Bioorganic & Medicinal Chemistry Letters
Evaluation of HIV-1 inhibition by stereoisomers and analogues
of the sesquiterpenoid hydroquinone peyssonol A
Daniel S. Treitler a, Zhufang Li b, Mark Krystal b, Nicholas A. Meanwell c, Scott A. Snyder a,
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a Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA
b Bristol-Myers Squibb, Department of Infectious Diseases, 5 Research Parkway, Wallingford, CT 06492, USA
c Bristol-Myers Squibb, Department of Medicinal Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized race-
mically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds
were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure–activity
relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A
are responsible for its potency, while the stereochemical configuration of the substituents on the ali-
phatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues
tested were as potent as the parent natural product, several exhibited greater therapeutic indices due
to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 November 2012
Revised 17 January 2013
Accepted 22 January 2013
Available online 31 January 2013
Keywords:
Peyssonol A
Human immunodeficiency virus
Sesquiterpenoid hydroquinones
Brominated natural products
Privileged scaffolds
The sesquiterpenoid hydroquinone and quinone natural prod-
ucts arguably contain a ‘privileged scaffold’1 due to their ubiquity
in nature and their incredible diversity of bioactivities.2,3 Across
that broad range of biochemical properties, however, it is their po-
tential as inhibitors of HIV-1 that has garnered much attention
over the course of the past quarter century.4–6 Perhaps the most
well-known compound with such activity is avarol; it, along with
its oxidized variant, avarone (1 and 2, Fig. 1), has been shown to in-
hibit HIV-1 in cell culture at concentrations as low as 300 nM.7
Mechanistic studies have implicated an intriguing pathway for
their activity that involves inhibition of the function of a suppres-
sor tRNA required for the readthrough of a UAG termination codon
in the gag-pol junction of the mRNA sequence.8 In the absence of
this particular tRNA, translation is terminated prior to synthesis
of the proteins encoded by the pol gene (reverse transcriptase,
integrase, and protease). Intriguingly, naturally occurring ana-
logues such as avarol F (3) and avarone E (4),9 as well as related
sesquiterpenoid (hydro)quinones ilimaquinone (5)10 and peysso-
nol A (6),11,12 have all been found to be allosteric inhibitors of re-
verse transcriptase. Thus, despite the structural similarity
between these compounds and avarol, it appears that they have
a complementary mechanistic pathway for HIV-1 inhibition. Nev-
ertheless, these compounds typically suffer from high cytotoxicity,
precluding their use in humans as pharmaceuticals.
In an effort to improve upon the potency and cytotoxicity of the
sesquiterpenoid (hydro)quinones, a number of analogues of ava-
rol13,14 and ilimaquinone10 have been synthesized via modification
of the parent structures and subsequently evaluated for HIV-1 inhi-
bition. To date, these modifications have focused exclusively on the
hydroquinone/quinone rings, and the resultant compounds have
generally proven to be less potent and/or significantly cytotoxic.
To the best of our knowledge, no structure–activity relationship
(SAR) studies have been undertaken to examine the effects of mod-
ifying the aliphatic decalin portion of the molecules; this situation
is presumably due to the difficulty of functionalizing this relatively
inert alkane-based portion of the framework. Herein, we describe
efforts that systematically investigate the importance of the deca-
lin framework of the sesquiterpenoid hydroquinone natural prod-
uct peyssonol A (6) for both anti-HIV-1 activity and overall
background cytotoxicity.
Our interest in this question derives from our recently pub-
lished racemic total synthesis of peyssonol A (6),15 the key step
being a bromonium-induced polyene cyclization cascade initiated
by
a
reagent pioneered by our group known as BDSB
bromodiethylsulfonium bromopentachloro-
(Et2SBrÁSbBrCl5,
antimonate).16 The key finding of these efforts was that the origi-
nally assigned structure for peyssonol A (16, vide infra), one postu-
lating a cis-decalin framework, was inaccurate. This structural
correction required the preparation of four different diastereomers
of the final structure, efforts which began, as shown in Scheme 1,
by transforming each of the four different geometric isomers of
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Corresponding author.
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