BMS Derivatives C7-Linked to β-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides

Article abstract of DOI:10.1002/cmdc.202100080

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1_NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4^th generation, are reported here for the first time.

Full text of DOI:10.1002/cmdc.202100080

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BMS Derivatives C7-Linked to β-Cyclodextrin and
Hyperbranched Polyglycerol Retain Activity against R5-HIV-
1
NLAD8 Isolates and Can Be Deemed Potential Microbicides
Elena Petit,[a] Lluís Bosch,[a] Anna M. Costa,[a] Ignacio Rodríguez-Izquierdo,[b]
Daniel Sepúlveda-Crespo,[b] M. Angeles Muñoz-Fernández,[b] and Jaume Vilarrasa*[a]
microbicides, such as carraguard (a natural sodium polysacchar-
idesulfate) and PRO2000 (a polynaphthalenesulfonate) were
soon shown to be inefficient. Indeed, many were contra-
indicated as they produced vaginal irritation so virus entry was
then enhanced. The addition of anti-HIV drugs, either entry
inhibitors (ENIs), nucleoside/nucleotide reverse-transcriptase
inhibitors (NRTIs), non-nucleoside RTIs (NNRTIs), integrase
inhibitors (INIs), or protease inhibitors (PIs), to gels, creams, and
rings was soon considered.[2] These so-called third-generation
microbicides (Figure 1, first row) have proved more successful,
but only a gel containing 1% of a tenofovir prodrug (a
commercially available RTI taken orally as tenofovir disoproxil
fumarate or as tenofovir alafenamide, which are usually mixed
with other RTIs or with RTIs and INIs in a single pill) and a
vaginal ring with dapivirine (a known NNRTI) have reached
Phase III clinical trials.[2] Unfortunately, a very recent report
indicates that this last approach reduces risk of transmission by
only 29%, whereas the other microbicides mentioned “had no
evident effect”.[2a] Fortunately, research into dendrimers,[2e]
electrospun fibers, probiotics, and mixtures of different types of
anti-HIV drugs[1d] is in progress.
Amides from indole-3-glyoxylic acid and 4-benzoyl-2-meth-
ylpiperazine, which are related to entry inhibitors developed by
Bristol-Myers Squibb (BMS), have been synthesized with
aliphatic chains located at the C7 position of the indole ring.
These spacers contain an azido group suitable for the well-
known Cu(I)-catalyzed (3+2)-cycloaddition or an activated
triple bond for the nucleophilic addition of thiols under
physiological conditions. Reaction with polyols (β-cyclodextrin
and hyperbranched polyglycerol) decorated with complemen-
tary click partners has afforded polyol-BMS-like conjugates that
are not cytotoxic (TZM.bl cells) and retain the activity against
R5-HIV-1NLAD8 isolates. Thus, potential vaginal microbicides
based on entry inhibitors, which can be called of 4th generation,
are reported here for the first time.
The term “microbicides” originally designated medicinal drugs
targeting sexually transmitted diseases in general. With the
advent of the AIDS pandemic, it is more commonly used for
chemicals that can be applied topically to the vagina or rectum
to kill, neutralize, or block HIV-1 as well as other viruses or
pathogens, as a prophylactic treatment. Microbicides can be
formulated as gels, creams, films, suppositories, tablets, or as
slow-release sponges or vaginal rings,[1] which may or may not
have spermicidal activity. HIV continues to spread, mainly in
sub-Saharan Africa; every year around 380,000 young women
are infected.[1] According to the WHO and the International
Partnership for Microbicides (IPM), increased availability of
microbicides would greatly empower women to protect
themselves,[1b,c] as the consent or even knowledge of their
sexual partner is not required.
For two decades, Bristol-Myers Squibb has been investigat-
ing several indole-glyoxamides[3] as ENIs, mainly in the first of
the three steps into which the entry process may be subdivided:
virus attachment, coreceptor binding, and membrane fusion.
Many of these glyoxamides (see Figure 1) were highly active, in
the nM range, but posed pharmacokinetic or toxicity issues.
