6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.10.088

Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck's raltegravir and Gilead's elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The em

Full text of DOI:10.1016/j.bmcl.2012.10.088

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7309–7313
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1
integrase inhibitors
Xue Zhi Zhao a, , Kasthuraiah Maddali b, Steven J. Smith c, Mathieu Métifiot b, Barry C. Johnson c,
⇑
Christophe Marchand b, Stephen H. Hughes c, Yves Pommier b, Terrence R. Burke Jr. a,
⇑
a Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States
b Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
c HIV Drug Resistance Program, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 27 October 2012
Although an extensive body of scientific and patent literature exists describing the development of HIV-1
integrase (IN) inhibitors, Merck’s raltegravir and Gilead’s elvitegravir remain the only IN inhibitors FDA-
approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing
mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors
against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that
show good IN inhibitory potency. This report describes the effects of introducing substituents into the
4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several
sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-
of-magnitude and we describe several compounds that are more potent than raltegravir against the clin-
ically relevant Y143R IN mutant.
Keywords:
HIV-1 integrase
Inhibit
Raltegravir
Sulfonamide
Published by Elsevier Ltd.
Integrase (IN) is an HIV-1 encoded polynucleotidyl transferase
that inserts viral cDNA into the host genome through a process
involving two sequential enzymatic steps, termed 30-processing
(30-P) and strand transfer (ST).1 Integration is required for viral rep-
lication and IN is a validated antiviral target for the treatment of
AIDS.2,3 There is an extensive body of scientific and patent litera-
ture describing the development of IN inhibitors.4,5 Raltegravir
(1) is the first IN inhibitor FDA-approved for the treatment of
HIV/AIDS (Fig. 1).6 Raltegravir binds at the interface of the macro-
molecular complex formed by IN and the viral DNA substrate,
blocking the active site and preventing the insertion of the viral
DNA into the host genome.7 Because it more potently blocks the
second enzymatic step, it is referred to as an IN strand transfer
inhibitor, or INSTI. All anti-HIV drugs select for resistant strains
of the virus and raltegravir is no exception. Because there are clin-
ical strains of HIV-1 that exhibit reduced sensitivity to raltegravir,8
‘second-generation’ inhibitors are being developed to treat pa-
tients failing raltegravir-based treatment.9 However, in in vitro
experiments exposure to such compounds selected IN mutants
showing reduced susceptability,10,11 suggesting that additional
work needs to be done to understand the underlying mechanisms
of resistance, and to develop new compounds that will be more
effective against resistant strains.
Raltegravir shares with other well-described INSTIs, the ability
to chelate two catalytic divalent metal ions (Mn2+ or Mg2+) through
a triad arrangement of heteroatoms (Fig. 1). We have previously
described structurally simple bicyclic 6,7-dihydroxyoxoisoindo-
lin-1-one-based IN inhibitors (2) that show good potency and
strand transfer selectivity in vitro in the presence of Mg2+ cofac-
tor.12 Our earlier reports focused primarily on the arylamide ‘right
side’ of the molecules.13,14 This paper describes the effects of sub-
stitutions at the two free aryl positions on the ‘left side’ of the mol-
ecule (Fig. 1). In designing new analogs we were guided by the fact
that Merck’s bicylic second-generation inhibitor MK-0536 (3)15,16
has carboxamido and isopropyl substituents at what would be
equivalent to positions 4 and 5 of our 1-oxoisoindoline ring system
(Fig. 1). We applied a variation of this theme to the dihydroxyoxo-
isoindoline nucleus by placing several different alkyl groups at the
5-position (4) and employing sulfonamido rather than carboxa-
mido functionality at the 4-position (5, Fig. 1).
Synthesis of derivatives of compound 4 modified at the 5-posi-
tion employed methodologies similar to those used to prepare the
unsubstituted congeners.12–14 Substituents that would ultimately
occupy the 5-position of the 6,7-dihydroxyoxoisoindolines final
products were derived from appropriately substituted methyl
dimethoxybenzyl ethers (6, Scheme 1). Methyl-substituted 6b
⇑
Corresponding authors. Tel.: +1 301 846 5906; fax: +1 301 846 6033 (T.R.B.);
tel.: +1 301 846 5907; fax: +1 301 846 6033 (X.Z.Z.).
