Synthesis, microbial transformation, and pharmacological evaluation of 4,5-dihydronaphtho[2,1-b]furan-2-ones and related analogues

Article abstract of DOI:10.1039/c3md00111c

Reaction of 5- or 7-methoxy-2-tetralone with an α-bromoester using lithium diisopropylamide as the base gave tricyclic naphtho[2,1-b]furan-2-ones in one step. Catalytic reduction, epimerization with triethylamine and microbial transformations yielded seve

Full text of DOI:10.1039/c3md00111c

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Medicinal Chemistry Communications
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DOI: 10.1039/C3MD00111C
Table of Contents Entry
A one-step reaction gave naphtho[2,1-b]furan-2-ones which showed anti-inflammatory and
breast cancer cell migration inhibitory effects.
O
R
O
O
8
X
X
6
2a: X = 6-OCH3, R = CH3
2b: X = 8-OCH3, R = CH3
2c: X = 8-OCH3, R = C6H5

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DOI: 10.1039/C3MD00P11a1gCe 2 of 8
allylamine, and unsaturated lactones 2b and 2c were subjected to
Synthesis, microbial
transformation, and
pharmacological evaluation of 4,5-
dihydronaphtho[2,1-b]furan-2-
ones and related analogues
microbial biotransformation screening using a standard battery of
microorganisms. The utilization of microbes as model systems to
55 predict metabolic pathways in humans, to increase the efficacy of
drugs by metabolic activation or to create novel and active
analogs has been well documented.6,7 This concept depends on
the fact that fungi, being eukaryotes, possess metabolizing
enzymatic machinery similar to those of mammals.
60 Biotransformation and biocatalysis offer many distinct
advantages, including: mild reaction conditions, highly stereo-,
regio-, and chemoselective, unique and varied chemistry, and
environmental safety.6,7 Other advantages of biocatalysis for
generating organic libraries include the natural diversity of
65 enzymatic reactions, the compatibility of reaction conditions and
high-throughput screening techniques, ease of automation, and
the ability to retrace synthetic pathways leading to active
products.6,7
5
Khalid A. El Sayed,a Ahmed I. Foudah,a
Alejandro M.S. Mayer,b A.
Daniel Songa,d
Michael Crider,c*
10 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted
Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The structural similarity of the naphtho[2,1-b]furan-2(3a)-ones
70 and related derivatives to that of the COX-2 selective inhibitor
rofecoxib, stimulated our interest in evaluating these compounds
for anti-inflammatory activity. COX-2 is a key inducible enzyme
controlling prostaglandin production, and inhibitors of COX-2
have been shown to induce apoptosis in various cancer cells.8,9
75 Thus, several of the microbial metabolites and synthetic
derivatives of the rofecoxib analogue 2c were tested in a number
of assays to assess anti-inflammatory and breast cancer
antimigratory activity. The synthesis, characterization, and
pharmacological evaluation of the 1-substituted-1,4,5,9b-
80 tetrahydronaphtho[2,1-b]furan-2-ones and related derivatives will
be described in this report.
Reaction of 5- or 7-methoxy-2-tetralone with an α-bromoester
using lithium diisopropylamide as
a base gave tricyclic
15 naphtho[2,1-b]furan-2-ones in one step. Catalytic reduction,
epimerization with triethylamine and microbial transformations
yielded several related analogues. Some naphtho[2,1-b]furan-2-
ones showed anti-inflammatory and breast cancer migration
inhibitory activities.
20 Introduction
As part of a program directed toward the discovery of ligands
with selectivity at dopamine (DA) receptor subtypes, cis-(±)-
2,3,3a,4,5,9b-hexahydro-8-hydroxy-3-n-propyl-1H-benz[e]indole
(cis-(±)-8-OH-PBZI, 1, Fig. 1) was shown to bind with high
25 affinity and selectivity at DA D3 receptors.1,2 During the course
of structure-activity relationship (SAR) studies with these
benz[e]indoles, the synthesis of 1-substituted-hexahydro-1H-
benz[e]indoles was initiated. We envisioned a reaction sequence
similar to the one employed by Lin et al.3 for the synthesis of
30 hexahydro-1H-benz[e]indoles. Unexpectedly, reaction of a 2-
tetralone with an α-bromoester using lithium diisopropylamide
(LDA) as the base afforded tricyclic naphtho[2,1-b]furan-2-ones
2a-c (Scheme 1).
10
O
O
O
R
2
1
H
9
N
H
O 3
3a
HO
9a
8
9b
X
4
7
6
5
H3CO2S
1 (cis-(+/-)-8-OH-PBZI)
2a: X = 6-OCH3, R = CH3
2b: X = 8-OCH3, R = CH3
3: Rofecoxib
2c
: X = 8-OCH3, R = C6H5
Scheme 1. Structures of PBZI (1), naphtho[2,1-b]furan-2-ones
(2a-c), and rofecoxib (3).
85
During the course of this investigation, Pal et al.4 reported the
35 synthesis of conformationally restricted 3,4-diarylfuranones
based on the naphthofuranone nucleus. These 4,5-
dihydronaphtho[2,1-b]furan-2(3aH)-ones can be viewed as
conformationally restricted 3,4-diarylfuranones that are
structurally related to the COX-2 inhibitor rofecoxib (3, Scheme
40 1). Compounds 4a-4b were prepared from appropriately
H3CO2S
O
O
X
4a
4b
: X = H
: X = CH3
substituted 1-tetralones by
a
three-step procedure. The
Scheme 2. Naphtho[2,1-b]furan-2-ones prepared by Pal et al.4
naphtho[2,1-b]furan-2-ones 4a-b (Scheme 2) exhibited
comparable in vitro COX-2 inhibition as rofecoxib, although with
less COX-2/COX-1 selectivity. Due to an increased risk of
45 adverse cardiovascular events, rofecoxib was withdrawn from the
market.5
Results and discussion
90 1. Chemical synthesis
In an effort to study a greater diversity of compounds, the 1-
substituted-4,5-dihydronaphtho[2,1-b]furan-2-ones 2a and 2c
were reduced to the corresponding 1-substituted-1,4,5,9b-
50 tetrahydrofuran-2-ones 10a and 10b, respectively. Lactone 2c
was transformed to corresponding lactam 16 by reaction with
Reaction of 5-methoxy-2-tetralone (5a) or 7-methoxy-2-tetralone
(5b) with an α-bromoester using LDA as the base afforded
tricyclic naphtho[2,1-b]furan-2-ones 2a-c (Scheme 3).
