A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities |
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Authors: | Jansa Petr Baszczyňski Ond?ej Dra?ínský Martin Votruba Ivan Zídek Zdeněk Bahador Gina Stepan George Cihlar Tomas Mackman Richard Holý Antonín Janeba Zlatko |
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Institution: | a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6, Czech Republic b Institute of Experimental Medicine, Academy of Sciences of the Czech Republic v.v.i., Vídeňská 1083, 142 20 Prague 4, Czech Republic c Gilead Sciences, Inc., Foster City, CA 94404, USA |
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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. |
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Keywords: | Prodrugs Phosphonodiamides Bis-amidates Acyclic nucleoside phosphonates GS-9219 |
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