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Molecules 2015, 20(10), 18437-18463; doi:10.3390/molecules201018437

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

1
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA
2
Discovery and Analytical Services, GVK Biosciences Pvt. Ltd., 28A IDA Nacharam, Hyderabad 500076, India
3
Clinical Immunotherapy Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
4
Department of Biochemistry, Universidad Central del Caribe-School of Medicine, P. O. Box 60327, Bayamón, PR 00960, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Fumi Nagatsugi
Received: 17 August 2015 / Revised: 20 September 2015 / Accepted: 22 September 2015 / Published: 9 October 2015
(This article belongs to the Special Issue Nucleoside Modifications)
View Full-Text   |   Download PDF [1310 KB, uploaded 12 October 2015]   |  

Abstract

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active. View Full-Text
Keywords: cladribine; nucleoside; guanosine; benzotriazole; (benzotriazol-1yl-oxy)-tris(dimethylamino)phosphonium hexafluorophosphate; BOP cladribine; nucleoside; guanosine; benzotriazole; (benzotriazol-1yl-oxy)-tris(dimethylamino)phosphonium hexafluorophosphate; BOP
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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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MDPI and ACS Style

Satishkumar, S.; Vuram, P.K.; Relangi, S.S.; Gurram, V.; Zhou, H.; Kreitman, R.J.; Montemayor, M.M.M.; Yang, L.; Kaliyaperumal, M.; Sharma, S.; Pottabathini, N.; Lakshman, M.K. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides. Molecules 2015, 20, 18437-18463.

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