2-PHENYLINDOLES WITH SULFUR-CONTAINING SIDE-CHAINS - ESTROGEN-RECEPTOR AFFINITY, ANTIESTROGENIC POTENCY, AND ANTITUMOR-ACTIVITY

The 2-phenylindole system has been identified as a suitable structure for the design of non-steroidal pure estrogen antagonists [E. von Ange rer et al.,J. Steroid Biochem. Molec. Biol. 49 (1994) 51-62]. Derivati ves with an amide function in the side chain antagonized the stimulato ry effect of estrogens both in vitro and in vivo, and showed no agonis tic activity when given alone. The findings of other groups who studie d steroidal antiestrogens prompted us to replace the amide function by sulfide, sulfoxide, sulfone, sulfonamide and related groups. The comp ounds with polar sulfur functions retained the high binding affinity f or the calf uterine estrogen receptor (RBA: 1-5% of estradiol; ICI 182 ,780; 6.2%). The estrogenic effect was quantified in a transcription a ssay using HeLa cells cotransfected with the expression vector HEG0 fo r the human estrogen receptor and a reporter plasmid that harbored a V it. A2 ERE and the luciferase gene driven by a thymidine kinase promot or. Pentylsulfide, -sulfinyl, and -sulfonyl groups, linked to the indo le nitrogen by a decamethylene spacer, were devoid of any transcriptio nal activity. These results were confirmed in the mouse uterine weight test. The sulfone (ZK 164,015) completely abolished the effect of a s tandard dose of estrone at a daily dose of 7 mg/kg. This compound stro ngly inhibited the growth of hormone-sensitive human MCF-7 breast canc er cells with an IC50-value close to 1 nM. Similar activity was found for the steroidal sulfoxide ICI 182,780. We were also able to demonstr ate significant antineoplastic activity in vivo for some of these new 2-phenylindole derivatives. Copyright (C) 1996 Elsevier Science Ltd.