Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives as novel anti-HIV agents

Article abstract of DOI:10.1016/j.bmcl.2018.04.049

SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors (NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA polymerase activity via a direct binding event. To further investigate the relationship between its structure and activity, four series of novel analogues were designed and synthesized with 12 of them inhibiting HIV-1 replication with IC₅₀s in the range 0.09–6.71 μM. Compound 4b, 4c, 4f, 2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant superbug. The result showed that RT- E138K/M184V mutant virus conferred 4.7–9.1-fold resistance to 4c, 4f, 2 and 6b, but only showed slight resistance to 4b (2-fold) which was better than SG-1.

Full text of DOI:10.1016/j.bmcl.2018.04.049

Accepted Manuscript
Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives
as novel anti-HIV agents
Xiaoyu Liu, Panpan Chen, Xiaoyu Li, Mingyu Ba, Xiaozhen Jiao, Ying Guo,
Ping Xie
PII:
S0960-894X(18)30361-5
https://doi.org/10.1016/j.bmcl.2018.04.049
BMCL 25796
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 February 2018
13 April 2018
18 April 2018
Please cite this article as: Liu, X., Chen, P., Li, X., Ba, M., Jiao, X., Guo, Y., Xie, P., Design, synthesis and biological
evaluation of substituted (+)-SG-1 derivatives as novel anti-HIV agents, Bioorganic & Medicinal Chemistry
Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.04.049
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Bioorganic & Medicinal Chemistry Letters
Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives as
novel anti-HIV agents
Xiaoyu Liua,1, Panpan Chenb,1, Xiaoyu Lia, Mingyu Bab, Xiaozhen Jiaoa, , Ying Guob, *, and Ping Xiea
a State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050,
People’s Republic of China
b
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, and Beijing Key Laboratory of New Drug Mechanisms and
Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050,
People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors
(NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA
polymerase activity via a direct binding event. To further investigate the relationship between its
structure and activity, four series of novel analogues were designed and synthesized with 12 of
them inhibiting HIV-1 replication with IC50s in the range 0.09 to 6.71 μM. Compound 4b, 4c, 4f,
2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant
superbug. The result showed that RT- E138K/M184V mutant virus conferred 4.7 to 9.1-fold
resistance to 4c, 4f, 2 and 6b, but only showed slight resistance to 4b (2-fold) which was better
than SG-1.
Keywords:
HIV
NNRTIs
SG-1
Structure-activity relationship
NNRTI-resistant
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Xiaozhen Jiao, Tel.: +86 10 63165241; fax: +86 10 63017757; e-mail: jiaoxz@imm.ac.cn
Ying Guo, Tel/Fax: +86 10 6316 1716; e-mail: yingguo6@imm.ac.cn,
1Authors Xiaoyu Liu, Panpan Chen contributed equally.

