Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides
- 21 August 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 85 (16), 10539-10551
- https://doi.org/10.1021/acs.joc.0c00928
Abstract
A series of 8-substituted 1-methyl-1,4-dihydropyrazolo-[3',4':4,5]pyrrolo[2,3-d]pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides have been designed and synthesized. Two synthetic approaches to the key heterocyclic aglycon 7, (i) a six-step classical heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole and (ii) a three-step cross-coupling and cyclization approach starting from the zincated 4,6-dichloropyrimidine, gave comparable total yields of 18% vs 13%. The glycosylation of 7 was attempted by three different methods but only the Vorbriiggen silyl-base protocol was efficient and stereoselective to give desired beta-anomeric nucleoside intermediate 17A. Its nucleophilic substitutions or cross-coupling reactions at position 8 and deprotection of the sugar moiety gave eight derivatives of pyrazolo-fused deazapurine ribonucleosides, some of which were weakly fluorescent. Methyl, amino, and methylsulfanyl derivatives exerted submicromolar cytotoxic effects in vitro against a panel of cancer and leukemia cell lines as well as antiviral effects against hepatitis C virus in the replicon assay.Funding Information
- Agentura Pro Zdravotnick? V?zkum Cesk? Republiky (15-31984A)
- Ministerstvo ?kolstv?, Ml?de?e a Telov?chovy (CZ.02.1.01/0.0/0.0/16_019/0000868, LM2015064)
- Grantov? Agentura Cesk? Republiky (19-08124S)
- Akademie Ved Cesk? Republiky (RVO 61388963)
- Gilead Sciences
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