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. 1497, 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 [alpha](D)(21) + 151degrees (c 0.5, MeOH) and [alpha](D)(21) -146degrees (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 (EC50 8.8 +/- 0.2 muM) as its (+)-counterpart (NSC 693194) (EC50 16.2 +/- 2.4 muM) 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. (C) 2003 Elsevier Science Ltd. All rights reserved.

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