Design, synthesis and qualitative structure-activity evaluations of novel hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]pyrrol- 2(1H)-one derivatives as anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2010.07.026

Polysubstituted hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives were synthesized and biologically evaluated as novel anticancer agents. These motifs were produced by five steps reaction sequence in whi

Full text of DOI:10.1016/j.ejmech.2010.07.026

European Journal of Medicinal Chemistry 45 (2010) 4615e4621
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and qualitative structureeactivity evaluations of novel
hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]
pyrrol-2(1H)-one derivatives as anticancer agents
,b,
Taleb H. Al-Tel a
*
a College of Pharmacy, University of Sharjah, University City Road, P.O. Box 27272, Sharjah, United Arab Emirates
b Sharjah Institiute for Medical Research, 27272, Sharjah, United Arab Emirates
a r t i c l e i n f o
a b s t r a c t
Article history:
Polysubstituted hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]pyrrol-2
(1H)-one derivatives were synthesized and biologically evaluated as novel anticancer agents. These
motifs were produced by five steps reaction sequence in which Achmatowicz oxidative cyclization, is the
basic protocol for such synthesis. To understand the structureeactivity relationships of the newly
synthesized motifs, two traditional medicinal chemistry strategies namely, ring expansion and
contraction, were followed in this article. These studies indicated that tetrahydropyrano[3,2-b]pyrrol-2
(1H)-one derivatives are more selective for breast cancer cell line compared to other cell lines under
investigations. Furthermore, it was found that hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one deriva-
tives are potent anticancer agents compared to tetrahydropyrano[3,2-b]pyrrol-2(1H)-one analogs. These
findings, however, form the foundation for further investigation in our continuing efforts to develop
selective anticancer agents.
Received 23 June 2010
Received in revised form
13 July 2010
Accepted 13 July 2010
Available online 21 July 2010
Keywords:
Pyrenones
Hexahydropyrano[3,2-c][1,2]diazepin-3
(4H)-one
Tetrahydropyrano[3,2-b]pyrrol-2(1H)-one
b
-ketoesters
Ó 2010 Elsevier Masson SAS. All rights reserved.
Achmatowicz reaction
Anticancer agents
1. Introduction
new molecules for cancer treatment is highly desired. Due to the
high failure rate of currently available therapies for most types of
Despite the availability of improved drugs, including targeted
cancer therapies, cancer is still one of the leading causes of
mortality worldwide. It is estimated to have accounted for 7.9
million deaths (around 13% of all deaths) in 2007, and w1.4 million
new cancer cases and w566,000 deaths from cancer occurred in
the United States in 2008 [1,2].
Currently, the world is unified to defeat the proliferation of
nuclear weapons and that of mass destruction. Similarly, the
oncologists, pharmacologists and medicinal chemists are unified in
defeating cancer at early stages and preventing its proliferation and
mass formation. To win this war on cancer, we must completely
understand the biological pathways that function in the oncogenic
state versus the normal, healthy state. This knowledge is necessary
to rationally design chemotherapeutic agents that selectively kill
cancer cells while sparing their healthy neighbors. Therefore, we
are at an important junction in cancer research where the design of
cancer, finding new leads is therefore the daily goal of scientists.
Additionally, the high mutation potential of cancer cells means that
patients may relapse following initial treatment, which creates
a need for new targeted agents that could be used as second line of
therapy [2,3]. This is due to lack of selectivity and in most cases
chemotherapeutic regimens target all proliferating cells based on
the principle that tumor cells proliferate at a faster rate than normal
cells, resulting in differential cytotoxicity [4e6]. Thus, much effort
has been made to increase tissue, cell, and target selectivity for
chemotherapy [7,8]. In this regard, extensive synthesis and design
of new structural motifs in order to overcome the aforementioned
problems and improve antitumor activity and selectivity are highly
desirable. The engine of such endeavor, however, will be driven by
the development of novel scaffolds that will lead to skeletally
diverse molecules to dissect the gap between the chemical and
biological space [9e12]. For this purpose, diversity oriented
synthesis to generate a plethora of novel scaffolds, is a powerful and
highly productive tool for lead development and analog design
[13e20]. Our recent findings of novel motifs, cyclopenta[b]pyranes
fused to pyrazolones [21] and tetrahydro-2H-pyrano[3,2-c]pyr-
idazin-3(6H)-one [22], that possesses selective anti-breast cancer
* College of Pharmacy, University of Sharjah, University City Road, P.O. Box 27272,
Sharjah, United Arab Emirates. Tel.: þ971 501732950; fax: þ971 6 5585812.
E-mail address: taltal@sharjah.ac.ae.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.026

4616
T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
activities, allowed us to further increase the diversity of closely
related scaffolds in the hope of gaining access to highly selective
antitumor agents and less toxic to normally proliferating cells. This
versatile synthesis has given us an opportunity to expand struc-
tureeactivity studies significantly and to test the importance of
new skeleton alterations on their anticancer activity.[23e25]
Herein we report on the anticancer activities of novel structural
motifs, hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetra-
hydropyrano[3,2-b]pyrrol-2(1H)-one, and assessing their potential
as selective anticancer agents. There has been upsurge in the
synthesis and biological evaluations of 1,2-diazepinic ring [26e30]
and
g-lactam [31,32] derivatives, however, to the best of our
Scheme 2. Synthesis of methyl 3-(6-hydroxy-3-oxo-2-phenyl-3,6-dihydro-2H-pyran-
2-yl)propanoate (4).
knowledge, the systems presented here, are novel scaffolds and
have not been described before.
3(4H)-one derivatives 8e14, we therefore, concentrated our efforts
on handling the major product 6 for such purpose and neglected the
minor product resulted from the anomeric protection protocol.
As was unambiguously concluded in our previous reports,
[21,22] the stereochemistry around structure 6 was confirmed
based on our earlier experience in the synthesis of similar systems
such as structures V and VI presented in Fig. 1. Furthermore, the
stereochemistry of the latter systems was unambiguously deduced
from extensive NMR nOe experiments [21,22]. Analogs of these
central elements had previously been shown by other groups to be
highly utilitarian in providing ready access to diastereoselective
syntheses of furo[c]pyrane scaffolds [33,34] and other poly-
substituted tetrahydropyranes [20].
Following the same synthetic strategy described in our previous
reports, hydrogenation of derivative 6 in the presence of Pd/C
produced compound 7.
The target compounds 8e14 were easily prepared following
standard reaction protocol between compound 7 and hydrazine
derivatives under acid catalysis (Scheme 4).
