Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: Insights into its structural requirements for anti-MRSA activity

Article abstract of DOI:10.1016/j.bmcl.2004.06.039

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on ant

Full text of DOI:10.1016/j.bmcl.2004.06.039

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4519–4523
Syntheses and anti-MRSA activities of the C3 analogs of
mansonone F, a potent anti-bacterial sesquiterpenoid: insights into
its structural requirements for anti-MRSA activity
Dong-Yun Shin,a Sun Nam Kim,a Jung-Hyun Chae,a Soon-Sil Hyun,a Seung-Yong Seo,a
Yong-Sil Lee,a Kwang-Ok Lee,a Seok-Ho Kim,a Yun-Sang Lee,a Jae Min Jeong,b
Nam-Song Choia and Young-Ger Suha,*
aCollege of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
bCollege of Medicine, Seoul National University, Seoul 110-744, South Korea
Received 17 May 2004; revised 12 June 2004; accepted 12 June 2004
Available online 3 July 2004
Abstract—Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal
structural requirements for its anti-MRSA activities as well as its structure–activity relationship including the C3 substituents effects
on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of
mansonone F are essential for anti-MRSA activities.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
highly potent anti-MRSA agents. In this connection, we
have recently reported isolation and excellent anti-
MRSA activity of mansonone F (1), a new anti-bacterial
sesquiterpenoid.5 It has been shown to have excellent
anti-bacterial activities against Gram-positive bacteria,
MRSA (2 lg/mL of MIC90 in vitro), which is compa-
rable to that of vancomycin. The unique structure of
Mansonone F consists of oxaphenalene skeleton and
ortho-naphthoquinone moiety (Fig. 1).
During the last two decades, the increasing prevalence of
antibiotic-resistant bacteria has had an enormous im-
pact on infection control policies.1 In particular, the
resistance to multiple antibiotics of Gram-positive bac-
terial strains, methicillin-resistant Staphylococcus aureus
(MRSA), is currently considered as serious clinical
problem. Even though vancomycin and teicoplanin of
glycopeptide antibiotics,2 quinupristin/dalfopristin,3 and
linezolid4 of new antibiotics are clinically used for the
treatment of MRSA infections, the structural complex-
ity or toxic side effects of these antibiotics as well as the
recent occurrences of new resistant strains have
prompted the increased efforts for novel antibiotics.
Thus, the discovery of novel classes of anti-bacterial
agents employing new mode of action is of great concern
due to the rapid acquirement of multidrug resistance by
Gram-positive pathogens.
We herein report syntheses and anti-MRSA activities of
the C3 mansonone F analogs. In addition, we describe
its structure–activity relationship, which revealed the
minimal structural requirements for anti-MRSA activity
and C3 substituents effects.
The mechanism of anti-bacterial activity of mansonone F
has not been completely elucidated yet. However, on the
O
Recently, one of the major efforts in our laboratory has
been the search, design, and synthesis of novel and
7
O
8
A
B
C
3
1
O
Keywords: Mansonone F; Anti-MRSA.
* Corresponding author. Tel.: +82-288-07875; fax: +82-288-80649;
e-mail: ygsuh@snu.ac.kr
2
Figure 1. Structure of mansonone F (1).
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.039

