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.

Directed Modulation of Protein Kinase C Isozyme Selectivity with Bisubstrate‐Based Inhibitors

“…Successful examples of this approach include the oligo-arginine-linked ATP analogues, [13][14][15][16][17] the known pseudosubstrate kemptide linked to staurosporine, [18] the tyrosine kinase inhibitors developed by Cole and co-workers, [19,20] complex phage-display-derived cyclic peptides linked to staurosporine, [21] potential aromatic ATP analogues linked to a peptide substrate for the Akt kinase, [22] and phenylpyrazolo-pyrimidine derivatives conjugated to a Src kinase substrate. [23] In all these studies, increases in both selectivity and affinity were observed indicating the validity of the concept.…”

“…Compound 20 features a urea moiety, which is uncharged but capable of forming strong hydrogen bonds acting both as a donor and an acceptor. It was prepared in good yield (77 %) by reacting 19 with N-(4-nitrophenyloxycarbonyl)propargylamine (23). [48] Similarly, carbamate 21, with one hydrogen-bond donor less than urea 20, was prepared by reaction of 19 with propargyl chloroformate in 69 % yield.…”

Catalytic Azido‐Hydrazination of Alkenes Enabled by Visible Light: Mechanistic Studies and Synthetic Applications

“…[3] The current preparations of ibrutinib were performed through the separate making of two heterocycle segments and then coupled through an S N 2 substitution. [37] Finally, switching the N-Cbz group to acryloyl rendered the target molecule (�)-ibrutinib 23 (Scheme 9). A plausible mechanistic working hypothesis.…”

“…The heterocycle moiety was then forged through a 2-step procedure to furnish 22 in 61% yield. [37] Finally, switching the N-Cbz group to acryloyl rendered the target molecule (�)-ibrutinib 23 (Scheme 9).…”

Cyclic peptides containing tryptophan and arginine as Src kinase inhibitors

“…In continuation of our efforts to develop new cyclic peptide scaffolds as Src kinase inhibitors, 11, 19 herein we report the design and evaluation of cyclic peptides containing charged and hydrophobic residues for potential applications as a new class of Src kinase inhibitors. The hydrophobic residues such as aromatic side chains of phenylalanine and tryptophan were expected to occupy and/or interact with a large hydrophobic pocket 19 in the ATP binding site. Furthermore, the indole ring of tryptophan could mimic the adenine base of ATP in binding to the nucleotide binding site.…”