2. Results and discussion
2.1. Chemistry
Scheme 1 contemplates three traditional medicinal chemistry
strategies we followed. These form the foundation for under-
standing the structureeactivity relationships of our developed
motifs. In the first, the tricyclic system of type I [21], developed
in our group, was simplified to bicylic scaffold such as II. Such
a process has previously lead to the discovery of potent and
selective antitumor agents [22]. Following the guidelines recently
reported from our group [21,22], we in this report have adopted
two more complementary drug design routes, namely ring
enlargement strategy, exemplified in structure III, and ring
contraction as formulated in IV. Furthermore, based on our earlier
experience in such systems, we in this article have chosen the
substitution patterns based on the structureeactivity relationships
concluded in our previous reports [21,22].
Our synthetic plan for the ring expansion strategy started by
gaining access to furfuryl alcohol 3 (Scheme 2). This was made
available through the reaction of furyl lithium with g-ketoester 2 at
The second ring contraction strategy was achieved using the
previously synthesized scaffold 15 (Scheme 5). In this scenario,
compound 15 was reacted with different aromatic primary amines
in the presence of catalytic amount of acetic acid to produce after
chromatographic purification compounds 16e22 in fairly good
yields.
ꢀ78 ꢁC. Subsequently, oxidative cyclization using mCPBA in DCM
delivered pyrenone 4, which in turn forms the building block
required to generate a library of hexahydropyrano[3,2-c][1,2]dia-
zepin-3(4H)-one derivatives. Therefore, compounds 8e14 were
synthesized through standard three-steps reaction sequence
starting from 4 (Schemes 3 and 4).
2.2. Biological assay and SAR
Forthis purpose, anomericprotectionofcompound4 usingAg2O/
MeI, delivered compound 5 as a mixture of diastereoisomers in fairly
good yield. Initial efforts to purify this mixture on silica gel using
EtOAc/hexane(5%v/v), wassuccessful, andcompound6 wasisolated
in 75% yield. Since our goal is to produce pyrano[3,2-c][1,2]diazepin-
Our previous studies provided us with important information
about the selectivity and cytotoxicity of related compounds such as
II (Scheme 1). However, one question remained to be answered:
What will be the effect on the activity and selectivity, if the fused
Scheme 1. Strategies used to understand the SAR of the new scaffolds.

T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
4617
Scheme 3. Synthesis of methyl 3-((2R,6S)-6-methoxy-3-oxo-2-phenyltetrahydro-2H-pyran-2-yl)propanoate (7).
six membered heterocyclic framework of II is expanded to seven
membered bicylic system as in III and/or contracted to five
membered ring system as in IV? [21] To answer this question, we
followed standard chemical and biological protocols. For the
chemical strategy, the tetrahydro-2H-pyrano[3,2-c]pyridazin-3
(6H)-one derivatives such as II (Scheme 1) was subjected to ring
expansion leading to 1,2-diazepinic ring systems 8e14 (Scheme 4).
On the other hand, the pyrano[3,2-c]pyridazin-3(6H)-one was
simplified through ring contraction leading to tetrahydropyrano
[3,2-b]pyrrol-2(1H)-one scaffolds 16e22 (Scheme 5), as another
possible promising approach. For the biological tools, however, we
followed the same guidelines reported previously from our labo-
ratory [21,22]. Thus, we tested all derivatives produced from the
aforementioned chemical strategies against five cancer cell lines.
To this end, hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one
analogs 8e14 were evaluated for in vitro anticancer activity against
five in house tumor cell lines. These are: A549 (non small cell lung
cancer), HCT116 (human colorectal cancer cells), SK-N-SH (human
Caucasian bone marrow neuroblastoma) cells, SK-BR-3 (HER2 over-
expressing breast cancer) and DU-145 (prostate cancer cell line).
Interestingly, results from Table 1 indicated that these new motifs
are potent anticancer agents, however, the selectivity for breast
cancer compared to our previously described tetrahydro-2H-pyrano
[3,2-c]pyridazin-3(6H)-one [21], were lost. The later systems were
previously shown to posses selective anti-breast cancer activity
compared the other investigated four cancer cell lines [21]. At this
point in time, it seems prudent that the ring enlargement strategy
followed so far do not enhance the selectivity of hexahydropyrano
[3,2-c][1,2]diazepin-3(4H)-one analogs 8e14 against SK-BR-3
(breast cancer cell line). At this junction we turned our attention
toward tetrahydropyrano[3,2-b]pyrrol-2(1H)-one scaffolds 16e22.
Interestingly enough, as indicated in Table 1, the ring contraction
strategy produced high selectivity toward breast cancer cell line (SK-
BR-3) compared to other tested cell lines, however, the general
potency of these motifs as anticancer agents is lowcompared to both
tetrahydro-2H-pyrano[3,2-c]pyridazin-3(6H)-one (II) [21], and
hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-ones 8e14.
to the other cell lines under investigation. At this stage, the intro-
duction of indolyl group (as in compound 12) on the 1,2-diazepinic
ring, increased the potency of these systems to about four folds
against SK-BR-3 (breast cancer cell line) compared to their toxicity
toward the other tested cell lines. Although we were not satisfied
with these results, some structureeactivity relationships could be
concluded from these results. Electron rich phenyl groups (e.g. 10,
18) or hetero-aryl rings on both series, increases their potency as
antitumor agents. In contrast, electron poor aryl systems (e.g. 14,
22) attached to the amide nitrogen decreases the potency of both
series.
3. Conclusions
In summary, we reported on novel classes of promising anti-
canceragents, hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives. Although
the two traditional medicinal chemistry strategies followed in
this article did not meet our expectations toward selectivity,
these findings however, form the foundation for further investiga-
tions and more focused studies in our laboratories will continue
to develop novel analogs as preclinical candidates as anticancer
agents. Furthermore, in this and the previous reports, we followed
a forward chemical genetics approach for finding lead molecules as
anticancer agents. Currently we are engaged in a process directed
toward targeted cancer studies in a reversed chemical genetics
manner. The later will allow us to understand the specific
biological target and the biochemical mechanism of action of our
developed motifs.
4. Experimental
4.1. General methods
All reagents were used as purchased from commercial
suppliers without further purification. The reactions were carried
out in oven dried or flamed graduated vessels. Solvents were dried
and purified by conventional methods prior use. All reactions
Interestingly, compounds 16, 18, 19 and 20, indicated about five
folds selectivity toward breast cancer cell line (SK-BR-3) compared
R
O
MeO
R
MeO
O
OMe
O
O
O
t BuO
O
V: R = H or Me
VI: R = H or Me
Scheme 4. Synthesis of hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one motifs.
Fig. 1. Structures of previously synthesized scaffolds.