Human immunodeficiency virus type 1 (HIV-1) is the
etiologic agent of acquired immunodeficiency syndrome (AIDS)
and there are currently more than 35 million
individuals worldwide living with HIV-1.1 Reverse transcriptase
(RT) of HIV-1 is an important target for anti-HIV drug
discovery. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) are non-competitive inhibitors of RT’s and serve as
pivotal components of highly active antiviral therapies
(HAART).2 The first-generation of NNRTIs, nevirapine (NVP)
and efavirenz (EFV) were approved in the late 20th century.
After more than 20 years of continuous clinical use, the incidence
of NNRTI-resistant mutations observed from clinical isolates
obtained from patients suffering with HIV-1.3 Moreover, some
major NNRTI-resistant viruses, such as RT-K103N and RT-
Y188L, showed strong cross-resistance between NVP and EFV.4
To combat these NVP/EFV-resistant viruses, second generation
NNRTIs such as Etravirine (ETR) and Rilpivirine (RPV) were
developed. These diarylpyrimidine containing (DAPY) NNRTIs
are not only potent to wild type RT, but also show higher genetic
barrier to the first-generation-NNRTI-resistance mutations since
both are able to bind RT in multiple conformations.5 However, it
was later found that RT-E138K and M184V mutations emerged
in patients when treated with Tenofovir (TDF)/Emtricitabine
(FTC)/ Rilpivirine. HIV-1 carrying RT-E138K/M184V mutations
are known to be resistant to both NNRTIs (RPV and ETR) and
NRTIs (FTC and 3TC). Furthermore, it was reported that when
HIV RT contained E138K/M184V/I, the virus exhibited a higher
replication capacity compared to the wild type virus. 6 Since this
‘super’ mutant HIV-1 occurred in patients treated with the second
generation of NNRTIs, the discovery and evaluation of novel
NNRTIs discovery is still of critical importance.
Fig.2. The structures of compound 1, 4, 5, 6 and 7
The synthetic strategies to access analogues 4 are described in
Scheme 1-4. The target compound 4a was synthesized using 4-(3,
4-dimethoxyphenyl) butanoic acid 8 as the starting material
(Scheme 2). 8 was converted to the Weinreb amide 9 using EDCI
as coupling agent in excellent yield.11 Nucleophilic addition of
the Weinreb amide 9 followed by reduction gave the alcohol 12.
Cyclization of 12 with HF-pyridine produced 4a.
Traditionally natural products (NP) have played an important
role in drug discovery and have proven to be vital source of
numerous drug leads. Many classes of natural products have been
shown to exhibit anti-HIV activity such as alkaloids, chromans,
flavonoids, lignins, triterpenes and coumarins.7,8 Recently, we
reported on the discovery of SG-1, a cyclolignan semi-
synthesized from a lignin isolated from Machilus robusta, as a
potent NNRTI with submicromolar concentration inhibitory
activity against RT polymerase. 9
Scheme 1. Synthesis of compound 4a. Reagents and conditions: (a) EDCI,
HOBT, N, O-Dimethylhydroxylamine hydrochloride, 4-Methylmorpholine,
CH2Cl2, 74%; (b) n-BuLi, THF, −78°C, 55%; (c) NaBH4, MeOH, rt, 87%; (d)
HF-pyridine, CH3CN, rt, 60%.
Fig.1. The structures of SG-1, (+)-isogalbulin (2) and (+)-galbulin (3)
In our previous report, we synthesized the natural products
(+)-isogalbulin (2) and (+)-galbulin (3) (Fig. 1).10 Considering
the structure similarity of the (+)-isogalbulin (2), (+)-galbulin (3)
and SG-1, we initially tested their activity against HIV-1. The
results showed that (+)-isogalbulin (2) had good inhibitory
activities against HIV-1 with an IC50 value (using VSV-G/HIV-1
infection assay) of 1.07 μM, while (+)-galbulin (3) showed no
anti-HIV activity at 10 µM, and this data illuminated some clear
SAR trends. The 5’-OMe group in aromatic ring B and the
absolute configuration at C7’ and C8’ may be important for the
activity. Based on this hypothesis result, we designed and
synthesized four series of novel analogues (4, 5, 6, 7) to further
explore this interested and potentially useful structure-activity
relationship (SAR) (Fig. 2).
The target compounds 4b and 4c were prepared through a
different synthetic strategy (Scheme 2). Compound 4b was
prepared from 4-(3,4-dimethoxyphenyl) butanoic acid 8 which
could be easily transformed to 13a (Scheme 2). An asymmetric
alkylation reaction of compound 13a produced compound 14a.
Removal of the chiral auxiliary under hydrolysis condition
followed by coupling and nucleophilic addition afforded
compound 17a which can subsequently be converted to 4b by
reduction and cyclization. The steric hindrance effect of the
adjacent methyl group probably resulted in the high anti
stereoselectivity of 4b.12 Following the same procedure as for the
synthesis of 4b, compound 4c was synthesized using (R)-4-
benzyl-2-oxazolidinone as auxiliary.