However, very recently, fostemsavir,[4] a prodrug of temsavir,
has been approved by the Food and Drug Administration (FDA)
First-generation microbicides, which were surfactants such
as nonoxynol-9 and savvy gel (a betaine), and 2nd generation
[a] Dr. E. Petit, Dr. L. Bosch, Prof. A. M. Costa, Prof. J. Vilarrasa
Organic Chemistry Section, Facultat de Química,
Universitat de Barcelona
Diagonal 645,
08028 Barcelona, Catalonia (Spain)
E-mail: jvilarrasa@ub.edu
[b] I. Rodríguez-Izquierdo, Dr. D. Sepúlveda-Crespo, Prof. M. A. Muñoz-Fernán-
dez
Laboratorio de Inmunobiología Molecular
Hospital General Universitario Gregorio Marañón (HGUGM)
Dr. Esquerdo 46,
28007 Madrid (Spain)
Figure 1. Molecular structures of RTIs used as microbicides (first row) and of
representative entry inhibitors (ENIs, second row).
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cmdc.202100080
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and the European Medicines Agency (EMA). BMS-599793, an
IPM microbicide, deserves to be highlighted as well.[5]
as well as with BMS-818251 and with BMS-814508[7d] indicated
that the more appropriate point of attachment is C7.
In this context, a few years ago we started a project aimed
at linking BMS derivatives to polyhydroxylic gels (1). The idea
was that the resulting gels and creams may block HIV-1 at the
initial stage of its life cycle and that the viruses would be bound
to such an easily removable product. If 3�1 BMS-type units
could be anchored to each polymer molecule, the antiviral
activity could be potentiated by simultaneous binding of the
trimeric gp120.[6] Here we report on the syntheses and screen-
ings of these “prototypes” of microbicides, which we call of
fourth generation. We recognize that optimized inhibitors, such
as the BMSs shown in Figure 1, could surpass the present
“prototypes”, if they too can be appropriately linked to standard
vaginal gels, but here we aim to demonstrate proof-of-concept.
We started our work by preparing series of simple indole-
glyoxamides, hoping to obtain structures of type 1 (Figure 2).
We were aware of the SAR studies by BMS indicating that large
substituents at N1, C4, C5, and C6 of the indole system were
poorly tolerated,[3] and there are very recent computational and
X-ray studies showing how BMS derivatives interact with the
binding site(s) of gp120.[7] Cocrystal structures of trimeric HIV-1
envelope glycoprotein (Env) with BMS-806 and with BMS-529[7c]
From indole (2a) and indole-7-carboxamides 2b–d we
synthesized BMS analogues 3–6 shown in Scheme 1, by means
of the known procedure for the integration of the piperazine
moiety onto C3 of the indole ring.[3] Compounds 3[3c,6,8] and 4[9]
were prepared to be used as additional reference samples in
the tests. Compounds 5 and 6 have spacers of three and ten
methylenes, respectively, and the terminal azido groups
required for the linkage via an azide–alkyne cycloaddition.[10]
We also prepared 7 from 5 by reduction of the azido group to
amine, followed by its acylation with propynoic acid (propiolic
acid). Compound 7 may not only be useful for a CuAAC
reaction,[10] but also for the addition of N- or S-nucleophiles[11]
to the conjugated triple bond.
The toxicity of these compounds was tested using TZM.bl
cells and the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) assay, indicating that none of them
was cytotoxic at 1–100 μM concentrations in aqueous DMSO
(1% v/v).
Also, as a preliminary work, the entry inhibition of 3–6 was
examined with two types of HIV-1 stocks (see Figure 3), namely,
the CCR5-tropic R5-HIV-1NLAD8 laboratory isolate obtained by
transient transfection with the pNL(AD8) plasmid and the NL4-3
strain, an X4-monotropic laboratory isolate, by comparison with
a known carbosilane-polysulfonate dendrimer (G2-S16, active as
ENI in the nM range).[12] See Supporting Information. We applied
the luciferase activity assay to monitor infection of TZM.bl cells.
Although the R5 virus infection (i.e., via interaction with CD4
and CCR5 coreceptors) is much more efficient[13] than the X4
virus infection (i.e., via interaction with CD4 and CXCR4
coreceptors), when enough sample was available, we often
examined both strains for the sake of comparison.