Apparently, after initial alkylation of the 2-tetralones 5a and 5b,
95 enolization of the ketoesters leads to the formation of the 4,5-

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DOI: 10.1039/C3MD00111C
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Medicinal Chemistry Communications
dihydronaphtho[2,1-b]furan-2(1H)-ones 6a-c, which after double
4.76 and 4.54 (J = 13.2 Hz, each). This carbon was assigned C-
migration during acidic work-up, affords the 4,5- 65 10, which replaced the methyl H3-10 in 2b. Therefore, 13 was
dihydronaphtho[2,1-b]furan-2(1H)-ones 2a-c (Scheme 3).
Support for this mechanism is found in a study by Chavan and
Govande10 in which the formation of butenolide 8 from the diol 7
was reported using an excess of Amberlyst 15 (Scheme 4). When
found to be 1-(hydroxymethyl)-8-methoxy-4,5-dihydronaphtho-
[2,1-b]furan-2(3aH)-one.
5
Metabolite 15 was identified as benzeneacetamide based on its
HRMS data (molecular ion peak at m/z 158.0579, [M+Na]+
only a catalytic amount (10 %) of Amberlyst 15 was used, the 70 corresponding to the molecular formula C8H9NO, calculated
ketoester 9 was the major product. These workers proposed that
the ketoester was a possible intermediate in butenolide formation.
10 This was confirmed by treating the ketoester with Amberlyst 15
158.0576) as well as NMR data. This compound was identified as
a biodegradation product of cyanohydrocarbons and diverse
nitriles by the bacterium Rhodococcus strain RL412 and nitrile
hydratase enzyme from the bacterium Rhodopseudomonas
in refluxing toluene to yield the butenolide 8.
The structures of 2b-2c were established based on extensive 75 palustris CGA009.13 This is the first report of this compound as a
analysis of their 1D and 2D NMR data (Table 1). The methyl
doublet H3-10 in 2b (δH 2.16) showed 3J-HMBC couplings to the
15 lactone carbonyl carbon C-2 (δC 175.2) and the downfield
olefinic quaternary β-carbon C-9b (δC 156.2). It also showed a 2J-
HMBC coupling to the olefinic quaternary α-carbon C-1 (δC
119.4), confirming the α,β-unsaturated lactone formation. The
fungal biotransformation product.
Reaction of 2c in toluene with allylamine for 72 h at room
temperature afforded the lactam 16 (Scheme 7). The HREIMS
data of 16 showed a molecular ion peak at m/z 332.1639 [M+H]+
1
80 corresponding to the molecular formula C22H22O2N. The H and
13C NMR data (Table 1) suggested an N-allyl lactam derivative of
2c. The upfield shift of C-3a (-17.5 ppm) in 16, compared to its
parent 2c, indicated the replacement of the lactone oxygen with a
lactam nitrogen. This was associated with additional new 1H and
85 13C NMR signals corresponding to an N-allyl group in 16 (Table
1). Therefore, 16 was shown to be 3-allyl-8-methoxy-1-phenyl-
3
oxygenated downfield proton H-3a (δH 4.49) showed J-HMBC
20 couplings to C-1, C-2, and C-5 (δC 27.0) and 1H-1H-COSY
couplings with the methylene protons H2-4 (δH 2.61 and 1.72)
and H3-10.
Catalytic hydrogenation of the unsaturated lactones 2a and 2c
readily afforded the corresponding 1,4,5,9b-tetrahydronaphtho-
25 [2,1-b]furan-2(3a)-ones 10a and 10b (Scheme 5). Hydrogenation
of the 1,9b-double bond proceeded with cis-addition of hydrogen.
The hydrogens at the C-1, 3, and 9b-positions are on the same
side of the ring and are designated cis-syn.1 Previously, single
crystal x-ray crystallography of the structurally-related
30 unsaturated tricyclic lactams showed that catalytic hydrogenation
also yielded cis-syn reduction products.11 Epimerization of the
cis-syn lactone 10b to the cis-anti diasteroisomer 11 was
accomplished by stirring with Et3N in CH2Cl2 for 48 h (Scheme
3,3a,4,5-tetrahydro-2H-benzo[e]indol-2-one.
O
R
OCH3
O
O
a
X
X
5a: X = 5-OCH3
5b
: X = 7-OCH3
O
O
O
R
R
R
OCH3
OH
O
O
1
5). The structures of 10b and 11 were confirmed by H and 13C
X
X
X
35 NMR, HRMS, and elemental analysis.
6a: X = 6-OCH3, R = CH3
6b
2a: X = 6-OCH3, R = CH3
2b
: X = 8-OCH3, R = CH3
6c: X = 8-OCH3, R = CH3
: X = 8-OCH3, R = CH3
2c: X = 8-OCH3, R = C6H5
2. Microbial transformations
Twenty-eight growing microbial cultures were screened for their
ability to bioconvert 2b and 2c. Of these, Rhizopus arrhizus
ATCC 11145 was selected for the scale-up bioconversion of each
40 compound. This selection was based on the TLC diversity of the
generated metabolites. Biocatalysis of 2b afforded two new
metabolites, 5α-hydroxy and 1-hydroxymethyl analogs of 2b (12
and 13, respectively) (Scheme 6). The naphthofuran analog 2c
was biotransformed by R. arrhizus to its 5α-hydroxy analogue
45 (14) and benzeneacetamide (15).
Scheme 3. Synthesis of naphtho[2,1-b]furan-2-ones ( 2a-c). (a)
90 LDA, RCH(Br)CO2CH3, THF.
O
O
O
H3C
R
R
OCH2CH3
OH
OH
OCH2CH3
O
O
Amberlyst 15
+
X
7
8
9
Scheme 4. Intramolecular cyclization of diol 7 using Amberlyst 15.10
The HREIMS data of 12 showed a molecular ion peak at m/z
242.0969 [M+H]+, corresponding to molecular formula C14H15O4.
