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Int. J. Mol. Sci. 2017, 18(11), 2292; https://doi.org/10.3390/ijms18112292

Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases

1
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
2
Department of Biotechnology, Center for High-Throughput Technologies, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, Croatia
3
Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovića 28a, HR-10000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Received: 13 September 2017 / Revised: 18 October 2017 / Accepted: 25 October 2017 / Published: 1 November 2017
(This article belongs to the Section Bioactives and Nutraceuticals)
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Abstract

A series of mono-pyrrolo[2,3-d]pyrimidines 4a4k, unsymmetrical bis-purine isosteres 5a5e 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. View Full-Text
Keywords: pyrrolo[2,3-d]pyrimidines; purinomimetics; 1,2,3-triazole; anticancer; pancreatic carcinoma (CFPAC-1) pyrrolo[2,3-d]pyrimidines; purinomimetics; 1,2,3-triazole; anticancer; pancreatic carcinoma (CFPAC-1)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bistrović, A.; Harej, A.; Grbčić, P.; Sedić, M.; Kraljević Pavelić, S.; Cetina, M.; Raić-Malić, S. Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases. Int. J. Mol. Sci. 2017, 18, 2292.

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