Abstract
A series of mono-pyrrolo[2,3-d]pyrimidines 4a–4k, unsymmetrical bis-purine isosteres 5a–5e and symmetrical bis-pyrrolo[2,3-d]pyrimidines 6a and 6b connected via di(1,2,3-triazolyl)phenyl linker were synthesized by click chemistry. Whereas mono- 4g and bis-pseudopurine 5e showed selective inhibitory activities on cervical carcinoma (HeLa) cells, bis-pyrrolo[2,3-d]pyrimidine 6b exhibited potent and selective anti-proliferative effect in the nanomolar range on pancreatic carcinoma (CFPAC-1) cells. Among these, compound 6b induced a significant reduction in the expression level of CDK9 (cyclin-dependent kinase 9)/cyclin T1 in CFPAC-1 cells concomitant with attenuation of proliferative signaling mediated by c-Raf (rapidly accelerated fibrosarcoma) and p38 MAP (mitogen-activated protein) kinases. Our findings encourage further development of novel structurally related analog of 6b to obtain more selective anticancer agent for treating pancreatic cancer.
Highlights
Kinases have emerged as one of the most intensively pursued classes of drug targets with approximately 30 various kinase targets being developed to the stage ready for clinical trials
The kinase activity of cyclin-dependent kinases (CDKs) is tightly regulated by the binding to cyclins, the levels of which depend on the balance between protein synthesis and proteasomal degradation, which plays an important role in regulating cellular processes [2]
I6tbiswinitthertehsetimngotsot pnrootenothuantcseydmemxpertersicsaiol nbios(fpcy-Rrraofloa[n2d,3p-d3]8pkyirnimasiedsinaels)ohyshboriwde6db twheitmh tohset pmootsetnpt rcoyntoosutnatciecdefefxepcrtsesasmioonnogf tch-eRsaef caonmdppo3u8nkdinsaasseesvaildsoensthforwomedththeeirmICo5s0tvpaoluteenst(cTyatbolseta1t)i.c Altogether, Western blot study has demonstrated that anti-proliferative effect of compound 6b in CFPAC-1 cells could be attributed to inhibition of CDK9/cyclin T1 and attenuation of oncogenic effects among these compounds as evident from their IC50 values (Table 1)
Summary
Kinases have emerged as one of the most intensively pursued classes of drug targets with approximately 30 various kinase targets being developed to the stage ready for clinical trials. Cyclin-dependent kinases (CDKs) belong to the serine/threonine kinases with fundamental role in the control of the cell cycle and/or proliferation and transcription [1]. The kinase activity of CDKs is tightly regulated by the binding to cyclins, the levels of which depend on the balance between protein synthesis and proteasomal degradation, which plays an important role in regulating cellular processes [2]. Deregulation of CDK-cyclin activity in cancer cells has provided a rationale for the investigation of CDK inhibitors for therapeutic intervention in various types of cancer. Over the past two decades, several CDK inhibitors have been developed as potential cancer therapeutics and tested in numerous clinical trials for several tumor types [4,5,6]. Ates on molecular targets CDK9/cyclin T1, p38 MAPK and c-Raf-1 kinases that regulate cell proliferation TThheeariemfotoree,vaalsueartieesthoefirmcyotnoost-a(ti4caa–c4tkiv)itaiensdanbdisf-uprstehuedr ionpvuesrtiingeaste(5thae–5efef,ec6tas,o6fbs)elwecetreed pcarnodviddaetdeswith the aoimn mtooleevcualaurattaergtheetsirCcDyKto9s/ctaytcilcinaTct1i,vpit3i8esMaAnPdKfuarntdhec-rRianfv-1esktiingaastees ttheaterfefgeuctlsatoefcseelllepcrtoeldifecrantiodnid. ates on molecular targets CDK9/cyclin T1, p38 MAPK and c-Raf-1 kinases that regulate cell proliferation
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