An enantiospecific synthesis of the human cytomegalovirus antiviral agent [(R)-3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4- hydroxybutyl]phosphonic acid.
The racemic isosteric phosphonate of ganciclovir monophosphate (BW2482U89, SR3745, [3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4- hydroxybutyl]phosphonic acid, 1) has potent and selective in vitro activity against human cytomegalovirus. An enantiospecific synthesis of the R-enantiomer of compound 1 starting from L-arabinose was developed. The synthesis involved (1) the preparation of a chiral acyclic moiety, (2) the coupling of the chiral acyclic moiety to diacetylguanine, (3) the introduction of phosphorus, and (4) the final deprotection. The R-enantiomer, which has stereochemistry analogous to the natural compound GMP, was tested against human cytomegalovirus and had an IC50 of 1.7 microM, which was approximately 2-fold more active than the racemic material. Both racemic and chiral compounds were less toxic than ganciclovir to bone marrow progenitor cells in an in vitro assay.
Chamberlain
S D
SD
Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
Biron
K K
KK
Dornsife
R E
RE
Averett
D R
DR
Beauchamp
L
L
Koszalka
G W
GW
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001854:Bone Marrow Cells; D003587:Cytomegalovirus / Q000187:drug effects*; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D006157:Guanosine Monophosphate / Q000737:chemistry; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010758:Phosphorus / Q000737:chemistry; D013237:Stereoisomerism
D000998:Antiviral Agents; C050216:9-(1-hydroxy-4-phosphinyl-2-butoxymethyl)guanine; C087148:(3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4-hydroxybutyl)phosphonic acid; D010758:Phosphorus; D006147:Guanine; D006157:Guanosine Monophosphate; D015774:Ganciclovir