Document 0700
 DOCN  M9590700
 TI    Small Hydroxylated Aromatic Inhibitors of HIV-1 Integrase as Potential
       Anti-AIDS Drugs
 DT    9509
 AU    Burke Jr TR; Fesen M; Driscoll J; Yung J; Kohn K; Pommier Y; Laboratory
       of Medicinal Chemistry, Developmental Therapeutics; Program, DCT, NCI,
       NIH; Bldg. 37, Rm 5C06; Bethesda, MD
 SO    NIH Conf Retroviral Integrase. 1995 Jan 19-20;:(Participants' abstracts
       and posters, abstract no. 1). Unique Identifier : AIDSLINE AIDS/95920019
 AB    A number of HIV integrase inhibitors have been identified using the
       cell-free assay originally developed by Craigie et al. based on the two
       step base deletion/transesterification mechanism of the enzyme. Many of
       these inhibitors contain ployhydroxylated aromatic rings, with several
       also having secondary degrees of unsaturation. One of these inhibitors,
       caffeic acid phenethyl ester (CAPE), was selected as a model compound
       for an examination of structural features important for integrase
       inhibition. Approximately 30 synthetic analogues were prepared, which
       focused on four aspects of CAPE structure: (1) the ester group, (2) the
       ring substituents, (3)conformation of the aryl ring and vinyl side
       chain, and (4) amide analogues. This study has yielded some interesting
       conclusions. (A) The ester group: While the nature of the aryl group was
       somewhat important, the connecting chain length (in the range from one
       to three carbons) was not. (B) Ring substituents: The number and nature
       of ring substituents greatly affected potency. Replacement of the
       hydroxyl groups with either one or two methyl ethers resulted in
       substantial or complete loss of potency, as did replacement of the
       hydroxyls with fluorines. Altering the 3,4-dihydroxy patter of CAPE to
       the 2,5- dihydroxy pattern of the protein-tyrosine kinase inhibitor
       erbstatin, resulted in a significant loss of potency, while addition of
       a third hydroxyl group increased potency. Data suggested that
       ortho-hydroxyl substitution is important for inhibition. (C)
       Conformationally restricted analogues: The dihydroxyphenyl portion of
       CAPE can rotate about the vinylic C-C bond, resulting in two distinct
       rotational isomers. Bicylic analogues were prepared which represented
       conformationally constrained analogues of the open-chain CAPE rotamers.
       Hydroxylation pattern had a significant effect on the potency of these
       bicyclic analogues. Additionally, unlike the open-chain series, where
       replacement of the phenethyl ester with a methyl ester abrogated
       potency, a similar change in the bicyclic series retained the full
       potency of parent CAPE. (D) The ester bond and vinylic double bond: The
       hydrogenated analogue of CAPE (lacking the side chain double bond)
       retained near full potency, while replacement of the ester oxygen with a
       nitrogen in this saturated series greatly reduced potency. Full potency
       of the amide derivative could be regained by addition of ortho hydroxyls
       to the phenethyl side chain. Although three analogues have been
       confirmed moderately active in the NCI in vitro anti-HIV screen, there
       did not appear to be a direct correlation with integrase inhibition
       potency. One limiting parameter seems to be cytotoxicity, which results
       in a low therapeutic index. Further work is in progress to improve the
       therapeutic index by decreasing cytotoxicity.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY/ENZYMOLOGY  Caffeic
       Acids/CHEMISTRY/*PHARMACOLOGY/THERAPEUTIC USE  DNA
       Nucleotidyltransferases/*ANTAGONISTS & INHIB  Enzyme
       Inhibitors/CHEMISTRY/PHARMACOLOGY  Esters  HIV/*ENZYMOLOGY
       Hydroxylation  Molecular Structure  MEETING ABSTRACT

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