Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2873
(5) Hara, M.; Akasaka, K.; Akinaga, S.; Okabe, M.; Nakano, H.;
Gomez, R.; Wood, D.; Uh, M.; Tamanoi, F. Identification of ras
Farnesyltransferase Inhibitors by Microbial Screening. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90 (6), 2281-2285.
(6) Kohl, N. E.; Mosser, S. D.; deSolms, S. J .; Giuliani, E. A.;
Pompliano, D. L.; Graham, S. L.; Smith, R. L.; Scolnick, E. M.;
Oliff, A.; Gibbs, J . B. Selective Inhibition of ras-Dependent
Transformation by a Farnesyltransferase Inhibitor. Science
1993, 260, 1934-1937.
(7) Patel, D. V.; Schmidt, R. J .; Biller, S. A.; Gordon, E. M.; Robinson,
S. S.; Manne, V. Farnesyl Diphosphate-Based Inhibitors of ras
Farnesyl Protein Transferase. J . Med. Chem. 1995, 38, 2906-
2921.
(8) Marciano, D.; Ben-Baruch, G.; Marom, M.; Egozi, Y.; Haklai;
R.; Kloog, Y. Farnesyl Derivatives of Rigid Carboxylic Acids -
Inhibitors of ras-Dependent Cell Growth. J . Med. Chem. 1995,
38, 1267-1272.
(9) J ames, G. L.; Goldstein, J . L.; Brown, M. S.; Rawson, T. E.;
Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucus, B. K.;
Levinson, A. D.; Marsters, J . C., J r. Benzodiazepine Peptido-
mimetics: Potent Inhibitors of ras Farnesylation in Animal
Cells. Science 1993, 260, 1937-1942.
(10) (Tetrahydropyranyloxy)pent-2,4-diyne was prepared from pro-
pargyl alcohol. THP-propargyl alcohol was subjected to Heck
reaction using (E)-1,2-dichloroethene and treated with nBu4NF
to remove hydrogen chloride, giving the above diyne in 24%
overall yield.
(11) v-Ki-ras-transformed NIH3T3 (ras/NIH3T3) cells were grown in
Dulbecco’s modified minimum essential medium (D-MEM) supple-
mented with 10% fetal bovine serum. Inhibition of cell growth
by the reported compounds was determined according to a
method using MTT as a dye. The morphological change of the
cells was observed under a microscope.
of substituents on the side chain phenyl ring was
observed in these compounds.
In conclusion, we have reported the synthesis and
inhibitory activity for ras transformation of aromatic
sulfonamide hydroxamates, which induce a flat pheno-
type in Ki-ras-transformed NIH3T3 cells. Among these
inhibitors, (2E)-5-[3-[(phenylsulfonyl)amino]phenyl]pent-
2-en-4-ynohydroxamic acid (14a ) proved to be the most
potent inhibitor and was categorized as the first com-
pound inducing genes with products that can interfere
with ras-dependent transformation.
Ack n ow led gm en t. The authors gratefully acknowl-
edge Dr. Hikaru Sonoda for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails with spectral data (14 pages). Ordering information is
given on any current masthead page.
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(12) Sonoda, H.; Nishida, K.; Yoshioka, T.; Ohtani, M.; Sugita, K.
Rasflatin:
A Novel Compound Which Reverses Malignant
Phenotype to Normal One via Induction of J unD. Oncogene, in
press.
J M960174K