With analogues 4 in hand, we next turned our attention onto
the preparation of analogues 5. The target compounds 5a and 5b
were synthesized from known compound 24.10 Nucleophilic
addition reaction of 24 with substituted bromobenzene, followed
by cyclization gave the compounds 5a and 5b (Scheme 5).
Scheme 5. Synthesis of compound 5a and 5b. Reagents and conditions: (a) n-
BuLi, THF, 53%; 71%; (b) HF-pyridine, CH3CN, rt, for 5a: 72%, d.r. > 19:1,
for 5b: 75%, d.r. > 19:1, diastereomeric ratio of 5a and 5b were evaluated by
1H NMR analysis.
Next, we embarked on the synthesis of analogues 6. The
synthetic strategies to access analogues 6 are described in
Scheme 6-7. The target compound 6a was prepared from the
starting material 27 (Scheme 6). After the preparation of
corresponding acyl chloride 28, and subsequent condensation
reaction, amide 29 was produced in high yield. An Ullmann
reaction13 of 29 with CuI produced compound 30. Finally,
reduction of 30 furnished compound 6a.
Scheme 2. Synthesis of compounds 4b and 4c. Reagents and conditions: (a)
Pivaloyl chloride, Et3N, LiCl, THF, −78°C to rt, for 13a: 83%, for 13b: 77%;
(b) NaHMDS, MeI, THF, −78°C, 1h, for 14a: 90%, for 14b: 71%; (c)
LiOH·H2O, H2O2, THF, 0°C to rt, for 15a: 63%, for 15b: 79%; (d) DIPEA,
HATU, HOBT, N,O-Dimethylhydroxylamine hydrochloride, DMF, for 16a:
82%, for 16b: 72%; (e) n-BuLi, THF, −78°C, for 17a: 73%, for 17b: 73%; (f)
NaBH4, MeOH, rt, for 18a: 73%, for 18b: 74%; (g) HF-pyridine, CH3CN, rt,
for 4b:71%, d.r. > 19:1, for 4c: 78%, d.r. > 19:1, diastereomeric ratio of 4b
and 4c were evaluated by 1H NMR analysis.
Compounds 4d and 4e were obtained using the same method
as reported for the synthesis of (+)-galbulin 3 (Scheme 3) and
target compound 4f was synthesized following the synthetic route
for (+)-Isogalbuline 2 (Scheme 4).
Scheme 6. Synthesis of compound 6a. Reagents and conditions: (a) SOCl2,
reflux, 6 h, 90%; (b) 3,4,5-trimethoxyaniline, Et3N, CH2Cl2, 0°C to rt, 81%;
(c) CuI, K2CO3, DMF, reflux, 4h, 64%; (d) BF3·Et2O, BH3·Me2S, THF, 65%.
Compounds 6b-6d were also prepared from 27 using a new
synthetic strategy (Scheme 7). Grignard reaction of 31 with
methyl, ethyl, or propylmagnesium bromide gave compounds
32b, 32c, and 32d. A reductive amination, followed by a
Buchwald-Hartwig cross-coupling reaction produced 6b, 6c and
6d in moderate yield.14,15
Scheme 3. Synthesis of compounds 4d and 4e. Reagents and conditions: (a)
n-BuLi, THF, −78°C, for 22a: 75%, for 22b: 72%; (b) HF-pyridine, CH3CN,
rt, for 4d: 75%, d.r. > 19:1, for 4e: 80%, d.r. > 19:1, diastereomeric ratio of
4d and 4e were evaluated by 1H NMR analysis.
Scheme 7. Synthesis of compounds 6b-6d. Reagents and conditions: (a)
DIPEA, HATU, HOBT, N, O-Dimethylhydroxylamine hydrochloride, DMF,
90%; (b) R3MgBr, THF, 0°C, for 32b: 60%; for 32c: 55%; for 32d: 55%; (c)
Scheme 4. Synthesis of compound 4f.