4618
T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
4.2. Biology
4.2.1. Cell growth inhibition assay
MeO
O
OMe
R-NH2
MeO
O
All stock cultures are grown in T-25 flasks. Freshly trypsinized
O
O
cell suspensions were seeded in 96-well microtiter plates with
compounds added from DMSO diluted stock. The plates were
incubated for an additional 72 h after attachment and addition of
compounds, and the assay was terminated by 10% TCA. Then, 0.4%
SRB dye in 1% HOAc was added to stain the cells for 10 min.
Unbound dye was removed by repeated washing with 1% HOAc and
the plates were air dried. Bound stain was subsequently solved with
10 mM trizma base, and the absorbance read at 515 nm. Stock
solutions of agents in DMSO at 1 mg/ml were prepared fresh for
each experiment and were diluted in cell culture medium to ach-
ieve desired concentrations upon addition to the target cells. All six
types of cells were incubated 48 hours at 37 ꢁC in 96-well micro-
titer plates to assess inhibition of cell proliferation by measuring
changes in protein content in triplicate wells. Cytotoxicity was
assessed using sulforhodamine-B (SRB) by measuring the extent of
inhibition of protein synthesis in treated cells compared with that
in untreated cells. Following 48 h treatment, cells were fixed by the
addition of cold (4 ꢁC) 50% trichloroacetic acid (50 mL/well). After
a 1 h incubation at 4 ꢁC, plates were gently washed five times with
deionized water and allowed to dry overnight. A 0.4% solution of
SRB in 1% acetic acid (50 mL) was added to each well, and plates
were incubated 10 min at room temperature. Wells were then
rinsed 5 times with 1% acetic acid and allowed to dry. To solubilize
the SRB dye, 150 ml/well of 10 mM Tris base (pH 10.5) was incu-
bated for 20 minutes at room temperature and plates were gently
vortex-mixed before absorbance at 570 nm was measured using
a spectrophotometer (Spectramax-Pro; Molecular Devices). Wells
containing untreated cells served as positive controls. The mean
absorbance of the corresponding set of blanks was subtracted from
the mean absorbance of wells incubated with each test agent. This
value was then divided by the difference between the mean
absorbance of the untreated cells and that of the blanks in order to
calculate a percent inhibition for each concentration of agent.
Growth inhibition of 50% (IC50) is calculated as the drug concen-
tration, which caused a 50% reduction in the net protein increase
during the drug incubation. The mean IC50 is the concentration
of agent that reduces cell growth by 50% under the experimental
conditions and is the average with SEM from at least two inde-
pendent determinations. The following human tumor cell lines
were used in the assay: A549 (non small cell lung cancer),
HCT116 (human colorectal cancer cells) and SK-N-SH (human
Caucasian bone marrow neuroblastoma) cells, SK-BR-3 (HER2 over-
expressin breast cancer), DU-145 (prostate cancer cell line).
Cells propagated in RPMI-1640 supplemented with 10% FBS, peni-
N
O
R
16: R = 4-Me-Ph
18: R = 3,5-DiMeO-Ph 19: R = 2-pyridyl
20: R = 5-indolyl 21: R = 3-indolyl
22: R = 3,5-dichlorophenyl
17: R= 4-NO2-Ph
15
Scheme 5. Synthesis of tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives.
were monitored by thin layer chromatography (TLC) using Merck
aluminum plates pre-coated with silica gel PF254; 20_20,
0.25 mm, and detected by visualization of the plate under UV
lamp (l¼ 254 or 365 nm). Spots were detected by spraying with
anisaldehyde e sulpharic acid in ethanol, followed by heating to
140 ꢁC. Compounds were purified through recrystallization or
using column chromatography which was performed on silica gel,
packed by the slurry method. Flash column chromatography was
performed with Silica gel 60, 0.040e0.063 mm (230e400 mesh).
Aluminum backed plates pre-coated with silica gel 60 (UV254)
were used for thin layer chromatography. 1H, 13C spectra were
recorded on 300 MHz/75 MHz spectrometer. Splitting patterns are
designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Chemical shifts (d) are given in ppm relative
to the resonance of their respective residual solvent peak, CHCl3
(7.27 ppm, 1H; 77.16 ppm, the middle peak, 13C). Spectra were
acquired in CDCl3 containing 1% TMS. High resolution Mass
spectra (HRMS) were recorded in positive ion mode by Electro-
spray Ionization (ESI) on a Bruker instrument. The samples were
dissolved in acetonitrile, diluted in spray solution (methanol/
water 1:1 v/v 0.1 % formic acid) and infused using a syringe pump
with a flow rate of 2 ml/min. External calibrationwas conducted
using Arginine cluster in a mass range m/z 175e871. For all HRMS
data, mass error: 0.00e0.50 ppm. Melting points (m.p.) were
determined on an Electrothermal Melting point Apparatus and
were reported uncorrected in ꢁC. All compounds were determined
to be >95% pure by high-performance liquid chromatography
(HPLC). Purity of compounds were determined on a Phenomenex
Luna C18- (2), 3 mm column, 4.6 mm i.d. ꢂ 30 mm length, with
30e75% acetonitrile/water/0.1% trifluoroacetic acid, 1.0 mL/min
elution at rt using 210, 254, or 280 nm wavelength.
Table 1
IC50 values for cellular proliferation inhibition results of compounds 8e22 against
cillin (100 IU/mL), streptomycin (1
mg/mL), and amphotericin B
different cancer cell lines.a
(0.25
m
g/mL), and were cultured at 37 ꢁC in a humidified atmo-
Compd IC50 ꢃ SD (
mM)
sphere of 95% air/5% CO2.
