title: Synthesis and anti-HBV activity of α-stereoisomer of aristeromycin based analogs.
abstract: The potential antiviral activity of aristeromycin type of derivatives (I) is limited by associated toxicity due to its possible 5'-O-phosphorylation and S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitory activity. Aristeromycin structure has major pharmacophoric motif as 5'-OH and adenosine base, which may have significant role in enzyme binding followed by activity and or toxicity. Thus, the structural optimization to alter this major motif by replacing with its bioisostere and changing the 5'-O conformation through stereochemistry reversal was of interest. Thus, the inverted stereochemistry at 4'-position coupled with bioisostere of adenosine base in the target compounds (6-7) to access antiviral potential. The stereoselective formation of a key stereoisomer (2a) was achieved exclusively from neplanocin sugar (1a) by reduction in a single step. The novel target molecules (6-7) were synthesized in 4 steps with 55-62% yield. Compound 6 was analyzed by single crystal X-ray diffraction, which confirms the stereoselective formation of α-analogs with highly puckered cyclopentane ring and 2'-endo conformation. The compound 6 shown significant anti-hepatitis B virus activity of 6.5μM with CC50>100μM and yielded a promising lead with novel structural feature.
authors.affiliation: Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Kasula
authors.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toyama
authors.affiliation: Chemistry Services, GVK Biosciences Pvt, Ltd, IDA Uppal, Hyderabad 500039, India.
authors.forename: Ramakrishnamraju
authors.initials: R
authors.lastname: Samunuri
authors.affiliation: Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Farhana
authors.initials: F
authors.lastname: Rozy
authors.affiliation: Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Chandralata
authors.initials: C
authors.lastname: Bal
authors.affiliation: Chemistry Services, GVK Biosciences Pvt, Ltd, IDA Uppal, Hyderabad 500039, India.
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Jha
authors.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Ashoke
authors.initials: A
authors.lastname: Sharon
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000621456:3-(5-bromo-4-methyl-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol; D000998:Antiviral Agents; D003517:Cyclopentanes; D011743:Pyrimidines; C030034:aristeromycin; C031096:neplanocin A; D000241:Adenosine
keywords: Aristeromycin; Hepatitis B virus; Mitsunobu reaction; Neplanocin A; Stereoselective reduction