Asymmetric synthesis of anticancer β-lactams via Staudinger reaction: Utilization of chiral ketene from carbohydrate

Article abstract of DOI:10.1016/j.ejmech.2009.11.024

We describe herein asymmetric synthesis of a novel anticancer β-lactam following Staudinger reaction with chiral carbohydrate as the ketene component with an achiral imine. The in vitro cytotoxicity studies of these β-lactams are also reported here.

Full text of DOI:10.1016/j.ejmech.2009.11.024

European Journal of Medicinal Chemistry 45 (2010) 846–848
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Asymmetric synthesis of anticancer
of chiral ketene from carbohydrate
b-lactams via Staudinger reaction: Utilization
,
b
b
Bimal K. Banik a , Indrani Banik , Frederick F. Becker
*
a Department of Chemistry, The University of Texas Pan American, 1201 West University Drive, Edinburg, TX 78539, USA
b Department of Molecular Pathology, Unit 951, The University of Texas M. D. Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77504, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein asymmetric synthesis of a novel anticancer b-lactam following Staudinger reaction
Received 21 June 2009
Received in revised form
9 October 2009
Accepted 12 November 2009
Available online 18 November 2009
with chiral carbohydrate as the ketene component with an achiral imine. The in vitro cytotoxicity studies
of these -lactams are also reported here.
b
Ó 2009 Published by Elsevier Masson SAS.
Keywords:
b-Lactams
Anticancer agents
Asymmetric synthesis
Carbohydrate
Staudinger reaction
In vitro tests
1. Introduction
reported here. This study has identified a highly active anticancer b-
lactam in vitro against a number of cancer cell lines.
Many of the currently available anticancer drugs are unable to
differentiate between normal and neoplastic cells or to overcome
primary or secondary resistance mechanisms evolved in the cancer
cells. Thus, there is a pressing need for new anticancer agents with
high potency, less toxicity in non-cancerous cells, and unique targets
of action [1]. Because b-lactams are widely and safely used as anti-
bacterials without significant toxicity, synthesis of these molecules
as new, novel anticancer agents could be timely and significant. We
2. Methodology
In previous publications, we demonstrated synthesis and biolog-
ical evaluation of some polyaromatic compounds, which were open-
chain amides to which the polycyclic residue was bound [9–13]. It is
known that conformationally constrained molecules often have
a greater effect on biological properties when compared to the rela-
tively flexible open-chain compounds [17–19]. On this basis, we
anticipated thatconformationallyconstrained analogues of ouropen-
chain diamides may increase their potency. With regard to the above
hypothesis, we envisioned that b-lactams would serve as conforma-
tionally constrained analogues of our open-chain compounds that
have been shown to have anticancer activity in vitro. We have
confirmed our hypothesis that certain
cancer activity compared to the linear diamide with a flexible side
chain. To prepare chiral analogues of these -lactams and to identify
their effectiveness against cancer cell lines, the following studies have
been performed. (Fig. 1)
have been engaged in the synthesis of b-lactams [2–8] and several
other biologically active compounds [9–13]. In continuation of our
research, we have described stereocontrolled synthesis and bio-
logical evaluation of novel b-lactams as anticancer agents for the
first time starting from polyaromatic imines [14–16] We have also
described mechanistic correlation of their anticancer activity and
demonstrated a remarkable G2 blockade that is clearly distinct in cell
cycle analysis [15]. In this paper, we describe the asymmetric
b-lactams have superior anti-
synthesis of our anticancer
imine following cycloaddition reaction with a chiral carbohydrate.
The in vitro cytotoxicity of these optically active -lactams is also
b-lactam starting from 6-chrysenyl
b
b
It has been demonstrated that the reaction of acyloxy, alkoxy,
and nitrogen-containing acid chloride with diaryl imines produces
cis-
b-lactams under Staudinger reaction conditions [20,21]. In
* Corresponding author. Tel.: þ1 956 380 8741; fax: þ1 956 384 5006.
E-mail address: banik@panam.edu (B.K. Banik).
contrast, reaction of polyaromatic imines [14–16] with acetoxy,
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.11.024