HCT116
SK-N-SH
SK-BR-3
DU-145
A549
4.3. Synthesis
8
9
2.50 ꢃ 0.30
1.70 ꢃ 0.30
7.30 ꢃ 0.30
3.20 ꢃ 0.04
2.10 ꢃ 0.01
1.00 ꢃ 0.08
4.60 ꢃ 0.90
7.11 ꢃ 0.47
3.50 ꢃ 0.20
9.40 ꢃ 0.90
2.70 ꢃ 0.30 2.20 ꢃ 0.50
7.70 ꢃ 0.20 9.20 ꢃ 0.20
1.20 ꢃ 0.03 2.40 ꢃ 0.09
1.12 ꢃ 0.03 1.29 ꢃ 0.08
1.20 ꢃ 0.01 1.13 ꢃ 0.03
2.40 ꢃ 0.12 4.10 ꢃ 0.40
6.35 ꢃ 0.35 8.46 ꢃ 0.40
1.10 ꢃ 0.09 4.40 ꢃ 0.30
6.30 ꢃ 0.11 8.10 ꢃ 0.10
1.10 ꢃ 0.01 6.10 ꢃ 0.20
3.17 ꢃ 0.10
9.49 ꢃ 0.20
2.90 ꢃ 0.02
1.48 ꢃ 0.01
1.11 ꢃ 0.06
5.10 ꢃ 0.80
6.13 ꢃ 0.22
3.92 ꢃ 0.10
7.15 ꢃ 0.20
4.11 ꢃ 0.40
8.70 ꢃ 0.20
2.10 ꢃ 0.03
1.40 ꢃ 0.01
1.10 ꢃ 0.09
3.10 ꢃ 0.40
6.52 ꢃ 0.51
4.30 ꢃ 0.70
8.00 ꢃ 0.10
10
11
12
13
14
16
17
18
19
20
21
22
4.3.1. General procedure for the synthesis of compounds 8e14
The pyranone ketoester 7 derived from the reduction product
of 6 (584 mg, 2 mmol) and the desired hydrazine derivative
(2.1 mmol) in 40 ml Toluene was heated to reflux in the presence
of 10 mole% pTSA for 12 h. The progress of reaction was monitored
by TLC. After 12 h, the dark brown mixture was cooled down,
concentrated on a rotary evaporator, and the crude was triturated
with EtOAc/hexane to produce a yellowish solid. This solid was
further purified through triturating with cold EtOH containing
traces of water to give the title compounds as light yellowish
solids.
6.10 ꢃ 0.100 7.20 ꢃ 0.19
7.30 ꢃ 0.10
5.30 ꢃ 0.20
7.13 ꢃ 0.14
11.24 ꢃ 1.16
5.10 ꢃ 0.130 1.10 ꢃ 0.08 8.30 ꢃ 0.120 6.11 ꢃ 0.150
4.40 ꢃ 0.10
8.20 ꢃ 0.19
9.67 ꢃ 0.72
1.30 ꢃ 0.10 4.10 ꢃ 0.19
2.30 ꢃ 0.12 7.33 ꢃ 0.13
6.54 ꢃ 0.55 8.17 ꢃ 0.69
5.10 ꢃ 0.14
5.20 ꢃ 0.11
7.53 ꢃ 0.61
a
Data represent mean values (SD) for two independent determinations.

T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
4619
4.3.2. General procedure for the synthesis of compounds 16e22
The pyranone ketoester 15 (556 mg, 2 mmol) and the desired
primary amine derivative (2.1 mmol) in 40 ml absolute DCM/MeOH
was heated to 50 ꢁC in the presence of 5 mole% acetic acid for 18 h.
The progress of reaction was monitored by TLC. The mixture was
cooled down, concentrated on a rotaryevaporator, and the crude was
triturated with EtOAc/hexane to produce a yellowish solid. This solid
was further purified through triturating with cold EtOH containing
traces of water to give the title compounds as yellowish solids.
J ¼ 5.9 Hz,1H), 3.64 (s, 3H), 3.42 (s, 3H), 2.46 (t, J ¼ 6.3 Hz, 2H), 2.14 (m,
2H).13C NMR(75 MHz, CDCl3, inppm)
195.4, 173.5, 145.7, 142.6, 129.1,
127.8, 127.2, 126.4, 103.1, 81.3, 55.4, 52.3, 34.5, 33.2. HRMS: m/z
calculated for C16H18O5 [M þ Naþ]: 313.10520, found 313.10529.
d
4.3.6. Methyl 3-((2R,6S)-6-methoxy-3-oxo-2-phenyltetrahydro-
2H-pyran-2-yl)propanoate (7)
To a stirred solution of 6 (580 mg, 2.0 mmol) in dry EtOAc/MeOH
(1:1, 20 mL) was added Pd/C (56 mg, 15% Pd/C w/w). The mixture
was placed under 1.0 atm of H2 pressure, and the progress of
reaction was monitored by TLC. After 2 h, the solid was removed by
filtration through a celite pad, which was washed repeatedly with
EtOAc. After concentration of the filtrate, the residue was purified
on silica gel column (elution with 5% ethyl acetate in hexane) to
give 7 as amorphous solid in 86% yield.1H NMR (300 MHz, CDCl3, in
4.3.3. Methyl 4-(furan-2-yl)-4-hydroxy-4-phenylbutanoate (3)
A suspension of furyl lithium was prepared under argon by slow
addition of n-BuLi (3.25 ml, 5.2 mmol of 1.6 M solution in hexane)
to furan (340 mg, 5 mmol) in THF (15 ml) at ꢀ78 ꢁC over 45 min
period. To this mixture, methyl 4-oxo-4-phenylbutanoate (960 mg,
5 mmol in 5 ml THF) was added over 5 min period. After stirring at
this temperature for 45 min, the mixture was warmed to 0 ꢁC after
that it was quenched with a saturated solution of NH4Cl (15 mL),
extracted with EtOAc (3 ꢂ 30 mL), dried over Na2SO4 and concen-
trated under vacuum to give a yellowish crude oil. The crude was
used in the next step without further purification. 1H NMR
ppm)
(s, 3H), 3.39 (s, 3H), 2.79 (m, 2H), 2.42 (t, J ¼ 6.4 Hz, 2H), 2.11e1.98
(m, 4H). 13C NMR (75 MHz, CDCl3, in ppm)
205.7, 173.1, 140.4,
d
7.49 (d, J ¼ 6.1 Hz, 1H), 7.28e7.21 (m, 4 H), 4.94 (m, 1H), 3.66
d
127.8, 126.9, 125.7, 95.8, 81.3, 55.9, 51.6, 35.2, 33.5, 32.9, 29.1.
HRMS: m/z calculated for C16H20O5 [M þ Naþ]: 315.12085, found
315.12091.
