Novel sulfonate derivatives: Potent antimitotic agents

Article abstract of DOI:10.1016/S0960-894X(01)00279-7

The synthesis and biological evaluation of novel sulfonate analogues of E-7010 are reported. Several of the compounds are potent inhibitors of cell proliferation and tubulin polymerization. Importantly, these compounds are also active against P-glycoprote

Full text of DOI:10.1016/S0960-894X(01)00279-7

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1671–1673
Novel Sulfonate Derivatives: Potent Antimitotic Agents
Stephen L. Gwaltney, II,* Hovis M. Imade, Qun Li, Laura Gehrke, R. Bruce Credo,
Robert B. Warner, Jang Yun Lee, Peter Kovar, David Frost, Shi-Chung Ng
and Hing L. Sham
Cancer Research, D47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 22 February 2001; accepted 12 April 2001
Abstract—The synthesis and biological evaluation of novel sulfonate analogues of E-7010 are reported. Several of the compounds
are potent inhibitors of cell proliferation and tubulin polymerization. Importantly, these compounds are also active against P-gly-
coprotein positive (+) cancer cells, which are resistant to many other antitumor agents. # 2001 Elsevier Science Ltd. All rights
reserved.
Microtubules are cellular structures formed by poly-
merization of the protein tubulin. Microtubules play an
important role in many cellular processes, including mito-
sis. Various agents that modulate tubulin polymerization
inhibit cancer cell proliferation.1
Substantial efforts have been made to develop new
antimitotic agents by preparing analogues of the natural
products mentioned above or by screening compound
libraries followed by traditional medicinal chemistry.
Often, the goals of this research are to improve the
therapeutic window (efficacy vs toxicity) of a compound
class or to improve physical or pharmacological prop-
erties (such as aqueous solubility or pharmacokinetics).
Of increasing clinical importance is the development of
agents that are active against multidrug resistant tumor
cell lines, since tumors composed of these cell types no
longer respond to traditional chemotherapy. One
mechanism responsible for the development of this
resistance is over-expression of P-glycoprotein (multi-
drug resistant phenotype, MDR+).
Three major classes of antimitotic agents, each with its
own binding site on tubulin, act to disrupt tubulin
dynamics. Compounds that bind to the taxane binding
site1,2 (e.g., paclitaxel and epothilone) act by preventing
the depolymerization of tubulin, thus stabilizing micro-
tubules. Compounds that bind to the vinca alkaloid
domain (e.g., vincristine, dolastatins, and cryptophy-
cins) and colchicine site binders (e.g., colchicine and
combretastatins) inhibit the polymerization of tubulin.1
Stabilization or destabilization of the microtubule
structure leads to cell cycle arrest in the M phase and
apoptosis.
E-7010 (Fig. 1) is an antitumor sulfonamide discovered
at the Tsukuba Research Laboratories of Eisai
Figure 1. E-7010 and analogues.
*Corresponding author. Tel.: +1-847-935-6604; fax: +1-847-938-5034; e-mail: stephen.gwaltney@abbott.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00279-7