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D.-Y. Shin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4519–4523
basis of structural features of mansonone F, its anti-
MRSA activities can be understood by two possible mode
of actions.6 The first mechanism involves generation of
superoxide, particularly cytotoxic superoxide radical,
which was reported for anti-bacterial and anti-protozoal
activities of several naphthoquinones and isoxazolyl
naphthoquinones.7 However, we have observed that no
strains survived when we cultured the strain of S. aureus
over the MIC of mansonone F in the presence of 4,5-
dihydroxy-1,3-benzene-disulfonic acid (Tiron, SIGMA),
a specific superoxide scavenger. This supported that the
anti-bacterial activity of mansonone F is not mainly due
to the production of cytotoxic superoxide radical. The
possible alternative mechanism is an attack of certain
nucleophile such as thiol, amine, or alcohol of the bacte-
rial growth-related enzymes to the enedione carbonyl of
mansonone F, thus rendering the corresponding enzyme
inactive although base stacking or intercalation of the
planar oxaphenalene system in bacterial DNA is also
possible.8 This is partly supported by recent report in
several literatures of 1,2 or 1,4-addition of thiol and
nitrogen nucleophile to quinone moiety.9 Thus, these
recent information gave us a starting point for the studies
on structure–activity relationship of mansonone F that
was initially focused on the identification of pharmaco-
phoric parts of mansonone F and the role of C-ring sys-
tem including C3 substituents effects on anti-bacterial effect.
NO2
O
O
i, ii
iii, iv
OH
OMe
6
OMe
5
7
Scheme 1. Reagents and conditions: (i) MeI, NaH, THF, 97%; (ii)
Cu(NO3)2ÆxH2O, Ac2O, rt, 73%; (iii) 10% Pd/C, H2, MeOH, rt; (iv)
Fremy’s salt, 0.06 M NaH2PO4, acetone, rt, 65% for two steps.
The analog 7, which consists of A,B-ring skeleton of
mansonone F, was prepared by four steps sequence as
shown in Scheme 1. O-Methylation of 2,5-dimethyl-1-
naphthol (5) with methyl iodide, nitration of the
resulting methyl ether, followed by catalytic hydroge-
nation, and Teuber oxidation afforded the naphthoqui-
none 7.
The tricyclic analogs 11a–f were prepared according to
the synthetic method5a developed for the synthesis of
mansonone F with some proper modifications. Sodium
borohydride reduction of the intermediate 8 or appro-
priate Grignard addition reactions provided the sec-
ondary alcohol 9a or the tertiary alcohols 9b, 9e, and 9f.
The vinyl alcohol 9c was obtained by reaction of 8 with
organocerium reagent prepared from vinylmagnesium
chloride and anhydrous cerium chloride. Reduction
(10% Pd/C, H2, MeOH) of nitro group of 9a, 9b, and
9d–f followed by direct amine oxidation gave the tri-
cyclic quinoids 10a, 10b, and 10d–f. Chemoselective
reduction of nitro group of the nitrated product of 9c in
the presence of terminal olefin could be achieved by a
combination of sodium borohydride and element sulfur.
Finally, dehydration of the tertiary alcohols was carried
out by Burgess procedure or under acidic or basic con-
ditions.
2. Chemistry
Most of the structural analogs were synthesized starting
from the intermediate 5 or 8 according to the divergent
synthetic routes as shown in Schemes 1 and 2. The
known analogs 2 and 3, which are devoid of ortho-qui-
none moiety, were prepared from the tricyclic ketone 85a
and the benzoquinone analog 4 as an A-ring equivalent
of mansonone F is commercially available.
The analogs 12a–c were obtained by hydrogenolysis of
the corresponding alcohols prepared by carbonyl
reduction or Grignard addition of 8. The dicarbonyl
moiety was introduced by analogy with 11a–f. The
analogs 13a and 13b were prepared by sequential Hor-
ner–Emmons reaction of ketone 8, catalytic hydroge-
NO2
O
O
O
O
OMe
2
3
4
O
O
O
O
O
iii, iv
v
i
OH
R
OH
R
O
O
O
O
R
10a R = H
11a R = H
8
9a R = H
11b R = CH CH
9b R = CH CH
10b R = CH CH
2
3
2
3
2
3
11c R = CHCH
9c R = CHCH
2
10c R = CHCH
2
2
ii
11d R = CH CH OH
2
2
3 2
2 2
9d R = CH CH OH
10d R = CH CH OH
2
2
2
2
11e R = CH(CH )
9e R = CH(CH )
10e R = CH(CH )
3 2
3 2
11f R = CH (CH ) CH
3
2
9f R = CH (CH ) CH
10f R = CH (CH ) CH
2
2 2
3
2
2 2
3
Scheme 2. Reagents and conditions: (i) DIBAL, CH2Cl2, )78 °C, 94% for 9a; RMgBr, Et2O, rt, 72–93% for 9b, 9e, and 9f; CH2CHMgBr, CeCl3,
THF, )78 °C to 0 °C, 78% for 9c; (ii) BH3ÆMe2S, THF, 0 °C then H2O2, NaOH, 43%; (iii) Cu(NO3)2ÆxH2O, Ac2O, rt, 65–87%; (iv) 10% Pd/C, H2,
MeOH, rt then Fremy’s salt, 0.06 M NaH2PO4, acetone, rt, 56–78% for 10a, 10b, and 10d–f; sulfur, NaBH4, THF, reflux then Fremy’s salt, 0.06 M
NaH2PO4, acetone, rt, 75% for 10c; (v) Burgess reagent, benzene, reflux, 47% for 11a; H2SO4/EtOH (1:20), reflux, 37–67% for 11b and 11d–f; MsCl,
DMAP, Et3N, CH2Cl2, )78 °C, 13% for 11c.

