Synthesis of HIV-1 capsid protein assembly inhibitor (CAP-1) and its analogues based on a biomass approach

Article abstract of DOI:10.1039/c6ob01731b

A biomass-derived platform chemical was utilized to access a demanded pharmaceutical substance with anti-HIV activity (HIV, human immunodeficiency virus) and a variety of structural analogues. Step economy in the synthesis of the drug core (single stage from cellulose) is studied including flexible variability of four structural units. The first synthesis and X-ray structure of the inhibitor of HIV-1 capsid protein assembly (CAP-1) is described.

Full text of DOI:10.1039/c6ob01731b

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Synthesis of HIV-1 capsid protein assembly
inhibitor (CAP-1) and its analogues based on
Cite this: DOI: 10.1039/c6ob01731b
a biomass approach†
Leonid V. Romashova and Valentine P. Ananikov*a,b
A biomass-derived platform chemical was utilized to access a demanded pharmaceutical substance with
anti-HIV activity (HIV, human immunodeficiency virus) and a variety of structural analogues. Step
economy in the synthesis of the drug core (single stage from cellulose) is studied including flexible varia-
bility of four structural units. The first synthesis and X-ray structure of the inhibitor of HIV-1 capsid protein
assembly (CAP-1) is described.
Received 10th August 2016,
Accepted 16th September 2016
DOI: 10.1039/c6ob01731b
www.rsc.org/obc
Currently available drugs against HIV are focused on the
inhibition of the five stages of the HIV life cycle (Fig. 1) and
Introduction
State-of-the-art healthcare urges for the on-demand production include CCR5 coreceptor antagonists (maraviroc), which
of pharmaceuticals1 and access to personalized medicine.2 prevent HIV from binding to CD4 cells; fusion inhibitors
The long term practical implementation of these goals is chal- (enfuvirtide), which block the HIV envelope from merging with
lenging to achieve due to unsustainable procedures of drugs the host CD4 cell membrane; nucleoside (lamivudine,
synthesis, which are typically characterized by large overall pro- zidovudine, emtricitabine, abacavir, azidothymidine, didanosine,
duction of toxic waste.3 In fact, the synthesis of drugs is etc.) and non-nucleoside (rilpivirine, etravirine, delavirdine,
accompanied by the largest amount of waste by-products efavirenz, etc.) reverse transcriptase inhibitors, which block the
among all chemical industry processes (25–100 kg of waste per conversion of HIV RNA into DNA; integrase strand transfer
1 kg of drug product).3 A breakthrough concept in this area is inhibitors (raltegravir, dolutegravir), which block the insertion
to connect improved synthesis and step-economy4 with sus- of HIV DNA into CD4 cell DNA; and viral protease inhibitors
tainable natural sources of chemicals.5 The use of biomass- (tipranavir, indinavir, lopinavir, ritonavir, darunavir, etc.), which
derived chemicals has opened up new possibilities in the sus- prevent the cleavage of newly synthesized viral polyproteins at
tainable synthesis of bulk and fine chemicals.6 In this article,
we describe a complete synthetic procedure to promising anti-
HIV pharmaceutical substances starting from a low cost
natural biomass (cellulose) and using a special optimized pro-
cedure for efficient fine organic synthesis applications.7
The search for effective anti-HIV drugs is one of the most
important challenges in modern science and medicine.8 AIDS
causes more than a million deaths annually.9 There is no cure
or vaccine against AIDS, but antiretroviral therapy can slow the
course of the disease and increase the survival time after infec-
tion.10,11 In this field, the rapid synthesis of candidate com-
pounds with the possibility of synthesizing close structural
analogues is of crucial importance.12
aZelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky prospect 47, 119991 Moscow, Russia. E-mail: val@ioc.ac.ru
bSaint Petersburg State University, Stary Petergof, Saint Petersburg, 198504, Russia
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. CCDC 1497315. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/c6ob01731b
Fig. 1 Therapeutic target stages of HIV life cycle and the corresponding
drugs.
