1. A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities.
- Author
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Jansa P, Baszczyňski O, Dračínský M, Votruba I, Zídek Z, Bahador G, Stepan G, Cihlar T, Mackman R, Holý A, and Janeba Z
- Subjects
- Adjuvants, Immunologic chemical synthesis, Adjuvants, Immunologic chemistry, Adjuvants, Immunologic pharmacology, Animals, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Cell Line, Cell Proliferation drug effects, Diamide chemistry, Drug Evaluation, Preclinical, Humans, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred C57BL, Prodrugs chemistry, Spectrometry, Mass, Electrospray Ionization, Diamide chemical synthesis, Diamide pharmacology, Nucleosides chemistry, Organophosphonates chemistry, Prodrugs chemical synthesis, Prodrugs pharmacology
- Abstract
A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis-amidates in excellent yields (83-98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
- Published
- 2011
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