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Synthesis and Evaluation of 3‐Phenylpyrazolo[3,4‐ d ]pyrimidine‐Peptide Conjugates as Src Kinase Inhibitors
Author(s) -
Kumar Anil,
Wang Yuehao,
Lin Xiaofeng,
Sun Gongqin,
Parang Keykavous
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700074
Subject(s) - peptide , chemistry , conjugate , pyrimidine , proto oncogene tyrosine protein kinase src , peptide synthesis , phosphorylation , combinatorial chemistry , biochemistry , mathematical analysis , mathematics
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 μ M ), and peptides Ac‐CIYKYY (IC 50 =400 μ M ) and Ac‐YIYGSFK (IC 50 =570 μ M ) 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 μ M ) and PhPP‐CH 2 CO‐YIYGSFK (IC 50 =2.7 μ M ), 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.