GEOMETRICALLY AND CONFORMATIONALLY RESTRAINED CINNAMOYL COMPOUNDS AS INHIBITORS OF HIV-1 INTEGRASE - SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR MODELING

Citation
M. Artico et al., GEOMETRICALLY AND CONFORMATIONALLY RESTRAINED CINNAMOYL COMPOUNDS AS INHIBITORS OF HIV-1 INTEGRASE - SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR MODELING, Journal of medicinal chemistry, 41(21), 1998, pp. 3948-3960
Citations number
50
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
41
Issue
21
Year of publication
1998
Pages
3948 - 3960
Database
ISI
SICI code
0022-2623(1998)41:21<3948:GACRCC>2.0.ZU;2-Q
Abstract
Various cinnammoyl-based structures were synthesized and tested in enz yme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrain ed analogues of caffeic acid phenethyl ester (CAPE) and were character ized by a syn disposition of the carbonyl group with respect to the vi nylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn dispositi on could favor anti-HIV-1 activity in cell-based assays. Geometrical a nd conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambr idge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclope ntanone, cyclohexanone, 1,3-diacetylbenzene, 2,4-dihydroxyacetophenone , 2,3-dihydro-1-indanone, 2,3-dihydro-1,3-indandione, and others. Whil e active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multipl ication in acutely infected MT-4 cells. Nevertheless, they specificall y inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellula r (RNA polymerase II) nucleic acid-processing enzymes. On the other ha nd, title compounds were endowed with remarkable antiproliferative act ivity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoiso merases. The SARs developed for our compounds led to novel findings co ncerning the molecular determinants of IN inhibitory activity within t he class of cinnamoyl-based structures. We hypothesize that these comp ounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disp osition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curc umin) which favorably interact with an ''accessory'' region of IN. Thi s region is supposed to be located adjacent to the binding site accomm odating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of co planarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain en ergy of the coplanar conformation.