(300 MHz, CDCl3, in ppm)
d 7.38 (m, 2H), 7.24 (m, 3H), 6.94
(t, J ¼ 2.9 Hz, 1H), 6.26 (dd, J ¼ 2.9, 5.8 Hz, 1H), 6.18 (d, J ¼ 2.8 Hz,
4.3.7. (5aR,7S)-7-Methoxy-5a-phenyl-2-p-tolyl-1,2,5,5a,7,8-
hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (8)
1H), 3.67 (s, 3H), 2.53 (t, J ¼ 8.7 Hz, 2H), 2.16 (m, 2H). 13C NMR
(75 MHz, CDCl3, in ppm)
d
172. 4, 156.7, 144.8, 140.3, 128.1, 127.8,
Yield: 61%, m.p. 183e184 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
127.5, 108.2, 106.7, 78.5, 52.2, 35.9, 35.3. HRMS: m/z calculated for
d
7.72 (d, J ¼ 12.1 Hz, 2H), 7.35 (t, J ¼ 5.7 Hz, 2H), 7.19e7.11 (m, 5H),
4.93 (t, J ¼ 4.6 Hz,1H), 4.56 (t, J ¼ 6.0 Hz,1H), 3.35 (s, 3H), 2.29e2.23
(m, 7H), 1.28 (m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
175.8,
C15H16O4 [M þ Naþ]: 283.09463, found 283.09458.
d
4.3.4. Methyl 3-(6-hydroxy-3-oxo-2-phenyl-3,6-dihydro-2H-
pyran-2-yl)propanoate (4)
151.4, 144.5, 143.7, 141.4, 130.8, 127.7, 126.3, 124.1, 121.8, 111.3, 106.5,
78.6, 55.9, 32.4, 31.1, 29.3, 21.4. HRMS: m/z calculated for
C22H24N2O3 [M þ Naþ]: 387.16846, found 387.16851.
A solution of furyl alcohols 3 (1300 mg, 5 mmol) in dicholo-
methane (40 mL) at 0 ꢁC was treated with m-chloroperbenzoic acid
(1376 mg, 8.0 mmol of 80% aqueous slurry) which was dissolved in
30 ml DCM, dried over Na2SO4, filtered, diluted with 50 ml toluene
and dried under reduced pressure and stirred at 0 ꢁC for 6 h.
Sodium sulfite solution (30 mL of 10%) was introduced, and the
layers were separated after 1 h of rapid mixing. The aqueous phase
was washed with saturated sodium bicarbonate solution (30 mL),
brine and water (30 mL) prior to drying and solvent evaporation.
The crude viscous yellowish oils 4 were used in the next step
without further purification. Yellowish oil. 1H NMR (300 MHz,
4.3.8. (5aR,7S)-7-Methoxy-2-(4-nitrophenyl)-5a-phenyl-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (9)
Yield: 63%, m.p. 175e176 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
8.49 (dd, J ¼ 5.7, 8.8 Hz, 2H), 8.14 (d, J ¼ 8.7 Hz, 2H), 7.34e7.17
(m, 5H), 5.14 (t, J ¼ 4.3 Hz, 1H), 4.48 (t, J ¼ 6.7 Hz, 1H), 3.39 (s, 3H),
2.43 (dd, J ¼ 12.4, 15.9 Hz, 2H), 2.11 (d, J ¼ 6.8 Hz, 1H), 1.94
(d, J ¼ 6.7 Hz, 1H), 1.45 (m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
d
176.1, 150.9, 148.4, 146.8, 143.6, 127.5, 126.3, 125.9, 124.6, 123.4,
110.7, 105.8, 78.7, 55.5, 32.4, 31.1, 28.3. HRMS: m/z calculated for
CDCl3, in ppm)
d
7.54 (d, J ¼ 6.3 Hz, 1H), 7.57 (d, J ¼ 6.2 Hz, 1H),
C21H21N3O5 [M þ Naþ]: 418.13789, found 418.13781.
7.26e7.22 (m, 8 H), 6.85 (dd, J ¼ 2.3, 9.2 Hz, 1H, H-5), 6.79
(dd, J ¼ 3.1, 10.0 Hz, 1H, H-5), 6.10 (d, J ¼ 9.6 Hz, 1H, H-4), 6.07 (dd,
J ¼ 1.1, 10.4 Hz, 1H, H-4), 5.65 (t, J ¼ 4.0 Hz, 1H, H-6), 5.59
(t, J ¼ 6.9 Hz, 1H, H-6), 3.55 (s, 3H, OMe), 3.45 (s, 3H, OMe), 3.02
(d, J ¼ 15.7 Hz, 1H, H-7), 2.98 (d, J ¼ 15.4 Hz, 1H, H-7), 2.53
(d, J ¼ 15.7 Hz, 1H, H-7), 2.42 (d, J ¼ 15.5 Hz, 1H, H-7), 2.43
(t, J ¼ 6.1 Hz, 2H), 2.41 (t, J ¼ 6.2 Hz, 2H), 2.24 (m, 4H). 13C NMR
4.3.9. (5aR,7S)-2-(3,5-Dimethoxyphenyl)-7-methoxy-5a-phenyl-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (10)
Yield: 57%, m.p. 177e178 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
7.31e7.13 (m, 5H), 6.98 (bs, 2H), 6.42 (bs, 1H), 4.89 (t, J ¼ 4.9 Hz,
1H), 4.54 (t, J ¼ 5.9 Hz, 1H), 3.83 (s, 6H), 3.39 (s, 3H), 2.39
(d, J ¼ 12.2 Hz, 1H), 2.27 (d, J ¼ 12.1 Hz, 1H), 1.97 (d, J ¼ 6.7 Hz, 1H),
1.85 (d, J ¼ 6.6 Hz, 1H), 1.34 (m, 2H). 13C NMR (75 MHz, CDCl3, in
(75 MHz, CDCl3, in ppm)
d 197.5, 197.4, 170.3, 169.0, 146.3, 145.5,
143.7, 142.5, 129.1, 127.8, 127.2, 126.4, 126.3, 87.7, 87.6, 79.6, 79.3,
55.5, 55.3, 45.4, 45.2, 32.4, 31.1, 27.0. HRMS: m/z calculated for
C15H16O5 [M þ Naþ]: 299.08955, found 299.08961.
ppm) d 175.5, 166.1, 150.9, 142.7, 142.5, 127.8, 126.4, 123.5, 110.3,
109.7, 106.1, 95.4, 79.6, 55.5, 55.2, 31.9, 30.8, 28.4. HRMS: m/z
calculated for C23H26N2O5 [M þ Naþ]: 433.17394, found 433.17388.