B.K. Banik et al. / European Journal of Medicinal Chemistry 45 (2010) 846–848
847
Fig. 1. Racemic anticancer trans b-lactam. Example of a racemic anticancer b-lactam.
phenoxy, and phthalimido acid chloride in the presence of triethyl
amine at ꢀ78 ꢁC to room temperature produced trans-
b
-lactams.
Because of the anticancer activity of our racemic
b-lactams we
Scheme 2. Asymmetric synthesis of anticancer
enantiomers of anticancer -lactam.
b
-lactam. Chiral synthesis of both
b
have devised method for the preparation of optically active
compounds. It is established in the literature that optically active
isomerof aracemiccompound havebetterselectivebiologicalactivity
in many cases. In contrast to the tremendous success achieved in
cycloaddition of optically active aminoketene with imines, the anal-
ogous reaction of imines with chiral hydroxyketene equivalents has
not been investigated systematically [22–25]. The majority of the
investigations aimed at achieving this goal deal with the reaction of
achiralalkoxyketeneswithchiraliminesderived fromopticallyactive
through Ferrier rearrangement. Hydrogenolysis of the benzyl ester
4 and the hydrogenation of the double bond were then achieved by
catalytic hydrogenation to afford acid 5. (Scheme 1) Cycloaddition
of the activated acid 5 with polyaromatic imine 6 produced
a mixture of diastereomeric O-glycosides of trans b-lactams 7 and 8
in a ratio of 45:55. It has been hypothesized that the electron
withdrawing polyaromatic ring at the nitrogen of the imine 6
stabilizes the iminium ion during cycloaddition, and this allows
a-oxy and a-amino carbonyl compounds [20,21]. Because of the
a rotation of the enolate and results in trans b-lactam formation
commercial availability of protected sugars with highly specific
multiple stereogenic centers, a carbohydrate-based approach will be
ideal to obtain both enantiomers of our anticancer b-lactams. Avail-
abilityof both enantiomers of the acetoxycompounds is necessary for
studying their anticancer activity. Asymmetric synthesis of cis-
[14–16,26–30]. The diasteromers 7 and 8 were separated through
column chromatography over silica gel using ethyl acetate and
hexanes as the solvent system. Acid-induced reaction then cleaved
the carbohydrate moiety and this resulted in the trans-hydroxyl
b
-lactams (þ)-9 and (ꢀ)-10 in excellent yield. The hydroxy
hydroxy
b-lactam (70% yield) using a-O-glycoside as the ketene
compounds were converted to the acetates (þ)-11 and (ꢀ)-12 using
component is reported with a diaryl imine [25]. The control of abso-
lute stereochemistry at the C3 center is the challenge. In this respect
the stereochemistry of the anomeric center of the carbohydrate is the
crucial determining factor. The chiral induction may depend on the
acetic anhydride in the presence of triethyl amine. The absolute
stereochemistry of the trans-acetoxy-
was confirmed by a directcomparison with known trans-
b
-lactam (þ)-11 and (ꢀ)-12
b
-lactam
described earlier with respect to optical rotation and NMR data in
the presence of a chiral shift reagent [31]. (Scheme 2)
stereochemistry of the anomeric carbon of the glycosides (a- and b-).
The absolute stereochemistry of the anomeric center in the ketene
component may dictate the absolute stereochemistry at the C3 center
of the b-lactam ring.
3.1. In vitro cytotoxicity of the
b-lactams
3. Results and discussion
These optically active -lactams were tested against seven
b
The starting
a
-glycosides was prepared by reacting 3,4,5-tri-O-
human cancer cell lines using cisplatin and racemic
controls; results are given in Table 1.
b-lactam as
acetyl -glucal 2 with benzyl glycolate in the presence of iodine
D
Scheme 1. Synthesis of the chiral acid. Synthesis of Ketene precursor from a carbohydrate.