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appropriate places for creating mature protein components of
the infectious HIV virion.13
Recently, a novel type of anti-HIV activity – inhibition of
HIV-1 capsid protein assembly, which is the last stage of HIV
maturation – was described.14 N-(3-Chloro-4-methylphenyl)-
N′-2-[(5-[(dimethylamino)-methyl]-2-furylmethyl)sulfanyl]ethyl-
urea (CAP-1) was one of the first compounds with such activi-
ty.14g,h The structure of CAP-1 was disclosed in patents,15
however, to the best of our knowledge, the methods of syn-
thesis have not been described and a 3D molecular structure
was not determined.
Results and discussion
Here we report an efficient synthesis of the CAP-1 molecule
which allows versatile structural variation (Fig. 2). The struc-
ture of CAP-1 can be subdivided into five fragments, which
should be introduced into the target molecule as individual
subunits. Retrosynthetic analysis of CAP-1 shows that this
approach can be easily realized on the basis of the 2,5-di-
substituted furan core (shown in red, Fig. 2), which is available
from natural biomass involving the 5-HMF (5-(hydroxymethyl)
furfural) platform-chemical7,16 pathway (Fig. 2). The first site,
which can be varied easily, is an amine group (drug unit 1,
Fig. 2). Variation at this position is possible via reductive amin-
ation of the 5-HMF aldehyde group with various primary and
secondary amines. The second site is a spacer of variable
length and flexibility (drug unit 2, Fig. 2). The third site (drug
unit 3, Fig. 2) is a linkage group, which connects the spacer to
an aromatic, aliphatic or heteroaromatic substituent (drug
unit 4, Fig. 2) and can also be involved in hydrogen bonding
with the substrate. The linkage can be composed of such
important groups as urea, amide, ester, carbonate, carbamate,
Scheme 1 Synthesis of CAP-1 from cellulose as the starting material
(similar color encoding of fragments was used, see Fig. 2).
sulphonamide, etc. Each of these four sites can be varied inde-
pendently, and the final molecule can be assembled using
efficient synthetic procedures. Thus, a library of CAP-1 struc-
tural analogues can be synthesized on the basis of this
biomass-derived approach.
A practical synthesis procedure is shown in Scheme 1. The
overall synthesis includes the following six steps: (1) CrCl3-
catalysed conversion of cellulose into 5-HMF in an ionic
liquid;7,17 (2) preparation of 5-(chloromethyl)furfural6b,c,18
(5-CMF) upon treatment of 5-HMF with HCl; (3) S-alkylation of
N-acetylcysteamine with 5-CMF; (4) reductive amination of the
formyl group by using dimethylamine; (5) alkaline hydrolysis
of the amide; (6) synthesis of the urea group by using aryliso-
cyanate. Each step was conducted smoothly, and compound
purification via chromatography was required only once, at the
final step. The target product was isolated in 57% overall yield
in a crystal form with >99.9% purity (see the ESI† for analysis).
Fig. 3 Molecular view of CAP-1 determined by X-ray analysis. Selected
geometry parameters: N(3)–C(9) = 1.475 Å, C(9)–C(8) = 1.497 Å, ∠N(3)C
(9)C(8) = 113.26°, C(5)–C(4) = 1.487 Å, C(4)–S(1) = 1.843 Å, ∠C(5)C(4)S(1)
= 107.61°, ∠C(4)S(1)C(3) = 102.25°, ∠S(1)C(3)C(2)N(1) = 168.33°, ∠C(1)N
(2)C(12)C(17) = 53.48°, and ∠N(1)C(1)N(2) = 115.17° (see the ESI† for
complete description).
Fig. 2 Retrosynthetic analysis of CAP-1 and its partitioning into sites of
structural variation: red – furan core, magenta – amine, orange –
spacer, blue – linkage group, green – aromatic, heteroaromatic or ali-
phatic substituent.
