ABSTRACT
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Subject(s)
Antiviral Agents/chemistry , Cyclosporine/chemistry , Hepacivirus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclization , Cyclosporine/chemical synthesis , Cyclosporine/pharmacology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Quinidine/chemistry , Stereoisomerism , Virus Replication/drug effectsABSTRACT
S-Adenosylmethionine (AdoMet) is a ubiquitous cofactor in biomethylations and, in that role, becomes S-adenosylhomocysteine (AdoHcy), which serves as a biofeedback inhibitor of the methylation process. In seeking to avail unexplored structural variations of AdoHcy for biological studies, its 6'-oxa analog and two corresponding carbocyclic nucleosides (based on aristeromycin and neplanocin) have been prepared via common convergent syntheses.
ABSTRACT
A synthetic route to (1S,2S,3R,5S)-3-(6-amino-9H-purin-9-yl)-5-fluorocyclopentane-1,2-diol (that is, the 4'-fluoro derivative of 4'-deoxy-5'-noraristeromycin, 3) is described via a fluorinated cyclopentanol, which is in contrast to existing schemes where fluorination occurred once the purine ring was present. Compound 3 was assayed versus a number of viruses. A favorable response was observed towards measles (IC(50) of 1.2 microg/mL in the neutral red assay and 14 microg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21-36 microg/mL). Among the viruses unaffected by 3 were human cytomegalovirus and the poxviruses (vaccinia and cowpox), which are three viruses that were inhibited by the 4',4'-difluoro analog of 3 (that is, 2).
Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Poxviridae/drug effects , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Cytomegalovirus/growth & development , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Poxviridae/growth & development , Stereoisomerism , Structure-Activity RelationshipABSTRACT
5'-Fluoro-5'-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with N6-bis-boc protected adenine. This procedure is adaptable to preparing a number of 5'-fluoro-5'-deoxycarbocyclic nucleoside analogs with diversity in the heterocyclic base. Antiviral analysis found promising activity for 2 toward measles but no other viruses. No cytotoxicity was observed for 2.
