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Figure 1. Tubulin polymerization assay. Tubulin polymerization in
the absence of any drug gave the control readings. Plotted values are
the means of four independent experiments.
(Table 1 and Fig. 1). Additionally, the 5-Cl substitution
also produced a somewhat good eect on antimitotic
and antiproliferative activity in case of the R1 sub-
stituent OCH3 (see 1 versus 5). For the G1 increase
phenotype, substitution at the 3- and/or 4-position of
the indole was essential. Especially the 3-Cl substitution
seemed to have predominant eect, judging from the
data that the 3-Cl compounds were about two times more
potent against colon 38 than the 4-Cl ones on the IC50
value basis (see 9 versus 10; 15 versus 16; 21 versus 22).
The tubulin polymerization test disclosed that compound
27, causing G1 accumulation at 4.0 mg/mL, moderately
inhibited microtubule assembly over 33.3mg/mL. How-
ever, the incidental antimitotic action was signi®cantly
diminished in 3,4-di-substituted compounds 28 and 31.
Steric limitations of the 4-substituent were evident by see-
ing antiproliferative pro®les of compounds 32 and 33.
As for selected antimitotic compounds, E7010, 2, 3, 8 and
20, there was a reasonable correlation among anti-
proliferative activity, mitotic arrest ability at 4.0 mg/mL,
and inhibitory activity against tubulin polymerization,
with a rank order of E7010 ꢁ 2 ꢁ 20 >3 >8. Considering
chemical structures of the new antimitotic sulfonamides,
they are likely to bind reversibly to b-tubulin in the
same manner as E7010. In this aspect, our compounds
are clearly distinguished from another antimitotic sulfo-
namide T138067 that contains the penta¯uorobenzene-
sulfonamide moiety and has been reported to modify b-
tubulin covalently at the Cys-239 residue.16 On the
other hand, intensive research on the G1-targeting sul-
fonamides led us to the discovery of N-(3-chloro-7-
indolyl)-1,4-benzenedisulfonamide (E7070), which has
progressed to Ph I clinical trials in Europe because of its
promising in vivo ecacy against human tumor xeno-
grafts and its unique mode of action.17 Further data on the
SAR of E7070-related compounds will be forthcoming.
Acknowledgements
We thank Dr. A. Sasaki, Mr. K. Nakamoto, Dr. K.
Ueno, and Dr. M. Yonaga for helpful discussions dur-
ing the preparation of this manuscript.
17. Owa, T.; Yoshino, H.; Okauchi, T.; Yoshimatsu, K.;
Ozawa, Y.; Sugi, N. H.; Nagasu, T.; Koyanagi, N.; Kitoh, K.
J. Med. Chem. 1999, 42, 3789.