Design, synthesis and biological evaluation of selected 7-azaindole derivatives and structurally related compounds as potential inhibitors of disease-related protein kinases

PhD (Pharmacy), North-West University, Potchefstroom CampusThe bulk of the myriad cellular processes pertaining to normal cellular function in humans are governed by a superfamily of proteins known as protein kinases. Protein kinases account for 1.7% of all human genes and are vastly explored due to their involvement in various diseases. This study focused on a panel of disease-related protein kinases, namely: HsCDK2/Cyclin A, HsCDK5/p25, HsCDK9/Cyclin T, HsHaspin, HsPIM1, SscCK1δ/ε, SscGSK3α/β and LmCK1. The selected scaffold of interest, 7-azaindole, has been known to have a propensity for producing derivatives that inhibit protein kinases. Therefore, a total of thirty-five 7-azaindole derivatives were synthesised for in vitro assessment for protein kinase inhibition against the designated panel of kinases. The C4-substituted 7-azaindole derivatives exhibited the best inhibition activity against the Haspin and CDK9/Cyclin T kinases, in general. 4-(4-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine exhibited best Haspin activity of the 7-azaindole derivatives; IC50 value of 0.118 μM. 4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridine exhibited the best CDK9/Cyclin T activity; IC50 value of 0.063 μM. Prompted by the success of the 7-azaindole scaffold, 19 structurally related C4-substituted 7H-pyrollo[2,3-d]pyrimidine (7-deazapurine) derivatives were synthesised and also evaluated against the designated kinase panel. The most potent 7-deazapurine derivatives were 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenol and 4-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine with IC50 values of 0.38 μM and 0.11 μM, against CDK9/CyclinT and Haspin, respectively. Both CDK9/Cyclin T and Haspin have been implicated in cancer, therefore, it may be concluded that the 7-azaindole and 7-deazapurine scaffolds are ideal for producing protein kinase inhibitors that may have potential benefit in cancer therapy in the future.Doctora