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

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.
AuthorsSakilam Satishkumar, Prasanna K Vuram, Siva Subrahmanyam Relangi, Venkateshwarlu Gurram, Hong Zhou, Robert J Kreitman, Michelle M Martínez Montemayor, Lijia Yang, Muralidharan Kaliyaperumal, Somesh Sharma, Narender Pottabathini, Mahesh K Lakshman
JournalMolecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 10 Pg. 18437-63 (Oct 09 2015) ISSN: 1420-3049 [Electronic] Switzerland
PMID26473811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Organophosphorus Compounds
  • Guanosine
  • Cladribine
  • benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
Topics
  • Antineoplastic Agents (chemical synthesis, pharmacology)
  • Cell Line, Tumor
  • Cladribine (chemical synthesis, pharmacology)
  • Guanosine (chemical synthesis, pharmacology)
  • Humans
  • Inhibitory Concentration 50
  • Leukemia, Hairy Cell (pathology)
  • Leukemia, Lymphocytic, Chronic, B-Cell (pathology)
  • Leukocytes, Mononuclear (drug effects, pathology)
  • Lymphoma, T-Cell (pathology)
  • Organophosphorus Compounds (chemistry)
  • Primary Cell Culture
  • Structure-Activity Relationship

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