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