ABSTRACT
Synthesis of 2' -beta-hydroxymethyl nucleosides 3-6 was accomplished, using stereoselective hydroxymethylation as a key step. Adenine nucleoside 3 showed potent anti-HCV activity, implying that 2' -beta-hydroxymethyl group has the appropriate electronic properties interfering with HCV polymerase.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Antiviral Agents/chemistry , Drug Design , Nucleosides/chemistry , Purines/chemistryABSTRACT
On the basis of potent anti-HCV activity of 2'-C-methyladenosine, novel 2'-C-hydroxymethyladenosine analogues 2a-c were synthesized from d-ribose in order to lead to favorable interaction with HCV polymerase. Among compounds tested, adenosine derivative 2a exhibited potent anti-HCV activity, indicating that the hydroxyl group of 2'-C-hydroxymethyl substituent led to favorable interaction with HCV polymerase.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/metabolism , Hepatitis C/drug therapy , Purine Nucleosides/chemical synthesis , Chemistry, Pharmaceutical/methods , DNA-Directed RNA Polymerases/chemistry , Drug Design , Models, Chemical , Purine Nucleosides/therapeutic use , RNA, Viral/chemistry , Ribonucleosides/chemistryABSTRACT
The preparative and stereoselective synthesis (45-50% overall yields) of the target compound 17 has been accomplished from D-ribose. The bulky protecting groups such as TBDPS and Trityl enforced the facial selectivity during Grignard reaction to give the tertiary beta-allylic alcohol 16 as the sole product, which was oxidatively rearranged to the key molecule 17 in excellent yield.
Subject(s)
Chemistry, Organic/methods , Nucleosides/chemical synthesis , Ribose/chemistry , Adenosine/analogs & derivatives , Adenosine/chemistry , Catalysis , Molecular Structure , Nucleosides/analysis , Oxidation-Reduction , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel apio analogue of neplanocin A was efficiently synthesized from D-ribose via stereoselective aldol-retroaldol reaction for introducing hydroxymethyl group and RCM reaction for synthesizing carbocycle, and its inhibitory activity against SAH hydrolase was assayed.
Subject(s)
Adenosine/chemical synthesis , Adenosylhomocysteinase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , Drug Design , Indicators and Reagents , Molecular Structure , Structure-Activity RelationshipABSTRACT
Stereoselective synthesis of apio-neplanocin A and its related purine nucleosides which combined the properties of neplanocin A and apio nucleoside was achieved, starting from D-ribose via regioselective hydroxymethylation and ring-closing metathesis (RCM) as key steps. However, all synthesized compounds did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase, unlike neplanocin A.