D.-Y. Shin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4519–4523
4521
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CO2Et
CO2H
13a
13b
12a
12b
12c
nation of the resulting double bond and the same pro-
cedure employed for 11a–f.
3. Results and discussion
The in vitro anti-bacterial activities of the synthesized
analogs along with the reference compounds were
assayed against 140 MRSA strains according to the
standard procedure, and the minimal inhibitory con-
centrations (MIC50, MIC90) are listed in Table 1.10;11
The transformations of the ketone 8 into the C3-trifluoro-
methyl analog 16 and the cyano analog 21 are summa-
rized in Schemes 3 and 4, respectively. Introduction of a
trifluoromethyl group to the carbonyl of 8 was executed
by fluoride-induced trifluoromethylation, followed by
the standard procedure employed for other analogs, to
give the C3-trifluoromethylmansonone F (16). The ini-
tially attempted dehydration of the trifluoromethyl
alcohol 15 was unsuccessful under the general conditions,
such as H2SO4/EtOH, Burgess reagent, PTSA/benzene,
or TFAA/Et3N. However, treatment of the alcohol 15
with excess POCl3/pyridine followed by direct amine
oxidation gave a 1.2:1 mixture of the dehydrated quinone
16 and the chloroquinone 17, which were separable by
flash column chromatography. Thioketal 18 prepared
from the ketone 8 by nitration and thioketalization was
mono-cyanated by TMSCN in the presence of SnCl4 to
give the cyano intermediate 19, which was further
transformed into the cyano sulfide 20. During this pro-
cess, the desired C3-cyano analog 21 was produced from
20 by spontaneous elimination of sulfoxide generated by
sulfide oxidation. Finally m-CPBA-induced syn-elimi-
nation of 20 afforded C3-cyanomansonone F (21).
The analogs 2 and 3 of which C7-hydrogen or C7-nitro
group replaces the dicarbonyl moiety of mansonone F
exhibit no anti-bacterial activities against MRSA even
at more than 100 lg/mL. The analogs 4 and 7, which
are devoid of C-ring or B,C-ring moiety of mansonone
F did also not show anti-bacterial activities up to the
highest concentration tested. These results revealed that
the ortho-quinone moiety as well as the tricyclic skele-
ton is essential for anti-MRSA activity of mansonone
F.
None of the analogs possessing bulky and/or lipophilic
substituents at C3 (11b, 11e, and 11f) displayed higher
potency than mansonone F, though 3-ethylmansonone
F (11b) and 3-isopropylmansonone F (11e) were nearly
equipotent. However, an introduction of vinyl sub-
stituent at C3 (11c) unexpectedly eliminated anti-bacte-
rial activity. It was anticipated that change of electronic
NH2
O
O
O
O
O
O
i, ii
iii, iv
v, vi
+
OH
CF3
OH
CF3
Cl
CF3
O
O
O
O
CF3
8
14
15
16
17
Scheme 3. Reagents and conditions: (i) (CH3)3SiCF3, TBAF, THF, rt; (ii) TBAF, THF, rt, 93% for two steps; (iii) Cu(NO3)2ÆxH2O, Ac2O, rt, 86%;
(iv) 10% Pd/C, H2, MeOH, rt, 87%; (v) P(O)Cl3, pyridine, rt; (vi) Fremy’s salt, 0.06 M NaH2PO4, acetone, rt, 21% for 16, 18% for 17 for two steps.
O
O
O
O
NO2
O
NO2
O
O
O
iv, v
iii
i, ii
+
CN
SPh
SPh
SPh
CN
SPh
O
O
CN
8
18
19
20
21
vi
Scheme 4. Reagents and conditions: (i) Cu(NO3)2ÆxH2O, Ac2O, rt, 94%; (ii) PhSH, BF3ÆOEt2, CH2Cl2, 0 °C, 87%; (iii) (CH3)SiCN, SnCl4, CH2Cl2,
0 °C, 93%; (iv) 10% Pd/C, H2, MeOH, rt, 72% (v) Fremy’s salt, 0.06 M NaH2PO4, acetone, rt, 81%; (vi) m-CPBA, CH2Cl2, rt, 86%.

