title: A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities.
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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic vvi, Flemingovo nám 2, 16610 Prague 6, Czech Republic. jansa@uochb.cas.cz
authors.forename: Petr
authors.initials: P
authors.lastname: Jansa
authors.forename: Ondřej
authors.initials: O
authors.lastname: Baszczyňski
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.forename: Ivan
authors.initials: I
authors.lastname: Votruba
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Zídek
authors.forename: Gina
authors.initials: G
authors.lastname: Bahador
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Richard
authors.initials: R
authors.lastname: Mackman
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003958:Diamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D009705:Nucleosides / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D003958:Diamide