Synthesis of purine and 7-deazapurine nucleoside analogues of 6-N-(4-Nitrobenzyl)adenosine; inhibition of nucleoside transport and proliferation of cancer cells.

Abstract

Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral infections, efforts have been made to better understand the mechanisms by which hENT1 modulates nucleoside transport. To that end, we report here the design and synthesis of novel tool compounds for the further study of hENT1. The 7-deazapurine nucleoside antibiotic tubercidin was converted into its 4-N-benzyl and 4-N-(4-nitrobenzyl) derivatives by alkylation at N3 followed by a Dimroth rearrangement to the 4-N-isomer or by fluoro-diazotization followed by SN Ar displacement of the 4-fluoro group by a benzylamine. The 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin antibiotics were prepared by the alkylation approach. Cross-membrane transport of labeled uridine by hENT1 was inhibited to a weaker extent by the 4-nitrobenzylated tubercidin and sangivamycin analogues than was observed with 6-N-(4-nitrobenzyl)adenosine. Type-specific inhibition of cancer cell proliferation was observed at micromolar concentrations with the 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin, and also with 4-N-benzyltubercidin. Treatment of 2',3',5'-O-acetyladenosine with aryl isocyanates gave the 6-ureido derivatives but none of them exhibited inhibitory activity against cancer cell proliferation or hENT1.

• Authors: Ramanjaneyulu Rayala, Patricia Theard, Heysell Ortiz, Sylvia Yao, James D Young, Jan Balzarini, Morris J Robins, Stanislaw F Wnuk
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 9 Pg. 2186-92 (Sep 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 24788480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 7-deazapurine
• Antibiotics, Antineoplastic
• Antineoplastic Agents
• Equilibrative Nucleoside Transporter 1
• Membrane Transport Modulators
• Purine Nucleosides
• Purines
• Pyrimidine Nucleosides
• SLC29A1 protein, human
• Toyocamycin
• Tubercidin

Topics

• Alkylation
• Antibiotics, Antineoplastic (chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Equilibrative Nucleoside Transporter 1 (antagonists & inhibitors)
• Humans
• Membrane Transport Modulators (chemical synthesis, pharmacology)
• Purine Nucleosides (chemical synthesis)
• Purines (chemical synthesis)
• Pyrimidine Nucleosides (chemical synthesis, pharmacology)
• Toyocamycin (analogs & derivatives, chemical synthesis, pharmacology)
• Tubercidin (chemistry, pharmacology)