O
1
The H and 13C NMR data suggested a monohydroxy derivative
H
O
R
R
H
of 2b. The oxygenated methine carbon at δC 66.9 which
50 correlated with the broad proton doublet at δH 5.09 was assigned
C-5. This was based on the COSY coupling of H-5 with H2-4.
The splitting pattern of H-5 and the small coupling value (J = 5.5
Hz) suggested its pseudoequatorial orientation. Therefore, the
pseudoaxial C-5 hydroxy should be β-oriented. Hence, 12 was
55 shown to be (5R)-5-hydroxy-8-methoxy-1-methyl-4,5-dihydro-
naphtho[2,1-b]furan-2(3aH)-one. Similarly, metabolite 14 was
found to be (5R)-5-hydroxy-8-methoxy-1-phenyl-4,5-dihydro-
naphtho[2,1-b]furan-2(3aH)-one.
O
O
H
a
X
X
2a: X = 6-OCH3, R = CH3
2b
10a:
X = 6-OCH3, R = CH3
10b: X = 8-OCH3, R = C6H5
: X = 8-OCH3, R = CH3
2c: X = 8-OCH3, R = C6H5
H
O
H
O
b
H
H
O
H
H3CO
O
H
H3CO
The HREIMS data of 13 showed a molecular ion peak at m/z
60 269.0789 [M+Na]+, corresponding to molecular formula
1
C14H14O4. The H and 13C NMR data suggested a monohydroxy
10b
11
95
derivative of 2b. The hydroxymethylene carbon at δC 55.6 which
correlated with a geminally-coupled proton doublet pair at δH

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Medicinal Chemistry Communications
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Scheme 5. Reduction of naphtho[2,1-b]furan-2-ones 2a-c and
colon, CNS, skin, ovary, kidney, prostate, and breast).
epimerization of 10b. (a) EtOH, 10% Pd/C, (b) CH2Cl2, Et3N, 48 h.
Unfortunately, the rest of compounds were not accepted for
screening in this assay. Compounds were tested at a single
concentration of 10 µM, and the percent growth of the 60 cell
50 lines was determined and presented in the form of mean graphs
(Figs. SI3-SI5, Table 3). These mean graphs provide insights into
the differential cell growth inhibition for each compound, as well
as a characteristic fingerprint pattern which possess a significant
correlation to the compound’s chemistry. Compounds 2b, 2c, and
55 16 showed mean percent growth of 73.9, 65.7, and 59.8,
respectively, across all the 60 cell lines (mean-60, Figs. SI3-SI5).
This proved significant growth inhibitory activities for these
compounds with similar fingerprint of activity and were selective
to cancer cells belonging to blood, prostate, skin, and breast
60 tissues. C-1 phenyl group in 2c showed better activity versus C-1
methyl group represented by 2b. The N-allyl lactam analogue 16
was slightly more active than its parent 2c, suggesting the
preference of N-substituted lactam over the lactone group.
Further SAR studies can prove the potential of 1-phenyl-3,3a,4,5-
65 tetrahydro-2H-benzo[e]indol-2-ones as antiproliferative entity.
O
O
O
HO
Rhizopus arrhizus
ATCC 11145
O
H3CO
O
O
H3CO
H3CO
14 Days
+
OH
2b
12
13
O
O
O
O
Rhizopus arrhizus
ATCC 11145
O
H3CO
NH2
H3CO
+
14 Days
OH
2c
14
Benzeneacetamide (15)
5
Scheme 6. Biotransformation of the naphtho[2,1-b]furan-2-ones
2b and 2c using the fungus Rhizopus arrhizus ATCC 11145.
O
O
N
3c. Migration inhibition of compounds 2b-16 on the highly
metastatic MDA-MB-231 human breast cancer cell line. The
wound-healing assay is a simple method for the study of
70 directional cell migration in vitro.17 Cell migration is relevant to
many cellular processes in morphogenesis, tissue repair, as well
as cancer invasion and metastasis.18 The ability of 4,5-
dihydronaphtho[2,1-b]furan-2(3aH)-ones 2b-16 to inhibit the
migration of the highly metastatic MDA-MB-231 human breast
75 cancer cell line in wound-healing assay was evaluated (Fig. 1,
Table 2). The doses used for the antimigratory assay were lower
than the cytotoxic levels to avoid false positive activity due to
possible cytotoxicity. Figure 1 shows cell migration across a
wound inflicted in an MDA-MB-231 cell monolayer for the
80 vehicle and positive controls. Compounds were tested at 2
different concentrations, 10 and 30 µM without any notable
cytotoxicity. Most compounds showed antimigratory activity at
both concentrations compared to vehicle control (Fig. 1, Table 2).
The most active compound, the lactam 16 showed better activity
85 at 10 µM, allowing only to 47.8% of MDA-MB231 cells to
migrate, compared to 48.3% migration of the same cell with a 50
µM dose of the positive drug control (Z)-5-(4-[ethylthio]-
benzylidene)-imidazolidine-2,4-dione (S-Ethyl, Table 2).19-21 The
4,5-dihydro-naphtho[2,1-b]furan-2(3aH)-ones 2b, 2c, and their
a
H3CO
O
H3CO
16
2c
Scheme 7. Transformation of the naphtho[2,1-b]furan-2-one 2c
10 to the lactam 16. (a) Allylamine, toluene, rt, 72 h.
