The lack of antiviral activity of recently described (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or (S)-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of (S)-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of (S)-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16, exhibited pan-genotypic anti-HCV activity at submicromolar concentrations.
- MeSH
- adenin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- Hepacivirus účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- organofosfonáty chemická syntéza chemie farmakologie MeSH
- prekurzory léčiv chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- adjuvancia imunologická chemická syntéza chemie farmakologie MeSH
- buněčné linie MeSH
- diamid chemická syntéza chemie farmakologie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- kyseliny fosforité chemie MeSH
- látky proti HIV chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nukleosidy chemie MeSH
- preklinické hodnocení léčiv MeSH
- prekurzory léčiv chemická syntéza chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