3,4,5-trimethoxyaniline, sodium triacetoxyborohydride, acetic acid, CH2Cl2,
for 33b: 50%; for 33c: 40%; for 33d: 35%; (d) Pd(PPh3)4, K2CO3, toluene, for
6b: 82%; for 6c: 78%; for 6d: 82%.
Chloride, commercially known as (±)-Cryptostyline III), were
tested using vesicular stomatitis virus glycoprotein (VSV-
G)/HIV-1 infection assay with Nevirapine as a positive control.
16,17
As indicated in Table 1, 4b showed the most potent
Compounds 7a and 7b were synthesized from Gallic acid
trimethyl ether 34 (Scheme 8). Acyl chloride 35, obtained from
compound 34, was converted to compound 36 through a Friedel–
Craft reaction. Treatment of 36 with hydroxylamine
hydrochloride or methoxyamine hydrochloride gave the
compounds (Z, E)-7a and (Z, E)-7b.
inhibitory activity against HIV-1 (IC50 0.09 μM) with compounds
2, 4f, 6b, 6c and 5b also showing impressive submicromolar IC50
values against HIV-1. Compounds 4a, 4c, 6a, 6d, and 5a
however showed much less inhibitory activity, with IC50 values in
the micromolar range. All other analogues tested exhibited no
obvious activities when tested up to a 10 μM concentration. This
data illustrates some clear SAR trends: (i) the methyl group at C-
8 is not necessary for activity (1 versus 4b); (ii) The S
configurations at C8’ and C7’ are essential for inhibition of HIV-
activity (2 versus 3; 4b versus 4c); (iii) The 5’-OMe group in
aromatic ring B improved HIV inhibitory activity (2, 3 versus 1;
5a versus 5b), however, the 3-OMe group in ring A decreases
the observed activity against HIV (4f versus 1); (iv) The “C”
cycle can tolerate major change, with inhibition maintained when
either a C atom at 7’-position was substituted by N atom or
reducing the size of the ring itself, (4 (Series I ) versus 5 (Series
II); 5 (Series II) versus 6 (Series III)). Finally, we observed a
concurrent reduction in activity when the C ring is completely
removed (4 (Series I), 5 (Series II), 6 (Series III) versus 7
(Series IV)).
Scheme 8. Synthesis of compounds 7a and 7b. Reagents and conditions: (a)
SOCl2, reflux, 6h, 92%; (b) AlCl3, CH2Cl2, 41%; (c) RONH2.HCl, AcONa,
MeOH, for 7a: 60%; for 7b: 58%.
To evaluate the anti-HIV activity of the SG-1 derivatives, all
the synthesized compounds, including the two described natural
products and compound 37 (an intermediate of Gantacurium
Table 1.
Antiviral activities of (+)-SG-1(1) and its derivatives against wild-type HIV-1.a
Comp.
R1
R2
R3
R4
R5
R6
R
Configuration IC50(μM)
of 7’
95% confidence
intervals (μΜ)
0.11-0.24
H
H
(S)-CH3
(S)-CH3
(S)-CH3
H
(S)-CH3
(S)-CH3
(R)-CH3
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
-OCH2-
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
-OCH2-
OMe
OMe
H
S
0.16
0.86
>10
6.71
0.09
1.02
>10
>10
0.69
4.42
0.34
4.96
0.94
0.72
1.28
>10
>10
>10
>10
>10
0.013
1
S
0.47-1.53
2
H
H
R
-
3
H
OMe
OMe
OMe
OMe
H
Wide
4a
(±)
S
H
H
(S)-CH3
(R)-CH3
(R)-CH3
(R)-CH3
(S)-CH3
0.04-0.18
4b
H
H
R
R
R
S
S
S
0.58-1.82
4c
H
(S)-CH3
(S)-CH3
(S)-CH3
-
4d
H
-
4e
OMe
OMe
H
0.50-0.92
4f
Wide
5a
OMe
Wide
5b
H
Me
Et
Wide
6a
(±)
(±)
(±)
(±)
0.56-1.55
6b
Wide
6c
Pr
Wide
6d
=O
-
30
OH
-
7a
OMe
-
7b
36
-
-
37
0.008-0.018
Nevirapine
a There was no cytotoxicity observed for all tested compounds at the final concentration of 10 μM.