3. Biological assays
3a. Anti-neuroinflammatory activity. The release of the
eicosanoid thromboxane B2 (TXB2) and the free radical
superoxide anion (O2 ) by activated brain microglia (BMΦ) has
-
15 been associated with several neuroinflammatory conditions.14
Escherichia coli lipopolysaccharide-activated rat neonatal BMΦ
have been extensively used as a convenient in vitro model to
study the ability of compounds to inhibit production of
neurotoxic TXB2 and O2.15 Selecting a concentration range
20 previously used with the in vitro microglia model16, we
investigated the effects of three concentrations (0.1 µM, 1 µM,
and 10 µM) of compounds 2b-16 on the release of BMΦ O2- and
TXB2, and concomitant induction of lactate dehydrogenase
(LDH) release,
a
well-established indicator of cellular
25 cytotoxicity for in vitro pharmacological studies.15 None of 2b-16
enhanced LDH release at the tested concentrations, except 10 µM
concentration of compound 2a, suggesting the potential toxicity
of the 6-methoxynaphtofurans. Most compounds also did not
90 microbial metabolites 12 and 14
showed the next best
antimigratory activity (Fig. 1). C-5 hydroxylation slightly
improved the activity of 2b and 2c, based on the activity of 12
and 14 (Table 2). Meanwhile, C-1 hydroxylation slightly reduced
the activity of 2b. The 6-methoxy analgue 10a and the simple
95 benzeneacetamide metabolite 15 were among the least active,
indicating the importance of 8-methoxy group and the 4,5-
dihydro-naphtho[2,1-b]furan-2(3aH)-one skeleton, respectively,
for the activity. The reduction C-1 epimeric product 11 had
optimal activity, especially at 30 µM dose (Table 2), indicating
100 no particular importance for ∆1,9b system and the C-1 chirality for
the antimigratory activity.
-
inhibit BMΦ O2 and TXB2 release even at 10 µM, the highest
30 concentration tested. However, compound 2c potently inhibited
TXB2 with an apparent IC50 of 1 µM, and did not affect O2 (Fig.
SI1). This appears to be a pharmacological result because
compound 2c neither affected LDH nor superoxide anion
generation. Furthermore, compound 16 potently inhibited both
-
-
35 BMΦ O2 and TXB2 with an apparent IC50 of 1 µM (Fig. SI2).
Thus our current data support further development of 2c and 16
as lead compounds for the development of novel anti-
inflammatory agents to modulate activated brain microglia.16
40 3b. Growth inhibition effect of compounds 2b, 2c, and 16 on
the National Cancer Institute 60-human cancer cell lines. The
growth inhibitory activity of 2b, 2c, and 16 was evaluated by the
National Cancer Institute’s Developmental Therapeutics Program
on a disease oriented panel. The panel consisted of 60-human cell
45 line panel (NCI60), including nine different tissues (blood, lung,
Conclusions
We have described the synthesis of 1-substituted-4,5-
105 dihydronaphtho[2,1-b]furan-2-(3a)-ones 2a-c in one step from
methoxy-2-tetralones, an α-bromoester, and LDA. This is the first
report of these compounds utilizing this method. In an effort to

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DOI: 10.1039/C3MD00111C
Page 5 of 8
Medicinal Chemistry Communications
a
1
Table 1. H and 13C NMR Data of Compounds 2b, 2c and 16.
2b 2c 16
δC
δH
δC
δH
δC
δH
119.
4, C
175.
2, C
122.9,
C
173.3,
C
122.9,
C
170.8,
C
1
2
4.49, ddq
(12.8, 4.8,
1.8)
79.0,
CH
77.5,
CH
5.08, dd
60.0,
(12.8, 4.8) CH
3a
4.43, m
2.61, dddd
(13.5, 5.6,
30.4, 4.8, 2.8)
2.71, dddd
(13.5, 5.6,
4.8, 2.8)
1.94, dddd CH2
(13.5, 12.8,
6.0, 4.8)
30.3,
CH2
29.3,
2.56, m
1.66, m
4
CH2
1.72, dddd
(13.5, 12.8,
6.0, 4.8)
Fig. 1: Antimigratory activity of 10 and 30 µM doses of
naphtho[2,1-b]furan-2-ones 2b, 2c, and 10-16 against the highly
metastatic MDA-MB-231 human breast cancer cell line in
10 wound-healing assay compared to DMSO vehicle control and 4-
mercaptoethylphenylmethylene hydantoin (S-Ethyl) as a positive
drug control.19
2.99,
2H,
m
27.0,
CH2
27.1,
CH2
27.5,
CH2
5
3.01, 2H, m
3.06, 2H, m
129.
6, C
130.
3,
CH
116.
5,
CH
158.
2, C
128.2,
C
129.2,
C
5a
6
7.17, d
(8.4)
130.4,
CH
130.1,
CH
Table 2. Percentage Migration of Breast Cancer Cell Line MDA-
15 MB231 after Treatment with 10 and 30 µM doses of Tested
Compounds.
7.14, d (8.4)
6.88, m
7.15, m
6.94, m
6.93, dd
(8.4, 2.6)
118.9,
CH
117.5,
CH
7
8
Compound
10 µM
71.4
76.7
87.6
90.7
100
30 µM
47.8
53.2
68.4
48.4
45.7
42.5
61.0
45.9
70.4
32.9
-
157.7,
C
157.4,
C
1
1
0
.
2b
2c
10a
10b
11
112.
6,
CH
6.87, m
6
,
6.81, m
7.15, d
(2.6)
110.8,
CH
9
C
51.6
81.8
54.4
94.5
47.8
48.3
100.0
12
H
13
130.
1, C
156.
2, C
130.6,
C
157.5,
C
132.5,
C
149.3,
C
9a
9b
10
14
15
10.2, 2.16, 3H, d
CH3
55.5,
CH3
(1.8)
16
8-
OMe
55.1,
CH3
128.9,
C
128.7,
CH
129.6,
CH
54.9,
CH3
129.8,
C
3.38, 3H,
s
3.84, 3H, s
3.47, 3H, s
S-Ethyla
DMSO
1`
-
128.5, 7.42, 2H,
2`, 6`
3`, 5`
4`
7.42, 2H, m
7.45, 2H, m
7.43, m
CH
m
a4-Mercaptoethylphenylmethylene hydantoin (S-Ethyl) 50 µM
129.9, 7.44, 2H,
dose was used as a positive drug control.19
CH
128.2,
CH
m
128.8,
CH
7.43, m
N-
Allyl
43.5,
CH2
134.0, 5.90,
CH
117.4, 5.22, 2H,
CH2
4.12, m
3.94, m
20 increase the structural diversity, the lactones 2a-c were
chemically modified or subjected to microbial biotransformation.