848
B.K. Banik et al. / European Journal of Medicinal Chemistry 45 (2010) 846–848
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Table 1
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7.66 12.33
15.7
6.1
22.0
5.99
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-lactam 11 is more potent than the racemic b-lactam 1 in 5/7
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1 cell line and greater in 1/7 cell lines (Table 1). The high degree of
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cancer cell lines. On this basis, it is expected that more potent
active isomer (þ)-11 would not be toxic against normal human
cancer cell lines.
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B.M. Bhawal, An efficient synthesis of cis-3-hydroxy-4-phenyl-
precursor for taxol side chain Tetrahedron 52 (1996) 5585–5590.
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The optically active b-lactam described herein is unique since it
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The stereochemical outcome of the Staudinger reaction as reported
hereinconfirms ourearlierresultswithachiralstartingmaterials. This
research will offer many additional opportunities to use b-lactams in
the synthesis of new compounds having anticancer properties.
b
b
ketene-imine cycloaddition: utilization of chiral ketenes from carbohydrates.
Tetrahedron Lett. 32 (1991) 1039–1040.
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Acknowledgments
[27] For the preparation of trans
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We gratefully acknowledge the financial support for this
research project from National Institutes of Health-SCORE,
2S06M008038-37 and the Cha Family Fund. We are also thankful to
the shared resources of the Pharmacology and Analytical Center
Facility of the UT M. D. Anderson Cancer Center.
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176 ꢁC; ½a 2D5
ꢃ
þ 149ꢁ (c 1.0, CH3OH); IR cmꢀ1 (neat) 1755, 1595, 1515, 1486, 1456,
1440,1394,1373,1314,1283,1219; 1H NMR (CDCl3)
d (ppm) 2.36 (s, 3 H), 5.54–5.55
b
(d, J ¼ 1.91 Hz,1 H), 5.77–5.78 (d, J ¼ 1.94 Hz,1 H), 7.26–7.31 (m, 3 H), 7.46–7.49(m,
2 H), 7.60–7.71 (m, 2 H), 7.77–7.80 (m, 2 H), 7.95–7.99 (m, 2 H), 8.38–8.41 (m,1 H),
8.45 (s, 1 H), 8.50–8.53 (d, 1 H), 8.63–8.66 (d, 1 H), 8.79–8.82 (m, 1 H); Anal. Calcd
for C29H21NO3: C, 80.72; H, 4.91; N, 3.25.12. Found: C, 80.69; H, 4.89; N, 3.19.
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(ꢀ)-trans-N-(6-Chrysenyl)
3-acetoxy-4-phenyl-2-azetidine-2-one
(12):
b
½
a 2D5
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ꢀ 150ꢁ (c 1.0, CH3OH). 7: 1H NMR (CDCl3)
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4.30–4.32 (m, 1 H), 4.42–4.46 (m, 2 H), 4.90–4.92 (m, 1 H), 5.11 (d, J ¼ 2 Hz, 1 H),
5.20(d, J ¼ 1.93 Hz,1H), 5.62(d, J ¼ 1.9 Hz,1H), 7.25–7.29(m, 3H),7.48(d, J ¼ 8 Hz,
2 H), 7.65 (m, 2 H), 7.70–7.71 (m, 2 H), 7.90–7.92 (m, 2 H), 8.41–8.43 (m, 2 H), 8.53
(d, J ¼ 8.19 Hz, 1 H), 8.58 (d, J ¼ 9.18 Hz, 1 H), 8.75–8.77 (m, 1 H) 13C NMR (CDCl3)
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(2003) 1699–1701.
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a
(ppm): 21.27, 21.47, 29.05, 63.27, 65.97, 67.63, 69.86, 56.60, 97.57, 115.42, 121.26,
123.20,124.94,126.81,127.06,127.18,127.22,127.43,127.78,127.88,129.03,127.35,
127.59, 130.40, 131.47, 131.92, 132.60, 136.65, 165.99, 170.50, 171.27. 8: 1HNMR
(CDCl3)
d
(ppm): 1.94 (s, 3 H), 2.1 (s, 3 H), 3.97 (dd, J ¼ 2.46 and 11.94 Hz,1 H), 4.30
(m,1 H), 4.29 (dd,J ¼ 5.01 and 11.85 Hz,1 H), 4.81 (m,1 H), 5.02 (d, J ¼ 1.83 Hz,1 H),
5.26 (s, 1 H), 5.59 (d, J ¼ 1.68 Hz, 1 H), 7.26 (m, 3 H), 7.48 (d, J ¼ 6.72 Hz, 2 H), 7.61
(m, 2H), 7.75 (m, 2H), 7.93, (d, J ¼ 8.7 Hz, 2 H), 8.38 (m, 1 H), 8.45 (s, 1 H), 8.54 (d,
J ¼ 8.16 Hz, 1H), 8.61 (d, J ¼ 9.18 Hz, 1 H), 8.77 (m, 1 H) 13CNMR (CDCl3)
d (ppm):
20.72, 21.10, 22.64, 23.68, 62.61, 63.23, 65.09, 66.74, 85.93, 97.61, 115.11, 120. 90,
122.87,123.60,124.52,126.68,126.73,126.76,126.88,127.03,127.39,127.56,128.93,
129.16, 130.05, 131.17, 132.22, 136.16, 165.54, 169.94, 170.78.