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D.-Y. Shin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4519–4523
Table 1. Anti-bacterial activities of the synthesized mansonone F analogs against MRSAs
Analogs
R1
R2
MIC50 (lg/mL)
MIC90 (lg/mL)
Vancomycin
Mansonone F
2
2
2
4
CH3
2
3
4
7
>32
>32
>32
>32
>32
>32
>32
>32
11a
11b
11c
11d
11e
11f
16
H
8
4
8
4
CH2CH3
CHCH2
CH2CH2OH
CH(CH3)2
CH2(CH2)2CH3
CF3
O
O
>32
>32
4
>32
>32
4
O
8
8
R
1
16
8
>32
16
21
CN
12a
12b
12c
13a
13b
10g
10b
17
H
H
CH3
16
8
16
16
H
O
O
H
CH2CH3
CH2CO2Et
CH2CO2H
CH3
32
16
32
32
O
H
H
>32
16
>32
>32
16
R
2
1
OH
OH
Cl
R
CH2CH3
CF3
16
16
16
The synthesis of 10g was reported in Ref. 5a.
The clinical isolates were obtained from Seoul National University Hospitals in Seoul Korea.
character of C3-substituent such as nitrile (16) or tri-
fluoromethyl (21) would enhance anti-bacterial activity
by inducing higher electrophilicity of quinone moiety
through the fully conjugated system. However, contrary
to our expectation, they reduced anti-bacterial activities
of mansonone F. The analog 11d, of which hydroxyethyl
group was introduced, in expectation of improved
physical properties of natural mansonone F, was dis-
appointingly inactive.
inal chemistry. Currently, the work on the novel anti-
MRSA agents based on the structure–activity relation-
ship of mansonone F is in good progress and the highly
advanced results will be reported in near future.
Acknowledgements
This research was supported by Grant from Center for
Bioactive Molecular Hybrids, Yonsei University.
The C2,3-olefin seems to be beneficial for anti-bacterial
activity because reduction of C2,3-olefin of mansonone
F drops the activities as shown in 12a–c compared to
those of mansonone F, 11a and 11c. In addition, the
hydroxy substitution (10g) for C3-H of 12b also reduced
the anti-bacterial activity as shown in 11d.
References and notes
1. Cafferkey, M. T. Methicillin-Resistant Staphylococcus
aureus; Marcel Dekker: New York, 1992.
2. Boger, D. L. Med. Res. Rev. 2001, 21, 356.
3. Allington, D. R.; Rivey, M. P. Clin. Ther. 2001, 23, 24.
4. Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed.
2003, 42, 2010.
5. (a) Suh, Y. G.; Shin, D. Y.; Min, K. H.; Hyun, S. S.; Jung,
J. K.; Seo, S. Y. Chem. Commun. 2000, 1203; (b) Shin, D.
Y.; Kim, H. S.; Min, K. H.; Hyun, S. S.; Kim, S. A.; Huh,
H.; Choi, E. C.; Choi, Y. H.; Kim, J. W.; Choi, S. H.;
Kim, W. B.; Suh, Y. G. Chem. Pharm. Bull. 2000, 48,
1805.
6. Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.;
Monks, T. J. Chem. Res. Toxicol. 2000, 13, 135.
7. (a) Gutteridge, J. M. C.; Quinlan, G. J.; Kovacic, P. Free
Radical Res. 1998, 28, 1; (b) Bogdanov, P. M.; Bertorello,
M. M.; Albesa, I. Biochem. Biophys. Res. Commun. 1998,
244, 561.
8. Walsh, C. Antibiotics; ASM: Washington, DC, 2003.
9. (a) Urbanek, R. A.; Suchard, S. J.; Steelman, G. B.;
Knappenberger, K. S.; Sygowski, L. A.; Veale, C. A.;
Chapdelaine, M. J. J. Med. Chem. 2001, 44, 1777; (b)
In conclusion, based on the studies on the anti-bacterial
activities of the synthesized analogs, both ortho-quinone
moiety and tricyclic system of mansonone F seem to be
essential for their excellent anti-MRSA activities.
Change of the C3-methyl or C2,3-olefin of mansonon F
reduces the anti-bacterial activity regardless of elec-
tronic and steric characters of the new substituents al-
though C3-alkyl substituents do not significantly affect
the anti-bacterial activity. During the studies on the
structure–activity relationship of mansonone F, the anti-
bacterial activity-enhanced analogs have not been
found. However, the information on structure–activity
relationship of mansonone F as well as the structural
requirements for its highly potent anti-MRSA activity
envisions development of the novel and promising anti-
MRSA agent. In addition, the unique procedures for
trifluoromethyl and nitrile introductions at C3-carbonyl
would be importantly utilized for wide range of medic-

D.-Y. Shin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4519–4523
4523
Feldman, K. S.; Quideau, S.; Appel, H. M. J. Org. Chem.
1996, 61, 6656; (c) Feldman, K. S.; Sambandam, A.;
Bowers, K. E.; Appel, H. M. J. Org. Chem. 1999, 64, 5794;
(d) Zheng, Z.-B.; Nagai, S.; Iwanami, N.; Kobayashi, A.;
Hijikata, M.; Natori, S.; Sankawa, U. Chem. Pharm. Bull.
1998, 46, 1950.
stored at )70 °C until use: Choi, K. H.; Hong, J. S.; Kim,
S. K.; Lee, D. K.; Yoon, S. J.; Choi, E. C. J. Antimicrob.
Chemother. 1997, 39, 509.
11. MICs were determined by an agar dilution method with
Mueller-Hinton agar (MHA, Difco Laboratories, Detroit,
MI) following the National Committee for Clinical
Laboratory Standards (NCCLS) procedure. The detailed
procedure is described in Ref. 5b.
10. Bacterial strains; Clinical isolates were obtained from
hospitals in Seoul, Korea between 1997 and 1999 and were