Synthesis, resolution, and determination of the absolute configuration of the enantiomers of cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide, an HIV-1NCp7 inhibitor.
The anti-HIV activity of (+/-)-cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide [(+/-)-cis-1,1-dioxo-[1,2]-dithiane-4,5-diol, NSC-624151] and its attack on the zinc finger domain of the HIV-1 nucleocapsid p7 (NCp7) protein has been established [Rice, W. G.; Baker, D. C.; Schaeffer, C. A.; Graham, L.; Bu, M.; Terpening, S.; Clanton, D.; Schultz, R.; Bader, J. P.; Buckheit, R. W.; Field, L.; Singh, P. K. Turpin, J. A. Antimicrob. Agents Chemother. 1997, 41, 419]. In order to determine which enantiomer of NSC-624151 is the more active component, the compound was resolved via its bis-'Mosher ester', which was prepared via its reaction with two equiv of (-)-(R)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride. The diastereoisomeric esters were separated, and each ester was hydrolyzed to yield enantiomers with (D)(21) +151 degrees (c 0.5, MeOH) and (D)(21) -146 degrees (c 0.5, MeOH). Single-crystal X-ray analysis of the (-)-bis-'Mosher ester' showed that the (-)-enantiomer is the (4S, 5R)-compound. The (-)-enantiomer (NSC 693195) was ca. twice as active (EC(50) 8.8+/-0.2 microM) as its (+)-counterpart (NSC 693194) (EC(50) 16.2+/-2.4 microM) in the XTT assay against HIV-1. All three compounds were found to be approximately equally effective in promoting Zn ejection from the NCp7 zinc finger. As the more anti-HIV active enantiomer is only slightly more active than the racemic form, it appears to offer no advantages over the racemic form.
Mayasundari
Anand
A
Department of Chemistry, The University of Tennessee, Knoxville, Knoxville, TN 37996-1600, USA.
Rice
William G
WG
Diminnie
Jonathan B
JB
Baker
David C
DC
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D036022:Capsid Proteins / Q000037:antagonists & inhibitors*; D015683:Gene Products, gag / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D014764:Viral Proteins; D016335:Zinc Fingers; D054301:gag Gene Products, Human Immunodeficiency Virus
C105419:1,2-dithiane-4,5-diol 1,1-dioxide; D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D013450:Sulfones; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus