6-(Het)aryl-7-deazapurine ribonucleosides as novel potent cytostatic agents

Journal of Medicinal Chemistry
Petr NaušMichal Hocek

Abstract

A series of novel 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.

References

Jan 1, 1991·Pharmacology & Therapeutics·W Plunkett, P P Saunders
Jul 1, 1985·Medicinal Research Reviews·R K Robins, G R Revankar
Jan 1, 1968·Journal of Medicinal Chemistry·J A Montgomery, K Hewson
Oct 5, 2001·Expert Opinion on Pharmacotherapy·S A Johnson
Jul 27, 2002·The Lancet Oncology·Carlos M GalmariniCharles Dumontet
May 15, 2003·Chemical Reviews·Luigi A AgrofoglioYoshio Saito
Jul 18, 2003·Current Drug Targets·L JordheimC Dumontet
Aug 16, 2003·The Journal of Organic Chemistry·Elizabeth C WesternKevin H Shaughnessy
Aug 1, 1964·Proceedings of the National Academy of Sciences of the United States of America·G ACSM MORI
Mar 27, 2004·Nucleosides, Nucleotides & Nucleic Acids·Xiaojing WangMichael T Migawa
Sep 10, 2004·Organic Letters·Peter SilhárMichal Hocek
Nov 15, 2006·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Jennifer E VelaAdrian S Ray
Dec 16, 2006·Current Medicinal Chemistry·S VittoriG Cristalli
Apr 5, 2007·Nature Protocols·Vanicha Vichai, Kanyawim Kirtikara
Jul 14, 2007·Current Topics in Medicinal Chemistry·Uwe Koch, Frank Narjes
Sep 7, 2007·Bioorganic & Medicinal Chemistry Letters·Michiko KimotoIchiro Hirao
Oct 16, 2007·Bioorganic & Medicinal Chemistry Letters·Lucie SpácilováJan Hlavác
Jan 29, 2008·Recent Patents on Anti-cancer Drug Discovery·Lars P JordheimCharles Dumontet
May 14, 2008·Current Medicinal Chemistry·C M GalmariniB Joseph
Jun 12, 2009·Organic Letters·Jan Pschierer, Herbert Plenio

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Citations

Jan 9, 2014·Bioorganic & Medicinal Chemistry·Raffaella CincinelliSabrina Dallavalle
May 27, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kevin H Shaughnessy
Dec 25, 2015·Chemical Reviews·Laurens M De CoenChristian V Stevens
Feb 22, 2017·Journal of Medicinal Chemistry·Michal TichýMichal Hocek
Oct 8, 2019·Nucleosides, Nucleotides & Nucleic Acids·Jong Hyun ChoRaymond F Schinazi
Jan 7, 2016·Beilstein Journal of Organic Chemistry·Hang RenBaicheng He
Jul 5, 2013·Organic & Biomolecular Chemistry·Martin KlečkaMichal Hocek
Jun 27, 2012·Chembiochem : a European Journal of Chemical Biology·Chahrazade El AmriMichael Smietana
Jan 29, 2016·Molecular Cancer Therapeutics·Pavla PerlíkováMichal Hocek
Jan 2, 2021·European Journal of Medicinal Chemistry·Jakob BoutonSerge Van Calenbergh
Nov 13, 2012·Bioorganic & Medicinal Chemistry Letters·Julien LalutFrançois-Xavier Felpin
Jun 30, 2011·Journal of Medicinal Chemistry·Aurelie BourderiouxMichal Hocek
Aug 11, 2021·International Journal for Parasitology. Drugs and Drug Resistance·Cai LinSerge Van Calenbergh
Mar 3, 2018·The Journal of Organic Chemistry·Guilherme M MartinsClaudio C Silveira

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