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

International Journal of Molecular Sciences
Andrea BistrovićSilvana Raić-Malić

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.

References

Oct 29, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·M G Wilkinson, J B Millar
Nov 15, 2002·International Journal of Cancer. Journal International Du Cancer·Steven J McClueDavid P Lane
Nov 24, 2004·Proceedings of the National Academy of Sciences of the United States of America·Pascal AuffingerP Shing Ho
Apr 21, 2005·Seminars in Cell & Developmental Biology·Julie P I Welburn, Jane A Endicott
May 23, 2006·Bioorganic & Medicinal Chemistry·Shu-Ting HuangChinpiao Chen
Sep 26, 2006·European Journal of Medicinal Chemistry·Vladimír KrystofMiroslav Strnad
Dec 15, 2006·European Journal of Medicinal Chemistry·Nageswara KodeShashikant Phadtare
Apr 22, 2008·Bioorganic & Medicinal Chemistry·Tatjana GazivodaMladen Mintas
Sep 3, 2008·European Journal of Medicinal Chemistry·Yan-Hui YangHong Chen
Oct 28, 2008·Journal of Enzyme Inhibition and Medicinal Chemistry·A Selcen AlpanZeki Topcu
Jan 28, 2009·Acta Crystallographica. Section D, Biological Crystallography·Anthony L Spek
Apr 11, 2009·Journal of Medicinal Chemistry·Yunxiang LuWeiliang Zhu
Jul 29, 2010·Molecular Cancer Therapeutics·David ParryEmma M Lees
Sep 9, 2010·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Christophe Le TourneauEric Raymond
Dec 28, 2010·European Journal of Medicinal Chemistry·Manish Singh, Vibha Tandon
May 11, 2012·Current Pharmaceutical Design·Radek JordaVladimír Krystof
Jul 10, 2012·European Journal of Medicinal Chemistry·Marek ZatloukalMiroslav Strnad
Nov 14, 2012·Journal of Medicinal Chemistry·Rainer WilckenFrank M Boeckler
Dec 1, 2012·Journal of the American Chemical Society·Ran YanErik Årstad
Jan 30, 2013·Pharmacology & Therapeutics·Santiago Diaz-MoralliMarta Cascante
May 7, 2013·Oncogene·Y J Choi, L Anders
Jan 7, 2014·Expert Opinion on Investigational Drugs·Mathew C CasimiroRichard G Pestell
Aug 12, 2010·ACS Medicinal Chemistry Letters·Kamil ParuchTimothy J Guzi
Jul 17, 2014·Molecular Cancer Therapeutics·Yi-Xiang ZhangAndrew J Wagner
Sep 13, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gaëlle Mariaule, Philippe Belmont
Jan 9, 2015·Acta Crystallographica. Section C, Structural Chemistry·George M Sheldrick
Jan 31, 2015·Nature Reviews. Drug Discovery·Uzma AsgharErik S Knudsen
Feb 28, 2015·Current Medicinal Chemistry·Silvana Raic-Malic, Andrijana Mescic
Mar 3, 2015·European Journal of Medicinal Chemistry·Alka SharmaKamaldeep Paul
May 16, 2015·Trends in Pharmacological Sciences·Peng WuMads H Clausen
Jul 25, 2015·Annals of Translational Medicine·Jonas CicenasMindaugas Valius
Nov 19, 2015·Bioorganic & Medicinal Chemistry·Silvija MaračićSilvana Raić-Malić
Feb 26, 2016·European Journal of Medicinal Chemistry·Sahil SharmaKunal Nepali
May 14, 2016·Journal of Medicinal Chemistry·Yogesh A SonawaneAmarnath Natarajan
Aug 6, 2016·Breast Care·Romualdo Barroso-SousaSara M Tolaney
Sep 19, 2016·European Journal of Medicinal Chemistry·Tatjana Gazivoda KraljevićSilvana Raić-Malić
Jan 28, 2017·Bioorganic Chemistry·Divya DheerRavi Shankar
Feb 9, 2017·Journal of Cancer Research and Therapeutics·R Priyadharsini Palanisamy
Feb 25, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Anna-Laura KretzJohannes Lemke

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Citations

Apr 3, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Valentina RepSilvana Raić-Malić
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrea Bistrović PopovSilvana Raić-Malić
Nov 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Silvija MaračićSilvana Raić-Malić

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column chromatography
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