A number of 6-alkyl-12-formyl-5,6-dihydroindolol[2,1-a]isoquinolines were synthesized by the Bischler-Napieralski reaction from the respective 1-alkyl-2-(3-methoxyphenyl)ethylamines and bromo-substituted (methoxyphenyl)acetic acid chlorides followed by a second ring closure reaction involving a base-generated benzyne intermediate. The methoxy functions in positions 3 and 9 or 10 were cleaved with BBr3 and the free hydroxy groups converted into the acetates. The enantiomers of the most potent derivatives were separated by liquid chromatography on triacetylcellulose. All of the compounds tested bind to the calf uterine estrogen receptor. The relative binding affinities (RBA) ranged from 0.5 to 3.9 (17 beta-estradiol: RBA = 100) and were dependent on the position of the oxygen function in the indole moiety. The 3,10-diacetoxy derivatives showed higher RBA values than the corresponding 3,9-substituted tetracycles. There was no major difference in binding affinity between (+)- and (-)-enantiomers. Computer-assisted molecular modeling studies showed that the chiral carbon atom 6 of the indoloisoquinoline is likely to mimic the C-11 atom of estradiol. In the mouse uterine weight test, only the 3,10-diacetoxy series exhibited weak estrogenic activity at higher doses. The antiestrogenic effects found with all the compounds varied considerably. Maximum inhibition of estrone-stimulated uterine growth was found for the ethyl derivative 7d (80% with 250 micrograms/animal per day). All derivatives strongly inhibited the growth of human breast cancer cells in vitro. There was no significant difference between hormone-sensitive MCF-7 cells and hormone-independent MDA-MB 231 cells. Cytostatic activity was higher for the 3,9-substituted indoloisoquinolines than for the 3,10-analogues and dependent on the length of the alkyl group at C-6. The maximum effect was found with the butyl derivative 7g. When the enantiomers of the ethyl (7c), propyl (7e), and butyl derivative were studied, a strong difference in activity was observed between the stereoisomers. The IC50 values of the (+)-forms were usually only a tenth of those of the levorotatory isomers. Maximum cytostatic activity was found with (+)-7g: 85% inhibition at 1 x 10(-7) M in MCF-7 cells and 94% inhibition at 2.5 x 10(-7) M in MDA-MB 231 cells. This stereospecificity indicates a selective action on a biochemical target. Since no interaction with DNA was observed, the precise mode of action still remains to be elucidated.

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Stereoisomeric dichloro [1,2-bis(4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-3a, (+/-)-3b, (+)-3c, (-)-3d) and their N,N'-dibutyl derivatives (meso-4a, (+/-)-4b, (+)-4c, (-)-4d) were synthesized and tested on antitumor activity. The most active compound, 3d, shows a modest inhibition of the [3H]estradiol receptor interaction and causes a marked effect on the growth of the hormone-dependent human MCF 7 breast cancer cell line. It is also active on the hormone-independent human MDA-MB 231 breast cancer cell line, on the ADJ/PC6 plasmacytoma of the Balb/C mouse, and on the L 5222 leukemia of the BD IX rat. Apparently the inhibition of the MCF 7 cell line is not mediated by the estrogen receptor system. Histopathological studies on 3d revealed very low toxicity.

The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (19, MIC 10.2 micrograms/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 micrograms/mL), and N-butyl-3,5-difluorobenzylamine (103, MIC 6.4 micrograms/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combinations of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.

Hydroxy-2-phenylindoles carrying substituted benzyl groups and similar substituents at the nitrogen were synthesized and tested for their ability to displace estradiol from its receptor. All of the derivatives tested exhibited high binding affinities for the calf uterine estrogen receptor, with RBA values ranging from 0.55 to 16 (estradiol 100). The mouse uterine weight tested revealed only low estrogenicity for this class of compounds. Several derivatives showed antiestrogenic activity with a maximum inhibition of estrone-stimulated uterine growth of 40%. Two of the compounds (6c, 21c) were tested for antitumor activity in dimethylbenanthracene- (DMBA-) induced estrogen-dependent rat mammary tumors. Only the 4-cyanobenzyl derivative 21c was active. After 4 weeks of treatment with 12 mg/kg (6 times/week), the average tumor area was decreased by 57% (control +204%). In vitro, an inhibitory effect of 21b was only observed with hormone-sensitive MCF-7 breast cancer cells but not with hormone-independent MDA-MB 231 cells. These results make a mode of action involving the estrogen receptor system likely.

1,1,2-Triphenylbut-1-enes, which are substituted with acetoxy groups on one, two, or three aromatic rings in the para and/or meta positions, were synthesized. The identity of the occurring E and Z isomers were established by 1H NMR spectroscopy. A study on structure-activity relationships was carried out with regard to estradiol receptor affinity and to inhibiting effects on the growth of a postmenopausal human mammary carcinoma implanted in nude mice. The para-substituted compounds generally exhibited a higher receptor affinity and a better antitumor activity than the corresponding meta-substituted ones. The E isomers were superior to the respective Z isomers in those two properties. The tumor-inhibiting effect of the mono- and disubstituted compounds was better than that of the trisubstituted ones. Except for the trisubstituted compounds, they all show a good correlation between estradiol receptor affinity and antitumor activity. One of the compounds was also tested on the 9,10-dimethylbenz[a]-anthracene-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat, and the results corresponded to those obtained in the xenograft tumor.

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Summary We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.