netLibrary - eBook Summary Structure-based Drug Design by ...

Document
Page 106
on the same ring or can potentially be positioned close together in three-dimensional space if rings stack
on top of each other. More recently it was shown that cosalane (II), a steroid-substituted derivative of
(I), was no better in inhibiting integrase in vitro than the parent compound, but showed promise in HIV
cytopathicity cell-culture assays [45]. Although cosalane and a number of related analogues inhibit both
HIV protease and integrase in vitro, the primary site of action is believed to be inhibition of gp120
binding to CD4 receptors.
In 1993, the effects of selected topoisomerase II inhibitors, antimalarial agents, DNA binders,
naphthoquinones, and various other agents on integrase activity in vitro were investigated [46].
Although certain effective topoisomerase inhibitors are also good HIV integrase inhibitors, this is not a
generalizable correlation. Since many topoisomerase inhibitors also bind DNA, it is difficult to assess
whether the observed in vitro effects result from specific interaction with integrase or from the
sequestering or distorting of the DNA substrate. However, several compounds were identified that are
not known to be DNA binders but that inhibited integrase with reasonable IC 50 values. These included
dihydroxynaphthoquinone (III), primaquine (IV), caffeic acid phenethyl ester (CAPE, V), and quercetin
(VI).
Motivated by the structural similarities between compounds III–VI, a more intensive structure-function
study of flavones was undertaken in which approximately 50 related compounds were screened for
inhibition of in vitro integrase activity [47]. Flavones are planar compounds containing three aromatic
rings substituted with various polar groups such as hydroxy substituents. General trends were observed
relating structure to inhibitory effectiveness; for example, inhibition required at least three hydroxy
groups, the most favorable arrangement being when they were located ortho to one another. The most
effective compound, quercetagetin (VII), is a potent topoisomerase II inhibitor and a known DNA
intercalator. It was noted by the authors that many flavones are not integrase-specific; rather, they inhibit
a broad range of enzymes including DNA polymerases, ATPases, and NAPDH-monooxygenases. They
are also, in general, capable of DNA intercalation. It has not been established that their inhibitory effects
are due to direct interactions with integrase.
A subsequent detailed structure-activity relationship study of CAPE (V) revealed that while the ortho
hydroxys were important for in vitro integrase inhibition, both the caffeic acid and phenethyl moieties
could be substantially modified [48]. Ortho hydroxyl groups in the context of other classes of
compounds also confer anti-integrase potency. For example, several semisynthetic compounds derived
from arctigenin, a topoisomerase I inhibitor that itself is not active against integrase, have been shown to
inhibit HIV integrase [49]. More compelling evidence of the importance of ortho hydroxyl groups was
provided by the tyrphostins, a group of synthetic compounds that are tyrosine kinase inhibitors. Several
of these also inhibit integrase in the submicromolar range
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_106.html [4/5/2004 4:52:16 PM]