Document 0074
 DOCN  M9580074
 TI    Synthesis, absolute configuration, and enantioselectivity of
       antiretroviral effect of (R)-(-)- and (S)-(+)-cytallene.
       Lipase-catalyzed enantioselective acylations of (+/-)-N4-acylcytallenes.
 DT    9506
 AU    Jones BC; Silverton JV; Simons C; Megati S; Nishimura H; Maeda Y;
       Mitsuya H; Zemlicka J; Department of Chemistry, Michigan Cancer
       Foundation, Wayne State; University School of Medicine, Detroit 48201,
       USA.
 SO    J Med Chem. 1995 Apr 14;38(8):1397-405. Unique Identifier : AIDSLINE
       MED/95248521
 AB    Enantioselectivity of acylations of (+/-)-cytallene (1b),
       (+/-)-N4-acetylcytallene (11a), (+/-)-N4-benzoylcytallene (11b), and
       (+/-)-N4-(9-fluorenylmethoxycarbonyl)cytallene (11c) using vinyl
       butyrate or acetate catalyzed by lipases in organic solvents was
       investigated. Reactions with 1b, 11a, and adenallene (1a) did not
       display a high enantioselectivity but all resulted in a predominant
       acylation of the (-)-enantiomers. Application of the Lowe-Brewster rule
       led to a tentative assignment of the R-configuration to all acylated
       products. Studies of the time course of acylation of
       (+/-)-N4-benzoylcytallene (11b) in chloroform, tetrahydrofuran (THF),
       tetrahydropyran (THP), tetrahydrothiophene (THT), and dioxane with
       lipase PS30 and/or AK showed that the reaction in THF catalyzed by
       lipase AK was the most promising for resolution of 11b. Indeed, a
       large-scale acylation afforded, after separation and deprotection of
       intermediates 3e and 10d, (+)- and (-)-cytallene (3c and 2b) in high
       yield and enantioselectivity. Acylation of 11c in THF led also to
       formation of 3c and 2b in high enantioselectivity. Single crystal X-ray
       diffraction established the S-configuration of (+)-cytallene (3c), thus
       confirming the assignment made on the basis of Lowe-Brewster rule. An
       improved large-scale synthesis of (+/-)-cytallene (1b) is also
       described. The R-enantiomer 2b inhibited the replication of a primary
       human immunodeficiency virus (HIV-1) isolate in
       phytohemagglutinin-activated peripheral blood mononuclear cells
       (PHA-PBM) with IC50 0.4 and IC90 1.7 microM. (+/-)-Cytallene (1b)
       exhibited IC50 0.8 and IC90 3.4 microM. Both compounds completely
       suppressed replication of HIV-1 at 10 microM with no detectable
       cytotoxicity. The S-enantiomer (3c) was inactive.
 DE    Acylation  Antiviral Agents/CHEMISTRY/CHEMICAL SYNTHESIS/*PHARMACOLOGY
       Catalysis  Cells, Cultured  Crystallography, X-Ray  Cytosine/*ANALOGS &
       DERIVATIVES/CHEMISTRY/CHEMICAL SYNTHESIS/  PHARMACOLOGY  Human
       HIV-1/*DRUG EFFECTS/PHYSIOLOGY  Lipase/*METABOLISM  Monocytes/VIROLOGY
       Stereoisomers  Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.
       Virus Replication/DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).