E-mail addresses: xuezhi.zhao@nih.gov (X.Z. Zhao), burkete@helix.nih.gov (T.R.
Burke).
0960-894X/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.10.088

7310
X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7309–7313
containing analog 6f was obtained from commercially-available
OH
O
F
(3,4,5-trimethoxyphenyl)methanol by methylation using iodo-
methane and sodium hydride (see Supplementary Scheme S5).
Treatment of the benzyl methyl ethers 6(a–f) with n-butyl lith-
ium followed by methyl chloroformate provided the corresponding
methyl esters 7(a–f) (Scheme 1). Transformation to the benzyl
chlorides 8(a–f) was then accomplished using acetyl chloride in
the presence of a catalytic amount of zinc chloride. Subsequent
ring closure to the isoindolin-1-ones 9(a–f) was achieved by cou-
pling with 3-chloro-4-fluorobenzylamine. The final 5-substituted
6,7-dihydroxyisoindolin-1-ones 2, 4(b–e, g, h) were obtained by
demethylation using boron tribromide in dichloromethane
(Scheme 1).
Introduction of sulfonyl functionality at the indolin-1-one
4-position was achieved by reacting the methyl ether-protected
intermediates 9(a–f) with chlorosulfonic acid gave the sulfonyl
chlorides 10(a–f, h) (Scheme 2). Further treatment with a variety
of primary and secondary amines yielded the corresponding sul-
fonamides 11(a–n)–11(f–n) and 11(h–n), where ‘n’ designates var-
iation in the sulfonamido group. Finally, deprotection of the methyl
ethers was accomplished by cleavage with boron tribromide in
dichloromethane to produce the final products 5(a–n)–5(e–n),
5(g–n) and 5(h–n) (Scheme 2).
O
N
H
OH
O
Cl
N
N
7
F
HO
1
6
N
HN
2
5
3
4
O
N
O
N
1
2
Raltegravir
OH
Dihydroxyisoindole
F
O
O
OH
O
N
Cl
HO
N
F
N
Cl
R1
O
N
R2
4 R1 = H
3
MK-0536
5 R2 = Sulfonamido
Figure 1. Structures of IN inhibitors discussed in the text.
OMe
OMe O
Our previous structural studies on 6,7-dihydroxyoxoisoindolin-
1-one-based IN inhibitors (2) were limited to analogs that were
unsubstituted at the 4- and 5-positions.12–14 An important objec-
tive of our current work was to explore the effects of incorporating
functionalities at the 5-position of the isoindolinone ring system
(compounds 4). MK-0536 (3) is one example of a diverse range
of IN inhibitors that have substituents in this region.5 We were also
interested in determining the effects of placing sulfonamido
groups at the 4-position. Highly potent IN inhibitors have been re-
ported that have sulfonamide groups located in this region. How-
ever, in almost all cases the sulfonamides are either in ‘reversed’
orientations, having the amine rather than the sulfur attached to
the metal-chelating aryl ring (for example19,20), or the sulfonamide
is attached indirectly through intervening structures (for exam-
MeO
R1
i
MeO
R1
ii
OMe
OMe
OMe
6(a - f)
7(a - f)
F
OMe O
OMe
O
Cl
MeO
R1
MeO
R1
iii
OMe
Cl
N
8(a - f)
9(a - f)
OH
F
O
Cl
HO
R1
iv
N
2, 4(b - e, g, h)
F
OMe
O
Cl
i
R1 = a, H; b, Me; c, nBu; d, Pr; e, Ph; f, OMe;
i
ii
9(a - f)
MeO
R1
g, OH; h,
O
O
N
S
NMe2
O
S
O
Cl
Scheme 1. Reagents and conditions: (i) nBuLi, ClCO2Me; (ii) AcCl, ZnCl2, Et2O; (iii)
3-chloro-4-fluoro-benzylamine, Et3N, CH3CN; (iv) BBr3, CH2Cl2.
10(a - f, h)
F
F
OMe
OH
O
O
Cl
Cl
iii
was obtained from vanillin using 4-hydroxy-3-methoxy-5-methyl-
benzaldehyde17 as an intermediate (see Supplementary Scheme
S1). The n-butyl-substituted compound (6c) was obtained seren-
dipitously in an attempt to prepare the isopropyl congener (6d).