4.3.5. Methyl 3-((2R,6S)-6-methoxy-3-oxo-2-phenyl-3,6-dihydro-
2H-pyran-2-yl)propanoate (6)
4.3.10. (5aR,7S)-7-Methoxy-5a-phenyl-2-(pyridin-2-yl)-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (11)
A solution of the anomeric mixture of 4 (600 mg, 3 mmol) in MeI
(15 mL) at rt was treated with 3.0 mmol of Ag2O. The progress of
reaction was monitored by TLC (12 h). When complete, the reaction
mixture was filtered over celite. The filtrate was washed with satu-
rated solutions of sodium sulfite, sodium bicarbonate and brine, dried
and evaporated. The residue was purified on silica gel column using
hexane/EtOAc (9:1) asan eluent. Yield: 79%, amorphoussolid.1H NMR
Yield: 54%, m.p. 189e190 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
9.13 (d, J ¼ 2.1 Hz, 1H), 8.63 (t, J ¼ 3.2 Hz, 1H), 8.12
(t, J ¼ 2.8 Hz, 1H), 7.34e7.12 (m, 6H), 4.79 (t, J ¼ 5.1 Hz, 1H), 4.48
(t, J ¼ 6.0 Hz, 1H), 3.36 (s, 3H), 2.33 (d, J ¼ 12.4 Hz, 1H), 2.27 (d,
J ¼ 12.3 Hz, 1H), 2.11 (d, J ¼ 6.6 Hz, 1H), 1.97 (d, J ¼ 6.7 Hz, 1H), 1.26
(m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
d 176.3,151.2,147.4,144.1,
141.9, 140.6, 128.1, 127.3, 126.8, 125.7, 123.4, 111.2, 105.5, 78.3, 55.6,
32.7, 31.4, 27.6. HRMS: m/z calculated for C20H21N3O3 [M þ Naþ]:
374.14806, found 374.14811.
(300 MHz, CDCl3, in ppm)
6.81 (dd, J ¼ 3.1, 6.2 Hz, 1H), 6.23 (dd, J ¼ 3.4, 8.5 Hz, 1H), 5.45 (d,
d
7.52 (d, J ¼ 6.3 Hz,1H), 7.26e7.22 (m, 4 H),

4620
T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
4.3.11. (5aR,7S)-2-(1H-Indol-3-yl)-7-methoxy-5a-phenyl-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (12)
Yield: 64%, m.p. 187e188 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
HRMS: m/z calculated for C22H23NO5 [M þ Naþ]: 404.14739, found
404.14731.
d
7.85 (d, J ¼ 7.9 Hz, 1H), 7.39e7.17 (m, 7H), 6.97 (t, J ¼ 5.7 Hz, 1H),
4.3.17. (3aR,5S)-5-Methoxy-3a-phenyl-1-(pyridin-2-yl)-3,3a,5,6-
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (19)
4.85 (t, J ¼ 5.3 Hz, 1H), 4.53 (t, J ¼ 6.2 Hz, 1H), 3.47 (s, 3H), 2.35 (d,
J ¼ 12.2 Hz, 1H), 2.27 (d, J ¼ 12.1 Hz, 1H), 2.09 (d, J ¼ 6.8 Hz, 1H), 1.98
(d, J ¼ 6.6 Hz, 1H), 1.26 (m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
Yield: 62%, m.p. 180e181 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
8.61 (bs, 1H), 8.41 (d, J ¼ 4.7 Hz, 1H), 7.67 (dd, J ¼ 6.2, 8.9 Hz, 2H),
d
177.4, 148.2, 145.5, 140.3, 134.1, 129.4, 127.5, 125.7, 125.3, 123.4,
7.45 (bs, 1H), 7.40 (d, J ¼ 4.7 Hz, 1H), 7.25e7.19 (m, 3H), 5.73
(t, J ¼ 4.6 Hz, 1H), 4.73 (t, J ¼ 6.1 Hz, 1H), 3.29 (s, 3H), 2.99
(d, J ¼ 17.5 Hz, 1H), 2.66e2.53 (m, 3H). 13C NMR (75 MHz, CDCl3, in
122.5, 122.1, 114.3, 109.5, 105.4, 98.1, 79.4, 55.8, 32.1, 31.4, 29.1.
HRMS: m/z calculated for C23H23N3O3 [M þ Naþ]: 412.16371, found
412.16379.
ppm)
d 171.8, 145.3, 142.1, 140.6, 138.4, 137.5, 126.3, 125.8, 123.6,
123.4, 109.7, 105.8, 82.9, 56.1, 44.6, 29.9. HRMS: m/z calculated for
4.3.12. (5aR,7S)-7-Methoxy-2-(4-methoxyphenyl)-5a-phenyl-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (13)
Yield: 68%, m.p. 181e182 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
C19H18N2O3 [M þ Naþ]: 345.12151, found 345.12159.
4.3.18. (3aR,5S)-1-(1H-Indol-5-yl)-5-methoxy-3a-phenyl-3,3a,5,6-
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (20)
d
7.43 (t, J ¼ 4.5 Hz, 2H), 7.27 (d, J ¼ 5.9 Hz, 2H), 7.20 (t, J ¼ 1.6 Hz,
2H), 7.07 (bs, 1H), 6.98 (d, J ¼ 7.1 Hz, 2H), 4.82 (t, J ¼ 4.1 Hz, 1H), 4.53
(t, J ¼ 6.4 Hz, 1H), 3.71 (s, 3H), 3.39 (s, 3H), 2.35 (bd, J ¼ 12.7 Hz, 1H),
2.27 (d, J ¼ 12.9 Hz, 1H), 2.14 (d, J ¼ 6.7 Hz, 1H), 1.94 (d,
J ¼ 6.8 Hz, 1H), 1.33e1.28 (m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
Yield: 51%, m.p. 166e165 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
10.75 (s, 1H), 7.51 (t, 5.3 Hz, 2H), 7.25e7.07 (m, 7H), 6.53 (d,
J ¼ 4.1 Hz, 1H), 5.87 (t, J ¼ 4.2 Hz, 1H), 4.69 (t, J ¼ 6.1 Hz, 1H), 3.42
(s, 3H), 3.29 (d, J ¼ 17.5 Hz, 1H), 2.79e2.58 (m, 3H). 13C NMR
d
176.9, 162.1, 151.4, 144.6, 139.3, 127.7, 126.5, 125.9, 123.3, 113.7,
(75 MHz, CDCl3, in ppm) d 172.0, 140.3, 138.5, 135.7, 133.2, 132.4,
109.2, 105.3, 79.8, 55.1, 54.8, 31.9, 30.7, 28.5. HRMS: m/z calculated
for C22H24N2O4 [M þ Naþ]: 403.16338, found 403.16341.
126.8, 125.6, 123.4, 114.7, 112.4, 111.3, 108.6, 106.3, 99.4, 82.6, 55.7,
45.1, 29.6. HRMS: m/z calculated for C22H20N2O3 [M þ Naþ]:
383.13716, found 383.13722.