Three novel hydroxylated microbial metabolites (12-14) were
obtained from lactones 2b and 2c with Rhizopus arrhizus. In the
in vitro LPS-activated brain microglia assay, the phenyl-lactone
25 2c potently inhibited TXB2 with an apparent IC50 of 1 μM. Using
m
m
a In CDCl3, J in Hz. 400 MHz for 1H and 100 MHz for 13C NMR.
Carbon multiplicities were determined by APT experiments, C =
quaternary, CH = methine, CH2 = methylene, CH3 = methyl
carbons.
-
this assay, the tricyclic lactam 16 inhibited both O2 and TXB2
with apparent IC50 values of
1
μM. Substituted-4,5-
5
dihydronaphtho[2,1-b]furan-2-(3a)-ones 2b, 2c, and the tricyclic

View Article Online
Medicinal Chemistry Communications
DOI: 10.1039/C3MD00P11a1gCe 6 of 8
H2O). After 48 h, a solution of 60 mg of 2b and 400 mg of 2c in
lactam 16 showed excellent breast cancer migration inhibition
and antiproliferative activity against several of the NCI-60 cell
lines panel at 10-30 µM doses. The results show that the 1-
EtOH was added to each flask (30 mg 2b/flask and 40 mg
2c/flask). After 14 days, the growth medium was filtered and
50 extracted with EtOAc (1 × 1000 ml for 2b and 4 x 1000 ml 2c).
The EtOAc layer was then concentrated under vacuum. Residue
obtained from 2b fermentation (130 mg) was purified on Si gel
60 column using isocratic CHCl3-MeOH (9.5:0.5) to afford 12
(5.5 mg, Rf 0.60, CHCl3-MeOH, 9.5:0.5, 17% yield), 13 (6 mg, Rf
55 0.39, CHCl3-MeOH, 9.5:0.5, 19% yield) and recovered 28 mg
non-metabolized starting material (2b). Similarly, purification of
fermentation extract of 2c (815 mg) on Si gel 60 using isocratic
EtOAc-n-hexane (3:7) system afforded 14 (4.5 mg, Rf 0.65,
EtOAc-n-hexane, 1:1, 2.6% yield), 15 (18 mg, Rf 0.17, EtOAc-n-
60 hexane, 1:1, 10.6% yield), and recovered 230 mg non-
metabolized starting material (2c).
substituted-4.5-dihydronaphtho[2,1-b]furan-2-(3aH)-ones
are
5
good candidates for further development as an anti-inflammatory
and antimigratory agents.
Table 3. The Percent Growth of the Most Sensitive Cell Lines in
Presence of 10 µM Dose of 2b, 2c, and 16.
2b
2c
16
Leukemia
HL-60(TB)
K-562
RPMI-8226
Prostate Cancer
PC-3
74.17
54.16
20.66
52.99
42.06
18.14
34.92
28.27
11.53
6-Methoxy-1-methyl-4,5-dihydronaphtho[2,1-b]furan-2-
(3aH)-one (2a). In a similar manner as described for 2b, 5-
Methoxy-2-tetralone (5a, 2.75 g, 15.6 mmol), lithium
65 diisopropylamide (10.4 mL, 15.6 mmol, 1.5 M in cyclohexane),
and methyl (±)-2-bromopropionate (2.87 g, 1.92 mL, 17.2 mmol)
in THF (50 mL) produced a yellow semisolid. Trituration with
hexanes afforded a yellow solid which was recrystallized from
Et2O-EtOAc to give 1.10 g (31%) of 2a: mp 176-177 ºC; IR
43.05
32.03
25.72
Melanoma
MALME-3M
M14
SK-MEL-5
UACC-62
Breast Cancer
MCF7
35.39
63.67
65.84
57.14
35.89
64.90
48.69
35.40
0.19
46.68
40.86
35.30
65.20
64.30
40.79
59.51
30.92
27.43
61.52
40.67
36.26
1
70 (neat) 2944, 2840, 1732, 1656, 1326, 1259, 1090, 791; H NMR
T-47D
MDA-MB-468
(CDCl3) δ 7.29 (m, 2H), 6.90 (d, 1H), 4.93 (m, 1H), 3.87 (s, 3H),
3.18 (m, 1H), 2.64 (m, 2H), 2.15 (d, J = 1.8 Hz, 3H), 1.66 (m,
1H); 13C NMR δ 174.9, 157.5, 156.1, 129.9, 126.7, 119.7, 119.4,
111.7, 78.5, 55.6, 29.4, 21.8, 10.0; HRESIMS m/z 253.0820,
75 [M+Na]+ 253.0820 (calcd for C14H14O3Na, 253.0835); Anal.
Calcd for C14H14O3: C, 72.02; H, 6.13. Found: 71.98; H, 6.00.
