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Cancer Chemopreventive Potential of Sulforamate, a Novel Analogue of Sulforaphane That Induces Phase 2 Drug-metabolizing Enzymes¹

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy [C. I. G., M. Y., J. M. P.], Department of Chemistry, College of Liberal Arts and Sciences [J. L., R. M. M.], and Department of Surgical Oncology, College of Medicine [M. H., R. G. M., R. C. M., and J. M. P.], University of Illinois at Chicago, Chicago, Illinois 60612

Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (±)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, 0.2 µM), but cytotoxicity was reduced by about 3-fold (IC₅₀ 30 µm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 µM by interaction with the antioxidant responsive element (5–14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 µm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.

¹ Support for this work was provided by Program Project P01 CA48112 funded by the National Cancer Institute. C. G. was supported in part by a Feodor-Lynen Fellowship awarded by the Alexander von Humboldt-Foundation. These data were presented in part at the 87th Annual Meeting of the AACR, April 20–24, 1996 in Washington, D.C. (45).

² Present address: German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, D 69120 Heidelberg, Germany.

³ To whom requests for reprints should be addressed, at the Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612. Phone: (312) 996-5967; Fax (312) 996-7107; E-mail: John.M.Pezzuto@uic.edu.

Received 9/25/96. Accepted 12/ 3/96.

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