those observed for wild type HIV-1, while this mutant HIV-1
reduced NVP susceptibility by 70-fold.
Since the approval of Zidovudine (AZT) in 1987, 26 HIV
drugs are currently used in the clinic. Combination antiretroviral
(ARV) therapy is the standard treatment for HIV infection.
However, emergence of resistance to this ARV regimen poses a
significant challenge to the successful treatment of HIV. WHO
reported that HIV resistance to ARV drugs was identified in 95%
of people with HIV in developing countries.18 As the efficacy of
active compounds to resistant virus is an important parameter, we
tested the effects of compounds 4b, 4c, 4f, 2, 6b and SG-1 on
three representative NNRTI-resistant HIV strains which carry
mutations in RT as K103N, Y181C, and E138K/M184V.
HIV-1 RT Y181C is the second most common mutation. It
causes virus resistance to NVP (more than 50-fold), EFV (2-fold),
ETR (5-fold), and RPV (3-fold).20 We therefore tested
compounds 4b, 4c, 4f, 2, 6b on HIV-RT-Y181C replication; and
none of the compounds tested exhibited any inhibitory activity up
to a concentration of 10 μM (Table 2). This indicated that Y181
is a critical residue for SG-1 derivatives’ interaction with RT and
plays a crucial role in blocking its binding.
As previously mentioned, HIV-1 RT containing
E138K/M184V routinely lead to therapeutic failure in patients
treated with RPV, FTC, and TDF. Furthermore, RT-
E138K/M184V also has higher processivity than the wild type
RT, which results in the mutant virus having a higher replication
capacity. 21 We therefore tested compounds 4b, 4c, 4f, 2 and 6b
on HIV-RT-E138K/M184V replication which showed that this
mutant virus conferred 4.7 to 9.1-fold resistance to 4c, 4f, 2 and
6b, but only exhibited slight resistance to 4b (2-fold) which was
better than SG-1(8.6-fold).
HIV-1 carries RT-K103N, the most common NNRTI-
resistance mutation, among 138,560 clinical isolates with an 8.36%
of isolates containing this RT-K103N mutation.19 K103 is located
distal to the RT active site and is found on the loop connecting β5
and β6 in the RT p66 subunit located at the entrance of NVP and
EFV binding pockets. As a non-polymorphic mutation, RT-
K103N reduces the efficacy of first generation NNRTI by up to
100 fold. As shown in Table 2, the activities of the 5 tested
compounds and SG-1 against HIV-RT-K103N were similar to
Table 2
Inhibitory effects of SG-1 (1), 4b, 4c, 4f, 2, 6b and the references NVP and 3TC on wild-type and NNRTI-resistant HIV-1
replication.
Comp.
HIV-1 wt
IC50 (μΜ)
HIV-1RT-K103N
HIV-1RT-Y181C
95% confidence
HIV-1RT-E138K, M184V
IC50 (μΜ)
95% confidence
Folds
IC50 (μΜ)
Folds
IC50 (μΜ)
95% confidence
intervals (μΜ)
0.65-7.26
Folds
intervals (μΜ)
intervals (μΜ)
0.16
0.09
1.02
0.69
0.86
0.94
0.013
0.51
0.18
0.15
1.73
0.76
1.38
1.40
0.91
ND
0.13-0.27
1.1
1.7
1.7
1.1
1.6
1.5
70
-
10.8
> 10
> 10
> 10
> 10
> 10
2.86
ND
Wide
67.5
>111
>9.8
>14.5
>11.6
>10.6
220
1.38
0.18
7.13
5.91
4.02
8.53
0.022
>10
8.6
2.0
1
4b
0.08-0.26
1.25-2.53
0.62-0.93
0.73-2.93
0.82-2.64
0.81-1.02
ND
-
0.11-0.28
Wide
-
7.0
4c
-
5.28-6.57
Wide
8.6
4f
-
4.7
2
-
Wide
9.1
6b
1.08-6.50
-
0.015-0.032
-
1.7
NVP
3TC
-
>19.6
In summary, a series of potent HIV-1 reverse transcriptase
inhibitors were designed and synthesized. Compound 4b showed
potent inhibitory activity against HIV-1 with an IC50 of 0.09 μM.
In addition, five compounds 2, 4c, 4f, 6b, 6c and 5b also showed
impressive submicromolar IC50 values against HIV-1. These
results have established preliminary SAR trends and the activities
of the 5 tested compounds and SG-1 against HIV-RT-K103N
were similar to those observed for wild type HIV-1, while this
mutant HIV-1 reduced NVP susceptibility by 70-
fold. Furthermore, this mutant virus (HIV-RT-E138K/M184V)
conferred 4.7 to 9.1-fold resistance to 4c, 4f, 2 and 6b, but only
slightly resistance to 4b (2-fold) which was better than SG-1.
Evaluation Study (No. BZ0150), the National Science and
Technology Major Project (No. 2015ZX09102-023-004), and the
Science and Technology Program of Beijing (No.
Z151100000115008).
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Highlights
• A series of potent HIV-1 reverse transcriptase
inhibitors were synthesized.
• Compound 4b showed potent inhibitory activity
against HIV-1(IC50 0.09 μM).
• These results in the paper have established
preliminary SAR trends.
• RT- E138K/M184V mutant virus conferred 2-fold
resistance to 4b (better than SG-1).

Graphical Abstract
Design, synthesis and biological evaluation of
substituted (+)-SG-1 derivatives as novel
anti-HIV agents
Xiaoyu Liua,1, Panpan Chenb,1, Xiaoyu Lia, Mingyu Bab,
Xiaozhen Jiaoa, , Ying Guob, *, and Ping Xiea
Leave this area blank for abstract info.