8-Methoxy-1-methyl-4,5-dihydronaphtho[2,1-b]furan-2(3aH)-
one (2b). A solution of 7-methoxy-2-tetralone (5b, 1.00 g, 5.7
mmol) in THF (10 mL) was cooled to 0o and lithium
80 diisoproylamide (3.78 mL, 5.7 mmol, 1.5 M in cyclohexane) was
slowly added over 5 min. The mixture was stirred for 30 min and
methyl (±)-2-bromopropionate (1.03 g, 0.69 mL, 6.2 mmol) was
added. The solution was allowed to warm to room temperature
and was stirred overnight. The reaction was quenched with 3 N
85 HCl to pH < 3, and the THF was removed under vacuum. The
residue was partitioned between CH2Cl2 (100 mL) and H2O (3 x
100 mL), dried (Na2SO4), filtered, and evaporated to yield a
yellow solid. Recrystallization from EtOAc-hexanes gave 0.47 g
(32%) of 2b as a white powder: mp 104-105.5 ºC; IR (KBr) 2945,
90 2837, 1747, 1653, 1493, 1321, 1170, 868 cm-1; 1H and 13C NMR
(see Table 1); HRESIMS m/z 269.0585, [M+K]+ (calcd for
C14H14O3K, 269.0575); Anal. Calcd for C14H14O3: C, 73.02; H,
6.13. Found: C, 72.92; H, 6.20.
8-Methoxy-1-phenyl-4,5-dihydronaphtho[2,1-b]furan-2(3aH)-
95 one (2c). Using the general procedure as described for 2b, 7-
methoxy-2-tetralone (5b, 1.00 g, 5.7 mmol), lithium
diisopropylamide (3.8 mL, 5.7 mmol, 1.5 M in cyclohexane), and
methyl (±)-2-bromophenylacetate (1.43 g, 0.98 mL, 6.2 mmol) in
THF (10 mL) afforded a light brown solid. Recrystallization from
100 EtOAc-hexanes gave 1.49 g (90%) of 2c as a tan solid: mp 155-
156.5 ºC; IR (KBr) 2945, 1745, 1647, 1562, 1485, 1155, 1036,
1004, 876 cm-1; 1H and 13C NMR (see Table 1); HRESIMS m/z
293.1191, [M+H]+ (calcd for C19H18O3, 293.1172); Anal. Calcd
for C19H18O3: C, 78.06; H, 5.52. Found: C, 77.82; H, 5.46.
10 Experimental
General experimental procedures
IR spectra were recorded on
a
Varian 800 FT-IR
1
spectrophotometer. The H and 13C NMR spectra were recorded
in CDCl3, using TMS as an internal standard, on a JEOL Eclipse-
1
15 400 NMR spectrometer, operating at 400 MHz for H and 100
MHz for 13C. The HREIMS experiments were conducted at
University of Mississippi on a Bioapex FTMS with electrospray
ionization. Elemental analyses were obtained from Oneida
Research Services, Inc., Whitesboro, NY. TLC analysis was
20 carried out on precoated Si gel 60 F254 500 μm TLC plates (EMD
Chemicals), using n-hexane-ethyl acetate of CHCl3-methanol as
mobile phases. 1% Vanillin in concentrated H2SO4 was used as
visualizing reagent. For column chromatography, Si gel 60 (E-
Merck, 63-200 μm) was used.
25 Biotransformation. Biotransformation studies were conducted as
described elsewhere.22 Twenty-eight growing fungi cultures were
screened for ability to biotransform 2b and 2c. These were:
Absidia spinosa ATCC 6648, Bauvaria bassiana ATCC 7159,
Botyris allii ATCC 9435, Chaetomium globosum ATCC 6205,
30 Cunninghamella elegans ATCC 7929, C. verticillata ATCC
8986, C. homothallica ATCC 16161, C. blakesleeana ATCC
8688b, C. blakesleeana ATCC 9245, Cunninghamella sp. ATCC
201991, Fusarium sp. ATCC 11599, Kluyveromyces africanus
ATCC 22294, Lipomyces lipofer ATCC 32371, Lipomyces
35 starkeyi ATCC 58680, Mucor ramannianus ATCC 9228, M.
griseocyanus ATCC 1207b, Mucor sp. ATCC 204009, Nocardia
acidophilus ATCC 22338, N. corallina ATCC 19148,
Phanerochaete chrysosporium ATCC 24725, Rhizopus arrhizus
ATCC 11145, R. niveus ATCC 200757, R. oligosporus ATCC
40 76011, R. stolonifer ATCC 6227a, Saccharomyces pastorianus
ATCC 2366, Streptomyces griseus ATCC 13968, S.
malaysienesis BAA-13 and S. spheroides ATCC 23965. R.
arrhizus ATCC 11145 was selected for biotransformation scale-
up and therefore was inoculated in twelve 1L flasks each
45 containing 250 mL compound medium-α (20 g glucose and 5 g of
each of peptone, yeast extract, NaCl, and Na2PO4 in 1 L distilled
105 cis-syn-6-Methoxy-1-methyl-1,4,5,9b-tetrahydronaphtho[2,1-
b]furan-2-(3a)-one (10a). The unsaturated lactone (2a, 244 mg,
1.06 mmol) and 10% Pd/•C (100 mg) in 95% EtOH was
hydrogenated on a Parr apparatus at an initial pressure of 40 psi.
The catalyst was filtered, and the solvent was evaporated under
110 reduced pressure to afford a white solid. Recrystallization from
Et2O-hexanes gave 121 mg (49%) of highly crystalline 10a: mp

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DOI: 10.1039/C3MD00111C
Page 7 of 8
Medicinal Chemistry Communications
72.5-73.5 ºC; IR (neat) 2949, 1756, 1583, 1334, 1258, 1172,
13C NMR: 122.9, C; 173.2, C; 80.1, CH; 40.8, CH2; 67.9, CH;
1134, 961, 752 cm-1; H NMR (CDCl3) δ 7.15 (m, 1H), 6.69 (m, 65 129.6, C; 131.4, CH; 116.4, CH; 158.2, C; 112.4, CH; 130.1, C;
1
2H), 4.97 (m, 1H), 3.83 (m, 3H), 3.82 (s, 3H), 2.77 (m, 2H), 2.17
(m, 1H), 1.86 (m, 1H), 1.03 (d, J = 8z, 3H); 13C NMR (CDCl3) δ
179.6, 157.3, 133.6, 127.0, 126.6, 123.0, 108.6, 77.7, 55.7, 41.5,
39.6, 27.5, 17.6, 13.8; HRESIMS m/z 255.0965 [M+Na]+ (calcd
for C14H16O3Na, 255.0991; Anal. Calcd for C14H16O3: C, 72.39;
H, 6.94. Found: 72.44; H, 6.95.
156.2, C; 54.9, CH3; 128.9, C; 128.7, CH; 129.6, CH; 128.8, CH;
+
HRESIMS m/z 331.0945, [M+Na] (calcd for C19H16O4Na,
331.940).