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Table 1 Synthetic scope in the preparation of CAP-1 analogues
Entry
1
R1
R2
R3
Linkage
Urea
Spacer
Yield, %
46
4-Methyl-3-chlorophenyl
Me
Me
2
3
4
5
7
8
9
10
Ph
Me
Me
Me
Me
Me
Me
Me
Cyclo-propyl
Me
Me
Me
Me
Me
Me
Me
H
Urea
Amide
Urea
Urea
Sulfonamide
Sulfonamide
Alcohol
Carbamate
–SCH2CH2–
–SCH2CH2–
–SCH2CH2–
–SCH2CH2–
–SCH2CH2–
–SCH2CH2–
–S–CH2CH2–
–SCH2CH2–
70
79
72
66
75
65
55
73
1-Adamantan-methyl
1-Chloro-3-adamantyl
p-Tolyl
2-Nitrophenyl
H
t-Bu
Me
The critical point of the synthetic procedure was to ensure the
use of purified 5-HMF (free from dimer and oligomer impuri-
Experimental
ties) to avoid formation of by-products, simplify separation 5-(Hydroxymethyl)furfural was prepared from cellulose accord-
and to increase the yield.7 The solid-state structure of the syn- ing to our recently published procedure.7a
thesized CAP-1 molecule was determined by single crystal
5-(Chloromethyl)furfural (1)20
X-ray diffraction for the first time and revealed a twisted linear
geometry (Fig. 3). The determined molecular structure (see the
ESI† for complete details) gives key information for performing
A 25 mL Erlenmeyer flask was loaded with 5-HMF (252 mg,
2 mmol), CH2Cl2 (10 mL), and conc. HCl (5 mL). The mixture
docking experiments, understanding the mechanism of action
was stirred at room temperature overnight. The aqueous layer
and the analysis of biological activity.
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phase was dried over sodium sulfate. Charcoal (50 mg) was
To demonstrate the applicability of the developed approach
several structural analogues of CAP-1 were synthesized
added and the mixture was stirred for 20 minutes and filtered
(Table 1). Variation in the substituents and in the nature of the
through a Celite pad. The solvent was removed under reduced
linkage were successfully carried out giving the products in
pressure to give 5-(chloromethyl)furfural (266 mg, 92%) as a
46–79% yield (from 5-HMF). The developed biomass-derived
approach was fully applicable for rapid access to various CAP-1
functionalized derivatives.
yellow liquid. The product should be stored below +5 °C to
1
prevent decomposition. H NMR (CDCl3, 400 MHz) δ = 9.61 (s,
1H), 7.18 (d, 1H, J = 3.5 Hz), 6.57 (d, 1H, J = 3.5 Hz), 4.59 (s,
2H). 13C{1H} NMR (CDCl3, 101 MHz) δ = 177.1, 156.0, 152.9,
121.6, 111.9, 36.5; Anal. Calcd for C6H5ClO2: C, 49.85; H, 3.49;
Conclusions
Cl, 24.52; Found: C, 49.84; H, 3.50, Cl, 24.49. HRMS (ESI):
calcd [M + Na]+ 166.9870, Found: 166.9872.
In conclusion, we have evaluated a convenient synthetic pro-
cedure for the preparation of the prominent HIV-1 capsid
protein assembly inhibitor CAP-1 using cellulose as a renew-
5-[[(2-Acetamidoethyl)thio]methyl]furfural (2)6b
able starting material. The structure of CAP-1 was determined A Schlenk flask was loaded with N-acetylcysteamine (203 mg,
by X-ray analysis. Using the developed procedure, several struc- 1.70 mmol) and a magnetic stirrer bar. The flask was filled
tural analogues of CAP-1 were successfully prepared and made with argon via three vacuum–argon cycles. 10 mL of absolute
available for high demand biochemical applications. Direct THF (distilled over sodium-benzophenone ketyl) was added.