It can be observed in Figure 3 that with 3–6 the percentages
of infection, from three measurements for each experiment (in
triplicate) at 1 μM in aqueous DMSO (1% v/v), were reduced to
40% as a mean value. The more active sample against R5
Figure 2. BMS-like derivatives conjugated to a polyol model.
°
Figure 3. Percentage of infection after incubation at 37 C of TZM.bl cells
with 1 μM solutions of 3–6 for 1 h (in relation to non-treated cells, see
C=control of infection) and then with R5 or X4 viruses for 3 h. The
carbosilane-polysulfonate dendrimer G2-S16 (16 sulfonate groups), a known
ENI,[12] was used as the reference. Mean values from nine measurements.
Scheme 1. Synthesis of 3–7. EDC=1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide, HOBt=1-hydroxybenzotriazole, DIPEA=diisopropylethyl-
amine, and DCC=dicyclohexylcarbodiimide.
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viruses appeared to be the C7-unsubstituted sample 3 (31�
6%), whereas the less active was 7, the substrate with the
longest-chain substituent at C7.
Although the antiviral activity of these simple BMS deriva-
tives, under the indicated conditions, is lower than that of the
BMS compounds highlighted in Figure 1, it seems it would
suffice, in the future, to use temsavir analogs with appropriate
spacers/pre-linkers to improve our results.
As a polyol model we chose β-cyclodextrin (β-CD). Its
reaction with an excess of propargyl bromide (3-bromo-1-
propyne) in NaH/DMF at rt, to produce a relatively homoge-
neous poly-propargylated mixture was systematically studied.
Although the polypropargylation of β-CD has been reported by
using 2100 mol% of BrCH2C�CH and NaH,[14] it was essential for
us to maintain the hydrophilic nature of the samples. Thus,
several experiments with 200–800 mol% of reagents were
undertaken. As shown in Scheme 2, with 500 mol% of NaH and
400 mol% of propargyl bromide, the MALDI-TOF/TOF mass
spectra indicated that the major product included five
propargyl groups, followed by tetrasubstituted and hexasub-
stituted compounds. The yield of the final sample (8, 85%) and
its homogeneity (5�2 propargyl groups) were optimum under
these conditions. It was not important to establish how many
primary (of 7) and secondary (of 14) hydroxy groups did react:
the point was and is to introduce a sufficient number of
potential linkers into suitable polyols.
Cu2(OTf)2 ·C6H6. At rt and 0.05 M concentrations in water or aq
tBuOH, the optimal conditions turned out to be 3 mol% of
CuOAc and 5 mol% of the sodium tris(triazolyl)ethylsulfate
BTTES·Na. The surfactant nature of BTTES·Na was clearly an
advantage in this case.
When these optimized conditions were applied to 8 and 5,
we had only to increase the reaction time and temperature to
reach good conversions (oligo-substitution). In this way, 9 was
obtained as a mixture comprising one β-CD scaffold randomly
decorated with 2�1 BMS-like substituents.
Similarly, a sample with a spacer of ten methylene groups
(10), instead of three methylenes, was prepared from 8 and 6 in
63% yield (10, n=0–3, m=1–4, see the Supporting Informa-
tion). As no significant differences were noted between 9 and
10 regarding the toxicity and anti-HIV-1 activity (see below), we
continued our studies with 9, that is, with the shorter length
spacer.
Our next step was the propargylation of hyperbranched
poly-glycerol (HPG). It is known that the biocompatibility and
absence of toxicity of HPG are excellent.[16] We formed a
copolymer of rac-glycidol and propargylated glycidol
(Scheme 3), added in a 5:1 ratio, from 2-ethyl-2-(hydroxymeth-
yl)-1,3-propanediol as the initiator, following the reports of Frey
et al.[17] We previously optimized the method by checking
different bases (KHDMS, CsOH, NaH, KOCH3), variable excesses
of glycidols, two solvents (THF in a microwave synthesizer at
°
°
The reaction of 8 with an excess of 5 in the presence of
Cu(I)[10,15] required previous exhaustive optimization. As models,
we chose the monoazide of β-cyclodextrin and, on the other
hand, the morpholine amide of propynoic acid and 1-hexyne.