4.3.13. (5aR,7S)-2-(3,5-Dichlorophenyl)-7-methoxy-5a-phenyl-
1,2,5,5a,7,8-hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one (14)
Yield: 70%, m.p. 168e169 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
4.3.19. (3aR,5S)-1-(1H-indol-3-yl)-5-methoxy-3a-phenyl-3,3a,5,6-
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (21)
d
7.79 (d, J ¼ 1.7 Hz, 2H), 7.41 (d, J ¼ 2.1 Hz, 1H), 7.32 (d, J ¼ 5.8 Hz,
Yield: 55%, m.p. 177e178 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
2H), 7.23 (t, J ¼ 6.1 Hz, 2H), 7.13 (m, 3H), 4.87 (t, J ¼ 4.7 Hz, 1H), 4.49
(t, J ¼ 6.1 Hz, 1H), 3.39 (s, 3H), 2.39 (d, J ¼ 12.4 Hz, 1H), 2.19 (d,
J ¼ 12.3 Hz, 1H), 1.99 (d, J ¼ 6.5 Hz, 1H), 1.88 (d, J ¼ 6.7 Hz, 1H), 1.29
d
8.31 (s, 1H), 7.51 (m, 3H), 7.23e7.12 (m, 4H), 7.05 (t, J ¼ 7.1 Hz, 1H),
6.45 (d, J ¼ 5.3 Hz, 1H), 6.12 (s, 1H), 5.92 (t, J ¼ 4.5 Hz, 1H), 4.74 (t,
J ¼ 6.3 Hz, 1H), 3.35 (s, 3H), 3.14 (d, J ¼ 17.6 Hz, 1H), 2.75e2.64 (m,
(m, 2H). 13C NMR (75 MHz, CDCl3, in ppm)
d
175.7, 150.9, 143.6,
2H), 2.54 (m, 1H). 13C NMR (75 MHz, CDCl3, in ppm)
d 171.1, 147.3,
140.2, 135.8, 127.6, 125.9, 124.7, 123.8, 122.5, 110.5, 105.9, 79.8, 55.1,
32.4, 30.9, 27.4. HRMS: m/z calculated for C21H20Cl2N2O3 [M þ Naþ]:
441.07487, found 441.07494.
140.0, 127.3, 126.4, 126.2, 125.9, 124.8,123.4, 114.6,107.5,106.6, 98.5,
81.4, 55.4, 44.6, 29.5. HRMS: m/z calculated for C22H20N2O3
[M þ Naþ]: 383.13716, found 383.13709.
4.3.14. (3aR,5S)-5-Methoxy-3a-phenyl-1-p-tolyl-3,3a,5,6-
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (16)
4.3.20. (3aR,5S)-1-(3,5-dichlorophenyl)-5-methoxy-3a-phenyl-
3,3a,5,6-tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (22)
Yield: 58%, m.p. 171e172 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
Yield: 61%, m.p. 170e171 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
d
7.94 (t, J ¼ 5.2 Hz, 1H), 7.32 (bs, 2H), 7.29e7.14 (m, 5H), 5.95
d
7.69 (dd, J ¼ 6.4, 9.1 Hz, 2H), 7.23e711 (m, 6H), 6.68 (bs, 2H), 6.12
(t, J ¼ 4.4 Hz, 1H), 4.64 (t, J ¼ 6.1 Hz, 1H), 3.49 (s, 3H), 2.95 (d,
(t, J ¼ 4.5 Hz, 1H), 4.67 (t, J ¼ 6.0 Hz, 1H), 3.47 (s, 3H), 2.97
J ¼ 17.4 Hz, 1H), 2.63e2.49 (m, 3H), 2.38 (s, 3H). 13C NMR
(d, J ¼ 17.3 Hz, 1H), 2.69e2.48 (m, 3H). 13C NMR (75 MHz, CDCl3, in
(75 MHz, CDCl3, in ppm)
d
173.2, 143.4, 140.6, 138.1, 135.5, 130.3,
ppm) d 173.2, 140.5, 139.3, 137.7, 136.4, 128.6, 125.8, 124.1, 123.5,
126.7,125.6,123.5,109.8,106.4, 84.3, 55.4, 44.5, 31.2, 22.1. HRMS: m/z
110.8, 107.9, 84.2, 55.6, 44.7, 31.0. HRMS: m/z calculated for
calculated for C21H21NO3 [M þ Naþ]: 358.14191, found 358.14186.
C20H17Cl2NO3 [M þ Naþ]: 412.04832, found 412.04838.
4.3.15. (3aR,5S)-5-Methoxy-1-(4-nitrophenyl)-3a-phenyl-3,3a,5,6-
tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (17)
Acknowledgements
Yield: 62%, m.p. 183e184 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
The authors are grateful to the National Research Fund (UAE)
and the College of graduate studies and research (University of
Sharjah) for financial support. Dr. A.R. Martinez (visiting Professor
at Tuebingen University, Germany) is greatly acknowledged for the
biological testing and data analysis.
d
8.17 (dd, J ¼ 6.9, 8.7 Hz, 2H), 7.61 (t, J ¼ 5.4 Hz, 2H), 7.29 (d,
J ¼ 8.9 Hz, 2H), 7.15 (m, 2H), 5.69 (t, J ¼ 4.3 Hz, 1H), 4.68 (t,
J ¼ 5.9 Hz, 1H), 3.45 (s, 3H), 3.11 (d, J ¼ 17.2 Hz, 1H), 2.72e2.51
(m, 3H). 13C NMR (75 MHz, CDCl3, in ppm)
d 172.9, 147.3, 141.8,
140.2, 137.7, 126.4, 125.9, 123.5, 118.9, 111.2, 107.6, 84.3, 55.6, 44.2,
30.3. HRMS: m/z calculated for C20H18N2O5 [M þ Naþ]:
389.11134, found 389.11139.
References
[1] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, M.J. Thun, CA Cancer J. Clin. 59 (2009)
225e249.
[2] WHO website: http://www.who.int/cancer/en (2010) and http://progress
report.cancer.gov (2007).
4.3.16. (3aR,5S)-1-(3,5-Dimethoxyphenyl)-5-methoxy-3a-phenyl-
3,3a,5,6-tetrahydropyrano[3,2-b]pyrrol-2(1H)-one (18)
Yield: 67%, m.p. 179e180 ꢁC. 1H NMR (300 MHz, CDCl3, in ppm)
[3] B. Goldman, J. Natl. Cancer Inst. 95 (2003) 255e257.
d
7.52 (dd, J ¼ 2.3, 7.7 Hz, 2H), 7.24 (m, 3H), 6.64 (d, J ¼ 4.4 Hz, 2H),
[4] D.W. Parsons, S. Jones, X. Zhang, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo,
H. Carter, I.M. Siu, G.L. Gallia, A. Olivi, R. McLendon, B.A. Rasheed, S. Keir,
T. Nikolskaya, Y. Nikolsky, D.A. Busam, H. Tekleab, L.A. Diaz Jr., J. Hartigan,
D.R. Smith, R.L. Strausberg, S.K. Marie, S.M. Shinjo, H. Yan, G.J. Riggins,
D.D. Bigner, R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein,
V.E. Velculescu, K.W. Kinzler, Science 321 (2008) 1807e1812.