The synthesis started from 5-bromovanillin and there was an unin-
tended introduction of the n-butyl group when n-butyl lithium
was used for metalation of the aryl bromide of intermediate 1-bro-
mo-2,3-dimethoxy-5-(methoxymethyl)benzene (see Supplemen-
tary Scheme S2). The desired isopropyl containing analog (6d)
was synthesized through the known 5-bromo-1-isopropyl-2,3-
dimethoxybenzene18 (see Supplementary Scheme S3). The phe-
nyl-substituted compound 6e was obtained through a route
involving Suzuki coupling of phenylboronic acid with the above-
mentioned 1-bromo-2,3-dimethoxy-5-(methoxymethyl)benzene
(see Supplementary Scheme S4). Finally, the trimethoxyphenyl-
MeO
R1
HO
R1
N
N
O
S
X
O
O
S
X
O
11(a-n) - 11(f-n), 11(h-n)
5(a-n) - 5(e-n), 5(g-n), 5(h-n)
R1
h
n
i
a b c d e f g
= , H; , Me; , Bu; , Pr; , Ph; , OMe; , OH;
,
O
O
S
NMe2
Scheme 2. Reagents and conditions: (i) ClSO3H; (ii) R2R3NH, Et3N, CH2Cl2; (iii) BBr3,
CH2Cl2.

X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7309–7313
7311
Table 1
Table 2
Inhibitory potencies using an in vitro IN assaya
Inhibitory potencies using an in vitro IN assaya
F
F
OH
O
OH
Cl
O
Cl
HO
HO
N
N
R
O
S
X
O
No.
R
IC50 values (
lM)
30-Processing
Strand transfer
2b
H
13.2 3.1
>111
>111
>111
>111
0.16 0.08
11.5 1.6
6.8 0.9
5.4 0.6
0.87 0.08
1.5 0.3
No.
X
IC50 values (lM)
30-Processing
Strand transfer
4b
4c
4d
4e
4g
Me
nBu
iPr
Ph
OH
5a-1
5a-2
NHMe
NEt2
17.5 3.0
9.5 1.2
0.12 0.04
0.054 0.009
H
36.0 6.0
5a-3
5a-4
14.7 1.7
15.9 1.3
0.11 0.01
0.24 0.02
Br
N
N
O
S
N
H
4h
>111
0.4 0.04
N
O
H
N
a
Assays were performed using
describe in Ref. 12.
a
gel-based protocol with Mg2+ cofactor as
N
5a-5
5a-6
30.2 2.3
19.3 0.6
0.32 0.05
0.31 0.03
O
b
Reported previously in Refs. 12–14.
H
N
N
HN
ple21). In some instances, carboxamide rather than sulfonamide
functionality is employed, as in MK-0536 (3).
The IN inhibitory IC50 values of the synthetic analogs against
both 30-P and ST reactions were determined using an in vitro assay
employing Mg2+ cofactor as previously described.12 Introduction of
substituents at the 5-position uniformly decreased ST inhibitory
H
N
5a-7
5a-8
23
23
3
4
0.37 0.04
0.4 0.08
N
N
N
N
potency relative to the unsubstituted parent (2; ST IC50 = 0.16
in most cases by more than one order of magnitude (Table 1). The
least deleterious substituents were phenyl (4e; ST IC50 = 0.87 M)
and 4-dimethylsulfonamidophenyl (4h; ST IC50 = 0.4 M). With
the exception of the 5-hydroxy analog (4g; 30-P IC50 = 36.0
M),
all the substituents we tested reduced the 30-P inhibitory potency
by at least an order of magnitude (30-P IC50 >111
M) relative to
the parent 2 (30-P IC50 = 13.2
M).