We compared Cu(I) sources and ligands,[15] using as small as
possible amounts of CuSO4/sodium ascorbate, CuOAc, or
90 C and diglyme in a vial at 90 C as well), and different
addition times. We used our best conditions to prepare 11
(Scheme 3). The MALDITOF-TOF/TOF mass spectrum of the
sample (11) showed the most intense [M+Na]+ peaks between
m/z 727.8 and 1338.5, mean MW�1100. Concentrations were
based on this mean value.
This sample, after training experiments to optimize the
CuAAC with a model (benzyl azide, azidomethylbenzene), was
Scheme 2. Synthesis of 8, a mixture of oligopropargylated β-CDs, and
conjugation with 5, to afford 9; np and ns =number of propargyl groups
linked to primary and secondary OH groups, respectively; mp and
ms =number of BMS-type unities linked to primary and secondary OH
groups. CuOAc=copper(I) acetate.
Scheme 3. Synthesis of 11, an oligomer/polymer mixture made from rac-
glycidol and propargylated glycidol. CuAAC reaction of 11 with an excess of
5 to afford 12.
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°
treated with 5 (400 mol%) for 7 days at 70 C in the presence of
50 mol% of Cu(I) and 60 mol% of BTTES·Na to afford, after an
appropriate workup, a yellowish viscous oil (12), as shown in
Scheme 3. The filtrates from the precipitation and purification
of 12 were combined, diluted with water, and extracted with
EtOAc to recover unreacted 5. The MALDI-TOF/TOF analysis of
12 (Supporting Information) indicated main peaks at m/z values
between 907.8 and 1612.4 (mean MW�1300).
The toxicity of 9, 10, 12, and 14 was evaluated against
TZM.bl cells (Figure 4). None was cytotoxic at concentrations
below 100 μM or, in the case of 9 and 10, below 50 μM.
β-Cyclodextrin, its propargylated derivative 8, HPG, its prop-
argylated derivative 11, and its disulfide 11 were also evaluated.
None was cytotoxic at 100 μM concentrations and none showed
anti-HIV-1 activity either (results not included in Figures 4 and 5
for the sake of simplicity).
The antiviral activity of 9, 10, 12, and 14 against R5 isolates
was finally evaluated as mentioned above: first at their non-
toxic concentrations and then at 1 μM (Figure 5). To our delight,
at their non-toxic concentrations, all were almost as active as
the reference dendrimer (which has 16 sulfonate ions per
molecule). Furthermore, 9 and 12 were still as much active at
1 μM as 4 and 5 and only slightly less active than the C7-
unsubstituted compound, 3 (Figure 3). In other words, the
antiviral performance of the BMS-type structures at blocking
gp120 of HIV-1 does not disappear when they are attached to
polyol scaffolds through C7-amide groups.
We also prepared a different HPG derivative, decorated with
thiol groups, in accordance with the procedure reported by Kim
et al.[18] After heating the starting triol with KOMe/MeOH and
°
evaporation to dryness, the solid was solved in diglyme at 90 C
and a huge excess of rac-glycidol (Scheme 4) was added over
16 h. The disulfide arising from glycidyl chloride and disulfide of
2-sulfanylethanol (2-mercaptoethanol) was also introduced via a
syringe pump. The SÀ S bond of the mixture (13) was cleaved
with tris(carboxyethyl)phosphine (TCEP) and, after precipitation
with acetone, the crude product was subjected to a conjugate
addition to the activated triple bond of 7 at physiological pH,
without any special catalyst.
In summary, the cytotoxicities of the C7-substituted BMS-
derived samples that we screened appear to be very low, with
non-toxic maximum concentrations relatively very high (50–
100 μM), which is a clear advantage from a pharmacological
point of view. Anti-HIV-1 activities of samples 9 and 12 are also
noteworthy, showing inhibitions similar to those of their
°
precursors after only 1 h of incubation at 37 C, when they are
later treated for 3 h with HIV-1. The fact that these inhibition
percentages occur using the R5 isolate, which is responsible for
the HIV-1 primoinfection, is of key importance for any ENI-type
vaginal microbicide. Moreover, there is room for improvement,
once the proof-of-concept has been demonstrated: we will
attempt to derivatize more active BMS compounds (such as
BMS-626529 or BMS-828251), to prepare oligo-substituted
scaffolds of much higher MW (in order to increase the gel
properties), and to submit them for screening against a large
panel of HIV-1 strains.