5
Reaction of allylamine with 2c. Preparation of 3-allyl-8-
70 methoxy-1-phenyl-3,3a,4,5-tetrahydro-2H-benzo[e]indol-2-
one (16). A solution of 50 mg of 2c in 2 mL toluene was added to
1 mL allylamine.23 The reaction mixture was stirred for 72 h at
rt. A brine solution (5 mL) was then added and the solution was
extracted with CHCl3 (2 x 10 mL). The organic layer was
75 washed with H2O (2 x 10 mL), dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue (167 mg) was
fractionated by MPLC on Si gel 60 (10 g) using CHCl3-MeOH,
gradient elution to afford 16 (17 mg, Rf 0.45, CHCl3-MeOH 9:1,
34% yield).
cis-syn-8-Methoxy-1-phenyl-1,4,5,9b-tetrahydronaphtho[2,1-
10 b]furan-2-(3a)-one (10b). In a similar manner as described for
the synthesis of 10a, the lactone 2c (509 mg, 1.74 mmol) and
10% Pd/C in 95% EtOH (100 mL) gave 237 mg (46%) of 10b as
a white crystalline solid after recrystallization from Et2O: mp
160-161 ºC; IR (neat) 2934, 1755, 1610, 1505, 1255, 1203, 1166,
1
15 953, 754 cm-1; H NMR (CDCl3) δ 7.20 (m, 3H), 7.00 (m, 1H),
6.81 (m, 2H), 6.60 (m, 1H), 5.46 (d, J = 2.6 Hz 1H), 5.17 (brt, J=
3 Hz, 1H), 4.47 (d, J = 9.2 Hz, 1H), 4.00 (dd, J = 10,7 Hz, 1H),
3.18 (s, 3H), 2.92 (m, 1H), 2.51 (m, 2H), 1.76 (m, 2H); 13C NMR
(CDCl3) δ 176.90, 156.9, 134.14, 131.43, 130.88, 129.58, 129.28,
20 128.25, 127.62, 114.89, 114.60, 76.96, 54.85, 53.19, 44.63,
26.88, 22.39; HRESIMS m/z 333.0898 [M+K]+ (calcd for
C19H18O3K, 333.0888; Anal. Calcd for C19H18O3: C, 77.53; H,
6.16. Found: C, 77.39; H, 5.95.
80 Anti-inflammatory Assays. Rat neonatal microglia (2 x 105
cells/24-well cell culture cluster) were stimulated with
Escherichia coli lipopolysaccharide (LPS) (0.3 ng/mL) in 1 mL
Dulbecco’s modified Eagle medium, with 10% fetal bovine
serum, penicillin, and streptomycin, for 17 h in a humidified 5%
85 CO2 incubator at 35.9 °C.15-16 The medium was then removed and
the microglia cells were washed with warm (35.9°C) Hanks’
balanced salt solution (HBSS) and then incubated with
compounds 2b-16 (0.1, 1 and10 µM) or vehicle (DMSO) for 15
min prior to stimulation with phorbol 12-myristate 13-acetate
90 (PMA) (1 µM) for 70 min. All experimental treatments were run
cis-anti-8-Methoxy-1-phenyl-1,4,5,9b-tetrahydronaphtho[2,1-
25 b]furan-2-(3a)-one (11). The cis-syn-lactone 10b (3.99 mg, 1.36
mmol) and Et3N (550 mg, 5.44 mmol) in CH2Cl2 (15 mL) was
stirred under nitrogen for 48 h. The solvent was evaporated to
yield after recrystallization from 95% EtOH 248 mg (62%) of the
cis-anti-lactone as a highly crystalline white solid: mp 130-132
30 ºC; IR (neat) 2947, 1759, 1611, 1499, 1266, 1142, 1003, 841, 748
cm-1; 1H NMR δ 7.39 (m, 1H), 7.05 (d, J = 8 Hz, 1H), 6.74 (dd, J
= 8, 3 Hz, 1H), 6.17 (d, J =4 Hz, 1H), 5.01 (m, 1H), 3.76 (m, 2H),
-
in triplicate and in final volume of 1 mL. O2 , TXB2 and LDH
release were determined as described elsewhere.14,15
NCI’s 60-Cell line panel growth inhibition assay24
The NCI’s human 60-cell lines were grown in RPMI 1640
3.73 (s, 3H), 2.74 (m, 1H), 2.18 (m, 1H), 2.07 (m, 1H); 13C NMR 95 medium containing 5% FBS and 2 mM L-glutamine. Cells were
(CDCl3) δ 176.63, 158.14, 137.0, 135.73, 129.80, 129.23, 128.93,
35 128.02, 127.55, 113.79, 113.21, 76.1, 54.79, 47.30, 27.28, 25.28;
HRESIMS m/z 333.0889, [M+K]+ (calcd for C19H18O3K,
333.0888); Anal. Calcd for C19H18O3: C, 77.53; H, 6.16. Found:
C, 77.29; H, 5.99.
inoculated into 96-well plates at plating densities 5,000-40,000
cells/well, based on the doubling time of individual cell lines.
Plates were then incubated at 37 °C, 5% CO2, 95% air and 100%
relative humidity for 24 h prior to addition of tested compounds.
100 After 24 h, two plates of each cell line were fixed in situ with
trichloroacetic acid (TCA), to represent a measurement of the cell
population for each cell line at the time of tested compound
addition. Tested compounds solubilized in DMSO at 400-fold the
desired final maximum test concentration and stored frozen prior
105 to use. An aliquot of each frozen tested concentrate was thawed
and diluted to twice the desired final maximum test concentration
with complete medium containing 50 µg/mL gentamicin. 100 µL
aliquot of tested drug dilution was added to appropriate wells
containing 100 µL of medium, resulting in required final drug
110 doses. Following tested compound addition, plates were
incubated for additional 48 h. The assay was terminated by the
addition of cold TCA for adherent cells. Cells were fixed in situ
by addition of 50 µL of cold 50% (w/v) TCA (final concentration,
10% TCA) and incubated for 60 min at 4 °C. Supernatant was
115 discarded, and plates washed 5 times with water and air dried.
Sulforhodamine B (SRB) solution (100 µL), 0.4% (w/v) in 1%
acetic acid was added to each well, and plates incubated for 10
min at rt. After staining, unbound dye was removed by washing
five times with 1% acetic acid and plates were air dried. Bound
120 stain was subsequently solubilized with 10 mM trizma base, and
absorbance was measured on plate reader at 515 nm. For
suspension cells, the methodology was identical except the assay
termination by fixing settled cells at the bottom of each well by
adding 50 µL of 80% TCA (final concentration, 16% TCA).