In contrast, introducing sulfonamide groups at the 4-position of
parent compound 2 had little effect on inhibitory potencies in 30-P
reactions relative to 2 (Table 2). However, ST inhibitory potencies
were generally increased (5a-1 to 5a-3 and 5a-9 to 5a-12) with
lM),
5a-9
21.2 1.9
6.8 1.1
0.19 0.08
N
H2N
O
l
N
l
5a-10
0.047 0.007
l
H
N
5a-11
5a-12
11.7 0.7
6.9 0.6
0.08 0.01
HO2C
HO2C
l
l
0.058 0.01
N
a
Assays were performed using
described in Ref. 12.
a
gel-based protocol with Mg2+ cofactor as
ST IC50 values ranging from 0.047 to 0.19 lM). These results are
similar to what has been reported for the effects of sulfonamido
functionality in this general structural region of other IN inhibi-
tors.19–21 A recent report showed that introduction of 5-sulfon-
amido groups onto N-(4-fluorobenzyl)-2,3-dihydroxybenzylamide
increased inhibitory potency.22 This is of note, since we had
originally designed the 6,7-dihydroxyisoindolin-1-ones as con-
formationally constrained variants of N-(4-fluorobenzyl)-2,3-
dihydroxybenzylamide.12 We found that this constraint increased
the inhibitory potency of the compounds in the ST reaction by
approximately ten-fold. The enhancing effects of sulfonamido sub-
stituents in our current conformationally constrained analogs is
consistent with enhancing effects reported for the ring-open
compounds.22
Although substituents at the 5-position (4b–4h) decreased
inhibitory potencies in the ST reactions compared to the parent
compound 2, these potentially represented biased examples, since
the compounds lacked functionalities at the adjoining 4-position
(Table 1). IN inhibitors often have substituents at both the 4 and
5-position, as exemplified by raltegravir (1) and MK-0536 (3).
Therefore, a series of analogs was prepared that combined sulfon-
amido functionality at the 4-position with various substituents at
the 5-position (Table 3). Adding a 4-sulfonamido group increased
the inhibitory potencies in the ST reaction relative to the com-
pounds described in Table 1. The increase was most pronounced
in the case of 5d-2 (ST IC50 = 0.19
at the 5-position. This led to a 20-fold enhancement in the ST reac-
tion relative to the parent i-Pr-containing 4d (Table ST
IC50 = 5.4 M). However, for a given 4-sulfonamido group, intro-
lM), which has an i-Pr group
1
l
ducing substituents at the 5-substituent decreased ST inhibitory
potency (Table 3).
Clinical resistance to raltegravir (1) is associated primarily with
IN mutations at amino acids Y143, Q148 and N155.23 In order to
examine the effects of these resistance mutations on the potency
of the new compounds, antiviral efficacy (EC50 values) were deter-
mined for select inhibitors using HIV vectors that replicated using
either WT IN or vectors carrying Y143R, N155H, or the G140S-
Q148H double mutant (designated as ‘SH’) (Table 4).24,25 Sub-
micromolar EC50 values were obtained against the wild-type vector
for several of the sulfonamide derivatives that lacked a substituent
at the 5-position (‘5a’ compounds, Table 4) and for certain com-
pounds, nanomolar potencies (17–40 nM) were observed. Compar-
ing in vitro IC50 values obtained for inhibition of ST reactions with
the cellular EC50 values revealed differing degrees of concordance.

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X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7309–7313
Table 3
in vitro in ST inhibition assays depend on factors, such as the con-
Inhibitory potencies using an in vitro IN assaya
centration of substrate DNA, that may be different in the cellular
environment.27 Two compounds (5a-11 and 5a-12) provided anti-
viral EC50 values that were higher than their corresponding in vitro
ST IC50 values. These compounds contained anionic carboxylic acid
functionality that would be expected to reduce cellular
bioavailability.
F
OH
O
Cl
HO
R
N
In cell-based assays performed with HIV vectors carrying the
Y143R mutant, raltegravir (1) has been reported to exhibit an
approximate 40-fold loss of potency relative to the WT en-
zyme.24,25 This loss of potency can be understood on the basis of
X-ray crystallographic studies with the prototype foamy virus
(PFV) intasome, which show that the oxadiazole ring of raltegravir
O
S
X
O
No.