Scheme 4. Synthesis of 13, an oligomer/polymer mixture made from rac-
glycidol and a disulfide derivative of rac-glycidol. Reduction to the thiol
derivative with TCEP [P(CH2COOH)3] and addition to the activated alkyne 7
under physiological conditions to afford 14.
Figure 5. Synthesis of 13, an oligomer/polymer mixture made from rac-
glycidol and a disulfide derivative of rac-glycidol. Reduction to the thiol
derivative with TCEP [P(CH2COOH)3] and addition to the activated alkyne 7
under physiological conditions to afford 14. Mean values from nine
measurements.
Figure 4. Cytotoxicity of samples 9, 10, 12, and 14 against TZM.bl cells, at
different concentrations (from 100 μM to 1 μM) in 1% aqueous DMSO (v/v).
C=control; dendrimer G2-S16=the reference.[12] Mean values from nine
measurements.
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The conjugation reactions here reported were carried out within
the PhD Thesis of E.P. (2015–2019), who also collaborated with
doctorate students at Hospital “Gregorio Marañón” in the micro-
bicide evaluations, with studentships provided by Grant CTQ2015-
71506R (Jan. 2016–Sept. 2019, Spanish Government and FEDER)
or by the Fundació Bosch Gimpera/UB (310770). The following
master students, under the supervision of L.B. or A.M.C., collabo-
rated for some months by preparing starting compounds: Ionela
Cialicu, Anna Mayans, Ares Martínez, Itzel A. Bernal (UAEMex),
Víctor Alcolea, and Javier Magaña. The microbicide evaluations
carried out at the Hospital General Universitario “Gregorio
Marañón” were funded by the Fondo de Investigación Sanitaria
(FIS) of the Instituto de Salud Carlos III (ISC-III, Grant PI19/01638),
the EPIICAL project, and the Spanish HIV BioBank (supported by
ISC-III, Grant RD16/0025/0019) as part of the Plan Nacional R+D
+I cofinanced by ISC-III-FEDER. J.V. acknowledges the collabora-
tion of colleagues who were at a preceding project on anti-AIDS
(the TRIoH project of the EU Commission): Dr. J. A. Esté (IrsiCaixa,
Hospital Can Ruti, Badalona, evaluation of anti-HIV activity), Prof.
I. Robina (Universidad de Sevilla, synthesis of ENIs), and Dr. J.
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Keywords: 4th generation microbicides · HIV entry inhibitors ·
BMS-type drugs · click chemistry · hyperbranched polyglycerol
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ChemMedChem 2021, 16, 1–7
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Communications
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Manuscript received: January 30, 2021
Revised manuscript received: April 2, 2021
Accepted manuscript online: April 11, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATIONS
Dr. E. Petit, Dr. L. Bosch, Prof. A. M.
Costa, I. Rodríguez-Izquierdo, Dr. D.
Sepúlveda-Crespo, Prof. M. A.
Muñoz-Fernández, Prof. J. Vilarrasa*
1 – 7
BMS Derivatives C7-Linked to β-
Cyclodextrin and Hyperbranched
Polyglycerol Retain Activity
against R5-HIV-1NLAD8 Isolates and
Can Be Deemed Potential Microbi-
cides
Making mighty microbicides: Entry
inhibitors similar to those reported by
Bristol-Myers Squibb have been
linked, through the C7 position of
their indole ring, to β-cyclodextrin or
hyperbranched polyglycerols by
means of click reactions. They are not
cytotoxic at all at 50–100 μM and two
of them maintain anti-HIV-1 activity
in vitro, against R5-HIV-1NLAD8 Isolates,
in the low μM range. This paves the
way for the development of a new
generation of vaginal microbicides.