[3,4-d]pyrimidine (PhPP) derivatives substituted with an alkyl or aryl carboxylic acid at the N1-endocyclic amine, such as PhPP-CH(2)COOH (IC(50)=250 microM), and peptides Ac-CIYKYY (IC(50)=400 microM) and Ac-YIYGSFK (IC(50)=570 microM) were weak inhibitors of polyE(4)Y phosphorylation by active c-Src. A series of PhPP-peptide conjugates were synthesized using PhPP as an ATP mimic and CIYKYY or YIYGSFK as a peptide substrate to improve the inhibitory potency against active c-Src kinase. PhPP derivatives were attached to the N terminus or the side chain of amino acids in the peptide template. Two N-terminal substituted conjugates, PhPP-CH(2)CO-CIYKYY (IC(50)=0.38 microM) and PhPP-CH(2)CO-YIYGSFK (IC(50)=2.7 microM), inhibited the polyE(4)Y phosphorylation by active c-Src significantly higher than that of the parent compounds. The conjugation of PhPP with the peptides produced a synergistic inhibition effect possibly through creation of favorable interactions between the conjugate and the kinase domain as shown by molecular modeling studies.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 41 Lower College Road, Kingston, Rhode Island 02881, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Yuehao
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Lin
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D010455:Peptides / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D010455:Peptides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019061:src-Family Kinases