connection of the drug core to renewable natural sources of Sodium hydride (95%, 52 mg, 2.17 mmol) was added and the
chemicals provides an efficient and green approach for the reaction mixture was stirred for 30 minutes. After that the solu-
production
of
these
pharmaceutical
substances. tion of 5-(chloromethyl)furfural (256 mg, 1.77 mmol) in 5 mL
Implementation of such methodologies into fine organic syn- of absolute THF was added dropwise. The reaction mixture
thesis procedures is crucial to achieve long term sustainable was stirred overnight at room temperature. The solvent was
drug development.
removed under reduced pressure and brine (55 mL) was
Conversion of natural carbohydrates into the 5-HMF plat- added. At this moment the color changed from light yellow to
form chemical is a sustainable process,7a,16 and nowadays the red-orange. The mixture was extracted with CH2Cl2 (4 ×
production of 5-HMF approaches an industrial multi-ton 40 mL), and the combined organic phase was washed with
scale.19 Therefore,
a
variety of efficient and practical brine (100 mL) and dried over anhydrous Na2SO4. Charcoal
implementations of biomass-derived drugs synthesis can be (70 mg) was added and the mixture was stirred for another
anticipated.
20 minutes and filtered through a 15 mm Celite® pad. The
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solvent was removed under reduced pressure to give 5-[[(2-acet- dichloroethane, 3-chloro-4-methylphenylisocyanate (90.3 mg,
amidoethyl)thio]methyl]furfural (332 mg, 86%) as a yellow oil. 0.539 mmol) was added and the mixture was heated at 50 °C
1H NMR (CDCl3, 400 MHz) δ = 9.57 (s, 1H), 7.19 (d, 1H, J = 3.5 overnight. The solvent was removed under reduced pressure
Hz), 6.46 (d, 1H, J = 3.5 Hz), 6.17 (brs, 1H), 3.79 (s, 2H), 3.45 and the residue was purified by column chromatography
(q, 2H, J = 6.2 Hz), 2.73 (t, 2H, J = 6.5 Hz), 2.03 (s, 3H). 13C{1H} (eluent CHCl3 : MeOH = 8 : 1 (v/v)). The product was dried
NMR (CDCl3, 101 MHz) δ = 177.2, 170.3, 158.8, 152.4, 122.7, in vacuo to obtain CAP-1 (159 mg, 81%) as a white solid. 1H
110.5, 38.3, 32.1, 28.0, 23.2. Anal. Calcd for C10H13NO3S: C, NMR (CDCl3, 500 MHz) δ = 7.51 (s, 1H), 7.38 (d, 1H, J =
52.85; H, 5.77; N, 6.16; Found: C, 52.81; H, 5.80, N, 6.14. 1.9 Hz), 7.13 (dd, 1H, J = 8.2, 1.9 Hz), 7.07 (d, 1H, J = 8.2 Hz),
HRMS (ESI): calcd [M + Na]+ 250.0508, Found: 250.0515.
6.15 (d, 1H, J = 3.0 Hz), 6.11 (d, 1H, J = 3.0 Hz), 5.82 (t, 1H, J =
5.8 Hz), 3.70 (s, 2H), 3.49 (s, 2H), 3.84 (q, 2H, J = 6.0 Hz), 2.69
(t, 2H, J = 6.0 Hz), 2.31 (s, 6H), 2.28 (s, 3H). 13C{1H} NMR
(CDCl3, 126 MHz) δ = 155.9, 152.2, 150.6, 138.2, 134.5, 131.1,
5-[[(2-Acetamidoethyl)thio]methyl]-N,N-dimethyl-
2-furanmethanamine (3)6b
The liquid dimethylamine (1 mL, prepared from dimethyl- 130.3, 120.6, 118.4, 110.7, 108.3, 55.9, 45.0, 39.4, 33.0, 28.7,
amine hydrochloride and solid NaOH) was added to a solution 19.4. Anal. Calcd for C18H24ClN3O2S: C, 56.61; H, 6.33; N,
of
5-[[(2-acetamidoethyl)thio]methyl]furfural
(410
mg, 11.00; Found: C, 56.33; H, 6.36, N, 10.72. HRMS (ESI): calcd
1.804 mmol) in 60 mL of absolute methanol and the resulting [M + H]+ 382.1351, Found: 382.1350. Crystals suitable for X-ray
mixture was stirred at room temperature for 40 minutes. The analysis were grown using a vapor diffusion method in a
solution became an intense orange. The reaction mixture was chloroform/hexane system .
