Promising anticancer compounds of the type 1,6-disubstituted 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-7-ones were identified. The target compounds were readily synthesized in a large scale via a sequence of reactions starting from the commercially available primary amines. Their in vitro anti-proliferative activity has been evaluated on prostate (DU-145), colon and melanoma (A375P) human cancer cell lines. The relationships between the structure and the anticancer activity, covering all tested cancer cell lines, revealed that the compound 5c with 2,4-dimethylphenyl substituent at R 2 was the most potent with the IC 50 values in the range as low as 0.16 to 0.40 µM.Key Words : Tetrahydropyrazolopyridinone, 3-Aminopyrazole, Anti-proliferative activity, Anticancer drugsThe fundamental research for the development of new drugs against cancer stands first among the priorities of life science research worldwide. 1 The systematic investigation in our research group towards the development of anticancer drugs resulted in designing new molecules based on the bicyclic tetrahydropyrazolopyridinone skeleton. The bicyclic tetrahydropyrazolopyridinones have many interesting pharmacological properties due to their analogy with purines. The core 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one has been reported as an inhibitor of blood coagulation factor Xa. 2 Among the wide variety of synthetic compounds recognized as potential anticancer drugs, the molecules based on the 3-aminopyrazole moiety have attracted a great interest. The 3-aminopyrazole, a well known adenine mimetic pharmacophore, was found in inhibitors of several classes of kinases such as Aurora, 3 CDK-2 4a and MAP 5 kinases. These kinases have great importance as the emerging targets in oncology drug discoveries. Based on the previously reported research on the potent anticancer activity of 3-aminopyrazoles, we have incorporated tetrahydropyridinone ring in our target molecules. Herein we report the synthesis and anticancer activity of novel 1,6-disubstituted 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-7-one derivatives. SAR studies were done using biologically evaluated disubstituted tetrahydropyrazolopyridinone analogues with the aim to find Scheme 1. General synthetic route of 1,6-disubstituted 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-7-one analogues. Reagents and conditions: (i) K2CO3, 4-bromobutyronitrile, CH3CN, reflux, 2 days, 80-95%; (ii) NaOEt, diethyloxalate, EtOH, reflux, overnight, 50-75%; (iii) hydrazinemonohydrate, glacial AcOH, EtOH, 65 o C, overnight, 95-100%; (iv) K2CO3, A, CH3CN, 80 o C, overnight, 60-95%; (v) chloropropionyl chloride, CH2Cl2, rt, 1 h, 60-90%. better anticancer molecules.The route adopted for the synthesis of 1,6-disubstituted 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-7-one derivatives is described in Scheme 1. The key intermediate 3-amino-6-Nsubstituted tetrahydropyrazolopyridinone 4 was synthesized in facile three steps by employing the approach reported by Blatter and Irvington. 6 with modifications to get better yield. The fir...