6.24 (bs, 1H), 5.89 (d, J ¼ 4.1 Hz, 1H), 4.68 (t, J ¼ 5.3 Hz, 1H), 3.89
(s, 6H), 3.41 (s, 3H), 2.98 (d, J ¼ 17.4 Hz, 1H), 2.73e2.62 (m, 3H). 13C
NMR (75 MHz, CDCl3, in ppm)
d 173.5, 163.8, 142.7, 139.9, 138.6,
126.5, 123.4, 110.8, 107.5, 97.5, 94.4, 83.9, 55.7, 55.3, 44.8, 31.3.

T.H. Al-Tel / European Journal of Medicinal Chemistry 45 (2010) 4615e4621
4621
[5] Paul D.W. Eckford, Frances J. Sharom, Chem. Rev. 109 (2009) 2989e3011.
[21] T.H. Al-Tel, M.H. Semreen, W. Voelter, Org. Biomol. Chem., in press.
[22] T.H. Al-Tel, Eur. J. Med. Chem. (2010), accepted for publication.
[23] T.H. Al-Tel, R.A. Al-Qawasmeh, S.S. Sabri, W. Voelter, J. Org. Chem. 74 (2009)
4690e4696 and references cited therein.
[24] T.H. Al-Tel, R.A. Al-Qawasmeh, M.F. Schmidt, A. Al-Aboudi, S.N. Rao, S.S. Sabri,
W. Voelter, J. Med. Chem. 52 (2009) 6484e6488.
[25] A.J. Rasras, T.H. Al-Tel, A.F. Al-Aboudi, R.A. Al-Qawasmeh, Eur. J. Med. Chem.
45 (2010) 2307e2313.
[26] C.V.C. Prasad, M. Zheng, S. Vig, C. Bergstrom, D.W. Smith, Q. Gao, S. Yeola,
C.T. Polson, J.A. Corsa, V.L. Guss, A.L.J. Wang, B.G. Sleczka, C. Dangler,
B.J. Robertson, J.P. Hendrick, S.B. Roberts, D.M. Barten, Bioorg. Med. Chem. Lett.
17 (2007) 4006e4011.
[27] M.H. Chen, O.P. Goel, J.-W. Hyun, J. Magano, J.R. Rubin, Bioorg. Med. Chem.
Lett. 9 (1999) 1587e1592.
[6] G.A. Ljungman, B. Ng, A. Milosavljevic, M.L. Gonzalez-Garay, J.R. Osborne,
R. Meyer, X. Shi, Y. Tang, D.C. Koboldt, L. Lin, R. Abbott, T. Miner, C. Pohl, G. Fewell,
C. Haipek, H. Schmidt, B.H. Dunford-Shore, A. Kraja, S.D. Crosby, C.S. Sawyer,
T. Vickery, S. Sander, J. Robinson, W. Winckler, J. Baldwin, L.R. Chirieac, A. Dutt,
T. Fennell, M. Hanna, B.E. Johnson, R.C. Onofrio, R.K. Thomas, G. Tonon, B.A. Weir,
X. Zhao, L. Ziaugra, M.C. Zody, T. Giordano, M.B. Orringer, J.A. Roth, M.R. Spitz,
I. Wistuba, B. Ozenberger, P.J. Good, A.C. Chang, D.G. Beer, M.A. Watson,
M. Ladanyi, S. Broderick, A. Yoshizawa, W.D. Travis, W. Pao, M.A. Province,
G.M. Weinstock, H.E. Varmus, S.B. Gabriel, E.S. Lander, R.A. Gibbs, M. Meyerson,
R.K. Wilson, Nature 455 (2008) 1069e1075.
[7] H. Wallerand, R.R. Reiter, A. Ravaud, Curr. Opin. Urol. 18 (2008) 524e532.
[8] B. Weinstein, Adv. Exp. Med. Biol. 617 (2008) 3e12.
[9] J.J. Perez, Chem. Soc. Rev. 34 (2005) 143e152.
[10] L. Xue, J. Bajorath, Comb. Chem. High Throughput Screen. 3 (2000) 363e372.
[11] A. Bender, R.C. Glen, Org. Biomol. Chem. 2 (2004) 3204e3218.
[12] B.M. Trost, Angew. Chem. Int. Ed. Engl. 34 (1995) 259e281.
[13] R. Noyori, Nat. Chem. 1 (2009) 5e6.
[14] P. Vuorelaa, M. Leinonenb, P. Saikkuc, P. Tammelaa, J.P. Rauhad, T. Wennberge,
H. Vuorela, Curr Med. Chem. 11 (2004) 1375e1389.
[15] M.J. Balunas, M. Kinghorn, Life Sci. 78 (2005) 431e441.
[16] A. Saklani, S.K. Kutty, Drug Discov. Today 13 (2008) 161e171.
[17] K.H. Altmann, J. Gertsch, Nat. Prod. Rep. 24 (2007) 327e357.
[18] D.J. Newman, J. Med. Chem. 51 (2008) 2589e2599.
[19] M.D. Burke, M. Eric, E.M. Berger, S.L. Schreiber, J. Am. Chem. Soc. 126 (2004)
14,095e14,104.
[28] G. Kolavi, V. Hegde, I.A. Khazi, Tetrahed. Lett. 47 (2006) 2811e2814.
[29] W. Wan, J. Hou, H. Jiang, Y. Wang, S. Zhu, H. Deng, J. Hao, Tetrahedron 65
(2009) 4212e4219.
[30] B. Insuasty, A. Garcia, J. Quinoga, R. Abonia, M. Nogueras, J. Cobo, Eur. J. Med.
Chem. 45 (2010) 2841e2846.
[31] A.Y. Egorova, Z.Y. Timofeeva, Chem. Heterocyclic Compd. 40 (2004)
1243e1264.
[32] S. Olla, F. Manetti, E. Crespan, G. Maga, A. Angelucci, S. Schenone, M. Bologn,
M. Bott, Bioorg. Med. Chem. Lett. 19 (2009) 1512e1516.
[33] P. Deshong, R.E. Waltermire, H.L. Ammon, J. Am. Chem. Soc. 110 (1988)
1901e1910.
[34] S.F. Martin, D.E. Guinn, J. Org. Chem. 52 (1987) 5588e5593.
[20] H. Guo, G.A. O’Doherty, Org. Lett. 8 (2006) 1609e1612.