(5R)-5-Hydroxy-8-methoxy-1-methyl-4,5-dihydronaphtho-
40 [2,1-b]furan-2(3aH)-one (12). Brown semisolid, IR
ν
(CHCl3)
max
2951, 1751, 1657, 1490, 1366, 1106, 965, 867 cm-1; H NMR:
5.39, ddq (12.8, 4.8, 1.8); 2.78, ddd (13.5, 4.8, 2.2), 1.83, ddd
(13.5, 6.0, 4.8); 5.09, d (5.5); 7.02, d (8.3); 7.38, dd (8.3, 2.6);
7.15, d (2.6); 2.16, 3H, d (1.8); 3.87, 3H, s; 13C NMR: 119.4, C;
45 175.8, C; 80.01, CH; 35.4, CH2; 66.9, CH; 129.8, C; 131.3, CH;
117.5, CH; 158.3, C; 111.6, CH; 131.1, C; 156.2, C; 11.2, CH3;
1
+
55.6, CH3.; HRESIMS m/z 247.0969, [M+H] (calcd for
C14H15O4, 247.0965).
1-(Hydroxymethyl)-8-methoxy-4,5-dihydronaphtho[2,1-
50 b]furan-2(3aH)-one (13). Brown semisolid, IR
ν
max
(CHCl3)
2950, 1750, 1657, 1490, 1366, 1106, 965, 867 cm-1; H NMR:
5.02, dd (12.8, 4.8); 2.66, m, 1.82, m; 3.04, 2H, m; 7.17, d (8.4);
6.98, dd (8.4, 2.6); 7.17, d (2.6); 4.76, d (13.2), 4.54, d (3.2);
1
3.83, 3H, s; 13C NMR: 120.4, C; 175.5, C; 78.6, CH;
30.5,
55 CH2; 26.9, CH2; 129.6, C; 130.3, CH; 118.3, CH; 160.2, C;
113.0, CH; 130.3, C; 158.2, C; 55.6, CH2; 55.2, CH3. HRESIMS
+
m/z 269.0789, [M+Na] (calcd for C14H14O4Na, 269.0784).
(5R)-5-Hydroxy-8-methoxy-1-phenyl-4,5-dihydronaphtho[2,1-
b]furan-2(3aH)-one (14). Brown semisolid, IR
ν
(CHCl3)
max
60 2950, 1752, 1657, 1490, 1366, 1106, 965, 867 17 cm-1;
1H NMR: 5.52, dd (12.8, 4.8); 2.85, ddd (13.5, 4.8, 2.1), 1.72,
ddd (13.5, 6.0, 4.8); 5.16, d (5.6); 7.34, d (8.4); 6.92, dd (8.4,
2.6); 6.99, d (2.6); 3.48, 3H, s; 7.44, 2H, m; 7.45, 2H, m; 7.46, m;

View Article Online
Medicinal Chemistry Communications
DOI: 10.1039/C3MD00P11a1gCe 8 of 8
Downers Grove, Illinois 60515. cDepartment of Pharmaceutical
Sciences, School of Pharmacy, Southern Illinois University
Edwardsville, Edwardsville, IL 62026. dPresent Address: Pfizer
Inc., Groton, CT 06340.
Antimigratory (wound-healing) assay19-21
The metastatic human breast cancer cells MDA-MB-231 cells
purchased from ATCC were cultured in RPMI 1640 medium
containing 10 mM HEPES, 4 mM L-glutamine, 10% FBS,
penicillin (100 IU/mL), and streptomycin (50 μg/mL), and
incubated in 5% CO2 atmosphere at 37 °C and plated onto sterile
24-well plates and allowed to recover for a confluent cell
monolayer formed in each well (>90% confluence) as previously
5
60
65
† Electronic Supplementary Information (ESI) available: [Mean
graphs showing the activity profile of the compounds on the
National Cancer Institute 60 cell line panel]. See
DOI: 10.1039/b000000x/
10 reported.19 Wounds were then inflicted to each cell monolayer
using a sterile 200 μL pipette tip. Media were removed, cells
were washed twice with PBS, and then test compounds added in
fresh media (same culturing media but with only 0.5% FBS).
Based on our optimization studies, 0.5% FBS was optimal to
15 maintain appropriate survival and viability of MDA-MB-231
cells for reproducible wound healing assay, which was also
consistent with literature.17-19 A stock solution of each analogue
was prepared by dissolving the compound in DMSO at 50 mM.
About 2 µL of each stock solution was transferred to 998 µL of
20 serum-free medium to obtain 100 µM concentrations (0.2%
DMSO). Serial dilutions were then conducted to get the desired
assay concentrations. Two non-cytotoxic concentrations (10 and
30 µM) of each compound were prepared in serum-free media
containing 0.5% FBS. Each concentration was tested in triplicate.
25 The negative control was prepared by adding 3 µL DMSO to
1497 µL serum-free media containing 0.5% FBS. (Z)-5-(4-
[ethylthio]benzylidene)-imidazolidine-2,4-dione (S-Ethyl) was
used as a positive drug control and DMSO as a vehicle
control.19,20 S-Ethyl was chemically synthesized by using base-
30 catalyzed condensation of hydantoin with 4-ethylthio-
benzaldehyde in aqueous ethanol in presence of catalytic amounts
of NaHCO3 and 2-aminoethanol and overnight reflux.20
Incubation was carried out for 24 h, after which media was
removed and cells were fixed and stained using DiffQuickTM
35 staining kit (Dade Behring Diagnostics, Aguada, Puerto Rico).
The number of cells migrated across the wound were counted
under the microscope in 3 or more randomly selected fields
(magnification: 40X). Final results expressed as % migration
([number of cells in the wound for treatment group/number of
40 cells in wound for DMSO] x 100%) per 40X field.
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Notes and references
*To whom correspondence should be addressed. Tel: 618-650-
50 5162. Fax: 618-650-5145.
E-mail: mcrider@siue.edu
aDepartment of Basic Pharmaceutical Sciences, College of
Pharmacy, University of Louisiana at Monroe, Monroe,
Louisiana 71201. bDepartment of Pharmacology, Chicago
55 College of Osteopathic Medicine, Midwestern University,