R
X
IC50 values (lM)
30-Processing
Strand transfer
5b-2
5c-2
5d-2
Me
nBu
iPr
NMe2
NMe2
NMe2
49.7 4.0
>111
2.8 0.6
2.3 0.4
makes extensive interactions through
p-stacking with the side
>111
0.19 0.03
chain aryl ring of Y212 of PFV IN (which is equivalent to Y143 of
HIV-1 IN). Replacement of Tyr with Arg eliminates these interac-
tions and is generally understood to account for the reduced po-
tency of raltegravir against the Y143R mutant.28 The retention of
relative good potency against the Y143R mutant shown by all sul-
fonamides in Table 4 is consistent with the absence of aromatic
functionality equivalent to raltegravir’s oxadiazole ring;29 none of
N
5d-10
5g-2
iPr
>111
0.41 0.06
0.26 0.08
O
NMe2
OH
7.6 0.8
O
S
N
5h-2
NMe2
35.2 2.6
0.25 0.06
O
these compounds rely on a p–p interaction with Y143.
Raltegravir has also been reported to exhibit an approximate
40-fold loss of antiviral potency in cellular studies employing
HIV vectors bearing the N155H mutant.25 Crystallographic studies
with the PFV intasome show that the side chain of N224 (equiva-
lent to N155 of HIV-1 IN) forms a hydrogen bond with the carbox-
ylate group of E221, which is part of the catalytic ‘DDE’ triad
chelating the divalent Mg2+ ions. In the case of N224H mutant,
the His imidazole ring makes electrostatic interactions with the
phosphate group of the 30adenosine of the viral DNA, causing a
shift in the position of the DNA backbone and the catalytic Asp
and Glu carboxlylates (PFV D128 and E221).28 Binding of INSTIs re-
quires the energetically unfavorable breaking of the His-phosphate
interaction. The sulfonamides shown in Table 4 exhibit a range of
sensitivities to the N155H mutation that are both greater and less
than what has been reported for raltegravir. Interestingly, com-
pounds having bulky n-butyl or i-propyl groups at the 5-position
were significantly less affected by the mutation (5c-2, 5d-2 and
5d-10, Table 4). Although the absolute potencies of these latter
compounds against the WT enzyme is not as good as some of the
other inhibitors shown in Table 4, their ability to retain inhibitory
efficacy against the N155H mutant may reflect an enhanced capac-
ity to break the H155 imidazole–phosphate interaction and re-
order the DNA needed to accommodate ligand binding.
Raltegravir has also been reported to exhibit an approximate
500-fold loss of antiviral potency in cellular studies employing
HIV vectors having the 140S/Q148H [designated as ‘SH’] double
mutant.25 G140 and Q148 correspond to PFV residues S209 and
S217, respectively, which occupy the termini of the ‘flexible loop’
bearing the Y212 residue (Y143 of HIV-1 IN), which is critical for
raltegravir binding. Crystallographic studies with the PFV intasome
show that the S217H mutation requires a shift in the His side chain
to accommodate binding of the fluorbenzyl ring of raltegravir.28
Due to their positions sat the termini of the flexible loop, the side
chains of the S140 and H148 residues are in close proximity. In the
‘SH’ double mutant, movement of the bulky H148 side chain is ste-
rically impeded by the side chain of S140. In antiviral studies using
the SH mutant, sulfonamides lacking substituents at the 5-position
exhibited two-orders-of-magnitude reductions in potency (5a-n,
Table 4). The 5-substituted sulfonamides showed less relative loss
of potency. However, similar to what was observed against the
N155H mutant, in most cases the absolute efficacy of these inhib-
itors against wild-type IN was also reduced.
a
Assays were performed using
a
gel-based protocol with Mg2+ cofactor as
describe in Ref.12.
Table 4
Antiviral potencies in cell infected with HIV-1 containing wild-type or mutant
integrase enzymesa
No.
CC50
(l
M)
EC50
(
lM)
SId
Integrase mutantse
b
c
Y143R
N155H
SHf
2
5.2
4.3
8.4
4.6
6.2
0.447
0.040
0.017
0.093
0.043
0.022
0.929
0.140
0.322
3.8
12
1x
1x
3x
1x
1x
2x
3x
2x
2x
1x
3x
4x
2x
4x
2x
8x
5a-1
5a-2
5a-3
5a-8
5a-10
5a-11
5a-12
5b-2
5c-2
5d-2
5d-10
5g-2
5h-2
108
494
49
144
241
115
680
20
2
3
2
29
19x
57x
68x
44x
23x
ND
272x
12x
4x
2x
2x
10x
16x
95x
300x
132x
430x
218x
ND
ND
30x
1x
4x
3x
ND
25x
5.3
106.6
95.2
6.3
7.0
12.1
5.9
3.6
3.4
0.159
0.132
4.6
2.8
21
a
Assays were performed as described in Ref. 25.