cooled to 0 °C and sodium borohydride (103 mg, 2.706 mmol)
Synthesis of CAP-1 derivatives
was added portionwise. The mixture was stirred at 0 °C for
20 minutes and then warmed up to room temperature. The
solvent was removed under reduced pressure and the residue
was dissolved in CH2Cl2, filtered from inorganic impurities,
and evaporated to dryness to give 5-[[(2-acetamidoethyl)thio]
methyl]-N,N-dimethyl-2-furanmethanamine (459 mg, 99%) as
The detailed description of the synthesis and characterization
of structural analogues of CAP-1 is provided in the ESI.†
Adamatane-containing isocyanates for the synthesis of ada-
mantyl derivatives were obtained according to the literature.21
1
a yellow oil. H NMR (CDCl3, 400 MHz) δ = 6.27 (brs, 1H), 6.11
(s, 2H), 3.69 (s, 2H), 3.41 (s, 2H), 3.30 (q, 2H, J = 6.2 Hz), 2.65
(t, 2H, J = 6.5 Hz), 2.24 (s, 6H), 1.95 (s, 3H). 13C{1H} NMR
(CDCl3, 101 MHz) δ = 170.2, 151.9, 151.4, 109.8, 108.2, 56.0,
45.1, 38.5, 31.8, 28.3, 23.3. Anal. Calcd for C12H20N2O2S: C,
56.61; H, 6.33; N, 11.00; Found: C, 56.21; H, 7.91, N, 10.90.
HRMS (ESI): calcd [M + H]+ 257.1318, Found: 257.1321.
Acknowledgements
This work was supported by the Russian Science Foundation
(RSF Grant 14-13-01030). The authors thank Dr Victor
Khrustalev for carrying out X-ray analysis and Dr Viktor
Burmistrov and Prof. Gennady Butov for precursors of
adamantyl derivatives.
5-[[(2-Aminoethyl)thio]methyl]-N,N-dimethyl-
2-furanmethanamine (4)
5-[[(2-Acetamidoethyl)-thio]methyl]-N,N-dimethyl-2-furan-
methanamine (44 mg, 0.172 mmol) was added to 2 mL of 2N
NaOH. The mixture was heated at reflux for 2.5 hours, then
cooled down to room temperature and extracted with CH2Cl2
(3 × 5 mL). The combined organic phase was washed with
brine (15 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was
dried in vacuo to give 5-[[(2-aminoethyl)thio]methyl]-N,N-
dimethyl-2-furanmethanamine (36 mg, 98%) as a pale yellow
oil. 1H NMR (CDCl3, 400 MHz) δ = 6.09 (s, 2H), 3.67 (s, 2H),
3.40 (s, 2H), 2.81 (t, 2H, J = 6.4 Hz), 2.59 (t, 2H, J = 6.4 Hz),
2.23 (s, 6H), 1.90 (brs, 2H). 13C{1H} NMR (CDCl3, 101 MHz) δ =
151.9, 151.3, 109.4, 108.0, 55.9, 45.0, 40.8, 35.7, 28.1. Anal.
Calcd for C12H18N2OS: C, 56.04; H, 8.47; N, 13.07; Found: C,
56.01; H, 8.48, N, 13.02. HRMS (ESI): calcd [M + H]+ 239.1213,
Found: 239.1217.
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