Synthesis and anti-HBV activity of α-stereoisomer of aristeromycin based analogs.
Bioorg Med Chem Lett
; 26(16): 3945-9, 2016 08 15.
Article
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| MEDLINE
| ID: mdl-27426303
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Antivirales
/
Pirimidinas
/
Adenosina
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Virus de la Hepatitis B
/
Ciclopentanos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
India