Cytotoxic concentration resulting in 50% reduction in the level of ATP in human
b
osteosarcoma (HOS) cells.
c
Values obtained from cells infected with lentiviral vector harboring WT IN.
Selectivity index calculated as the ration of CC50–EC50
Cells were infected with viral constructs carrying IN mutantion as described in
d
.
e
Ref. 25 and indicated values correspond to the fold-change in EC50 relative to WT.
f
G140S-Q148H double mutant.
Compounds 5a-1, 5a-2, 5a-3 and 5a-10 gave EC50 values (0.04,
0.017, 0.93 and 0.022
better than the corresponding in vitro ST IC50 data (0.12, 0.054,
0.11 and 0.047 M, respectively, Table 2). Compound 5a-8 showed
a 10-fold enhancement in its cellular antiviral EC50 value relative to
its in vitro ST IC50 data (0.043 and 0.4 M, respectively). This is
somewhat unexpected, because 5a-8 contains a piperazine nitro-
gen that should be protonated at physiological pH, and this
charged species would be expected to reduce cell membrane
transit.
lM, respectively, Table 4) that were slightly
l
l
It is not uncommon for cell-based antiviral efficacy to be greater
than the IC50 data obtained in vitro in ST inhibition assays.12–14,26
This may be due in part to the fact that IC50 values obtained
Except for those compounds bearing free carboxylic acid groups
(5a-11 and 5a-12), which may adversely affect cellular uptake,

X. Z. Zhao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7309–7313
7313
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cytotoxicity CC50 values for all sulfonamides in Table 4 were uni-
formly in the low micromolar range and very similar to the value
of 5.2 lM reported for the parent 6,7-dihydroxyisoindolinone (2).
6. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.;
Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer,
R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.;
Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. J. Med. Chem. 2008, 51,
5843.
7. Pommier, Y.; Marchand, C. Nat. Rev. Drug Disc. 2012, 11, 25.
8. Charpentier, C.; Karmochkine, M.; Laureillard, D.; Tisserand, P.; Belec, L.; Weiss,
L.; Si-Mohamed, A.; Piketty, C. HIV Med. 2008, 9, 765.
Although cytotoxicity remained unchanged, several of the sulfon-
amide-containing analogs exhibit cellular EC50 values that are
approximately two orders-of-magnitude better than the parent 2.
The overall effect was to improve the ‘selectivity index’ (SI =
CC50/EC50) for several sulfonamides by two orders-of-magnitude
relative to 2.
Our current report describes the effects of introducing substitu-
ents into the 4- and 5- positions of the parent 6,7-dihydroxyoxois-
oindolin-1-one platform. We found that several sulfonamide-
containing analogs exhibit potencies in cell-based HIV assays that
are enhanced by more than two orders-of-magnitude. The overall
effect of these efforts has been to generate several compounds
exhibiting better absolute efficacy than raltegravir against the
clinically relevant Y143R IN mutant and with SI values exceeding
100. Although cytotoxicity remains an issue, our current work
has advanced the development of the 6,7-dihydroxyisoindolinone
platform.
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Acknowledgments
This work was supported in part by the Intramural Research
Program of the NIH, Center for Cancer Research, Frederick National
Laboratory for Cancer Research and the National Cancer Institute,
National Institutes of Health and the Joint Science and Technology
Office of the Department of Defense. The content of this publica-
tion does not necessarily reflect the views or policies of the Depart-
ment of Health and Human Services, nor does mention of trade
names, commercial products, or organizations imply endorsement
by the US Government.
Supplementary data
24. Metifiot, M.; Maddali, K.; Naumova, A.; Zhang, X.; Marchand, C.; Pommier, Y.
Biochemistry 2010, 49, 3715.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.10.088.
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