Synthesis and biological evaluation of 7-azaindole-based chalcones and related compounds as protein kinase inhibitors
Abstract
Protein phosphorylation is a major molecular mechanism through which proteins’ functions are regulated. Protein phosphorylation occurs through protein kinases, and it consists of the transfer of a phosphate group from a donor to specific amino acid residues on proteins, usually tyrosine, serine and threonine. Processes regulated by protein phosphorylation include cell cycle progression, transcription, translocation, endocytosis, phagocytosis and apoptosis. Deregulation of protein kinase activity leads to aberrant regulation of biological processes and thus the diseases such as cancer. Because of their role in the pathogenesis of many diseases, protein kinases have emerged as attractive therapeutic targets, and they are considered the second most important drug targets after G-protein-coupled receptors. Several strategies have been developed to target protein kinases. Among others, the use of small molecules that inhibit kinase-substrate interactions, or those that bind to the adenosine triphosphate (ATP) binding site of the enzyme to inhibit catalysis are the most common.
7-Azaindole is noteworthy as an excellent scaffold for protein kinase binding; the pyridine moieties’ N atom of 7-azaindole serves as a hydrogen bond acceptor, while the pyrrole moieties’ NH acts a hydrogen bond donor, and together they form bidentate hydrogen bonds with the hinge region of the kinase. Chalcones on the other hand exhibit a wide range of biological properties, and they have been reported to regulate kinase activities through either direct enzyme inhibition or altering kinase expression.
The present study aimed to investigate novel 7-azaindole-based compounds as inhibitors of tumorigenic protein kinases. In this study, various substituents (benzocycloalkanones and benzaldehydes) were attached to position 3 of 7-azaindole. The compound bearing 3-coumaranone was further derivatised at position 6 of the coumaranone ring with various aryl-alkyl substituents and the resultant analogues maintained novelty. All compounds were screened against a panel of disease-relevant protein kinases (CDK2/CyclinA, CDK5/ p25, CDK9/CyclinT, Haspin, PIM1, CK1ε, GSK-3β and ABL1 and LmCK1 (from the Leishmania major parasite)) and were considered active if they inhibited ≥ 70% of kinase activity.
A majority of active compounds synthesised in this study are potent inhibitors of Haspin kinase, and also exhibit dual inhibition for Haspin and GSK-3β. A few active compounds also demonstrated dual inhibition for Haspin and CDK9/CyclinT, as well as GSK-3β and LmCK1. Haspin has only recently been classified as a protein kinase, and identification of its inhibitors may supply valuable candidates for biological studies and cancer treatment. Interestingly, this study further discovered that hybridising 7-azaindole with α-tetralone generates dual inhibitors of Haspin and CDK9/CyclinT. It is believed that dual inhibition of protein kinases could be an
effective strategy in cancer therapy because it overcomes incomplete efficacy and drug resistance, thus providing optimal effects in cancer therapy.
This study established that 3-coumaranone and α-tetralone are optimum substituents for the design of 7-azaindole-based potent Haspin inhibitors, as well as dual inhibitors of Haspin and CDK9/CyclinT. Furthermore, derivatisation of 8l led to synthesis of novel mono- and disubstituted compounds with dual activity against Haspin and GSK-3β, as well as GSK-3β and LmCK1. Compounds synthesised in this study may therefore be of value as novel anti-proliferative and
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