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S. L. Gwaltney, II et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1671–1673
Company.3 This compound inhibits tubulin poly-
merization by binding to tubulin at the colchicine bind-
ing site.4 E-7010 has shown good antitumor activity in
vivo against both rodent tumors and human tumor
xenografts.5 Structurally related compounds 16 and 27
have also been reported and possess activity similar to
that of E-7010.
lines with IC50’s of 130 nM and 56 nM, respectively. In
contrast, E-7010 inhibits these same cell lines with IC50’s
of approximately 350 nM. Importantly, both compound
4 and E-7010 maintain activity against the MDR (+) cell
line HCT-15, which indicates that they are not substrates
for P-glycoprotein mediated transport.
We next prepared compounds where the olefin in com-
pound 4 was replaced by an amide. The synthesis of
these compounds is shown in Scheme 2. Sulfonylation
of 3-hydroxy-2-nitropyridine gave sulfonate 5. Reduc-
tion of the nitro group, followed by acylation gave tar-
get compounds 6 and 7. Amides 9–12 could be prepared
from methyl salicylate by sulfonylation, hydrolysis, and
coupling to an aniline. Alternatively, the reverse amides
14–26 could be prepared by sulfonylation8 of 2-amino-
phenol followed by acylation.
As part of our program to identify novel antimitotic
agents, we have synthesized some sulfonates related to
the compounds discussed above. The synthesis of the
first compound examined is shown in Scheme 1. Salicyl-
aldehyde was treated with 4-methoxybenzenesulfonyl
chloride under standard conditions8 to provide
sulfonate 3. Condensation7 of 3 with 4-picoline gave
compound 4.
Compound 4 was tested for antiproliferative activity
against two cancer cell lines: NCI-H460 and HCT-15.
NCI-H460 is a human lung carcinoma that does not
express P-glycoprotein, while HCT-15 is a human colon
carcinoma that expresses a high level of this protein.
Compound 4 inhibited the proliferation of these cell
The pyridine-containing compounds 6 and 7 and ben-
zamides 9–12 proved to be inactive (IC50>10 mM)
against both cell lines tested. However, several of the
anilides 14–26 showed good activity against these tumor
cell lines (Table 1).
Scheme 1. Synthesis of compound 4.
Scheme 2. Synthesis of sulfonate analogues of E-7010.

S. L. Gwaltney, II et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1671–1673
1673
Table 1. Inhibition of cellular proliferation (IC50) for sulfonate
analogues of E-7010
Since several of the sulfonate analogues above showed
activity comparable to that of E-7010, the pharmacoki-
netic behavior of these compounds was examined.
Sprague–Dawley rats were given an intravenous or oral
10 mg/kg dose of compounds 4, 16, 22, and 26. These
compounds all exhibited short iv half-lives (t1=2 <1 h)
and poor oral bioavailability (Fꢀ0).
Compd
R
IC50 (nM),
HCT-15a
IC50 (nM),
NCI-H460b
14
15
16
17
18
19
20
21
2-Furyl
4-Fluorophenyl
4-Pyridyl
19
89
89
110
24
550
55
300
2-Pyridyl
3-Pyridyl
In conclusion, we have synthesized sulfonate analogues
of E-7010 and have found several of these compounds
to be potent in vitro inhibitors of the proliferation of
two cancer cell lines. These compounds also inhibit the
polymerization of tubulin. Further work to identify
novel antimitotic agents is ongoing and will be reported
in due course.
>3000
>10,000
>10,000
>10,000
600
>6000
>10,000
>10,000
>10,000
720
Quinolin-4-yl
Quinolin-6-yl
4-(Dimethylamino)-phenyl
4-Pyridinylmethyl
Phenyl
22
23
310
410
24
25
26
E-7010
NH-Phenyl
O-Phenyl
2-Pyrazinyl
>10,000
>10,000
68
>10,000
>10,000
250
N.A.
340
350
aMDR (+), multidrug resistant.
bMDR (À), not multidrug resistant.
References and Notes
Table 2. Inhibition of tubulin polymerization (IC50) for sulfonate
analogues of E-7010 and for E-7010 itself
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IC50 (mM)
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16
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26
3.46
3.73
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3.10
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Examination of Table 1 reveals that several different
types of aromatic substitutions at the amide site are well
tolerated. The 2-furyl analogue (14) was quite potent;
however, this compound proved relatively unstable and
was not further examined. The 4-pyridyl group is well
tolerated (16), and is better than either the 2- or 3-sub-
stituted compounds (17 and 18). Increasing chain length
between the aromatic nucleus and the amide results in
decreased potency (22).
Selected compounds that showed significant anti-
proliferative effects were also tested for their ability to
inhibit the polymerization of tubulin9 (Table 2). The
results of this work demonstrate that the sulfonates tes-
ted are antimitotic agents with potency comparable to
that of E-7010.
7. Hidaka, H.; Matsura, A.; Matsuda, M. International
Patent WO 95/27699, 1995; Chem. Abstr. 1996, 124, 145916.
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