Dissociation of estrogenic and cytotoxic properties of an estrogen receptor-binding platinum complex in human breast cancer cell lines.

The Pt complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]diaqua -Pt(II) sulfate (meso-6-PtSO4) was designed with the concept of combining the cytotoxic cisplatin with an estrogen receptor (ER)-binding ligand for targeting to ER+ mammary tumor cells. This Pt complex selectively inhibits growth of ER+ mammary tumors in rodents. To study the cellular mechanisms of action, cultures of two human mammary tumor cell lines, MCF-7 (ER+) and MDA-MB231 (ER-), were used and the effects of estradiol, tamoxifen, and cis-Pt compared with those of meso-6-PtSO4. The relative binding affinity of the meso-6-PtSO4 to the ER in MCF-7 cells was 0.35 compared to estradiol (relative binding affinity, 100). Nevertheless, the Pt complex was able to induce ER processing and increase the level of the progesterone receptor at concentrations of 1-10 nM. Growth of MCF-7 cells was inhibited at concentrations of meso-6-PtSO4 greater than 10 microM. MDA-MB231 cells were inhibited likewise by the Pt complex, indicating a lack of selectivity for the ER+ cells. The results show that meso-6-PtSO4 possesses both estrogen-like and cis-Pt-like properties. Since growth inhibition did not correlate with ER-mediated processes, these two properties are expressed independently at the cellular level. The selective growth inhibitory effect of meso-6-PtSO4 in vivo is suggested to involve endocrinological and/or immunological factors.

Anticancer drugs: estrophilic cisplatin derivatives.

Our approach to develop platinum complexes with a selective effect on the hormone-dependent MC by exchanging the two NH3 groups of cisplatin by an 1,2-bis(4-hydroxy-phenyl)ethylenediamine derivative which possesses estrogenic activity, was successful. The most interesting compound of this new platinum complex series, meso-(1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine)dichloroplati num(II) (meso-1-PtCl2) and its water soluble sulfatoplatinum(II) derivative (meso-1-PtSO4) were significantly more active on the DMBA-MC and the receptor positive MXT-MC than cisplatin and the related ligand 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (meso-1). According to our proposed mechanism of action, meso-1-PtX (X = Cl2 or SO4) should be enriched in the nuclei of mammary tumor cells, which possess an intact ER system (i.e. an intact cytoplasma nucleus translocation process), thereby causing very strong tumor growth inhibition. Preliminary studies of meso-1-PtSO4 on the DMBA-MC confirm this assumption. In the tumor tissue we found higher Pt-levels than in uterine tissue, which also contains ERs. The Pt-levels of the tumor tissue are much higher than those of skeletal muscle and of blood. In therapeutic dosages meso-1-PtSO4 does not cause kidney damages in rats.

Investigation of the configurational and conformational influences on the hormonal activity of 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines and of their platinum(II) complexes. 1. Synthesis, estradiol receptor affinity, and estrogenic activity of diastereomeric [N-alkyl- and N,N'-dialkyl-1,2- bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes.

N-Monoalkylated (Et) and N,N'-dialkylated (Me and Et) 1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamines and their dichloroplatinum(II) complexes were synthesized, and their configuration and conformational behavior were 1H-NMR spectroscopically clarified. The latter was brought in relation to their relative binding affinity (RBA) to the estrogen receptor as well as to their estrogenic potency. In contrast to the RR/SS-configurated diamines, the R/S-configurated ones showed marked estrogenic properties which correlate with the RBA's. In the related R/S-configurated complexes the estrogenic activity is determined by the same structural requirements as in the diamine series. However, a correlation between RBA's and estrogenic potencies is missing. The connection between spatial structure and activity is discussed by use of a drug-receptor model recently proposed by Höltje and Dall.

Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 2. Synthesis and estrogen receptor binding affinity of 4,4'-, 5,5'-, and 6,6'-disubstituted metahexestrols.

The syntheses of symmetrically 4,4'-, 5,5'-, and 6,6'-disubstituted derivatives of the mammary tumor inhibiting antiestrogen metahexestrol [meso-3,4-bis(3-hydroxyphenyl)hexane] (1) are described [4,4'-substituents: F, (2), Cl (3), Br (4), I (5), CH2N (CH3)2 (6), CH3 (7), CH2OCH3 (8), CH2OC2H5 (9), CH2OH (10), NO2 (11), NH2 (12), N(CH3)2 (13), COCH3 (14), and C2H5 (15); 5,5'-substituents: OH (16) and Cl (17); 6,6'-substituents: OH (18), F (19), Cl (20), and CH3 (21)]. The synthesis of 1-3, 16, and 19 was accomplished by reductive coupling of the propiophenones with TiCl4 /Zn and subsequent hydrogenation of the cis-3,4- diphenylhex -3- enes . Compounds 17, 18, 20, and 21 were synthesized by coupling the 1-phenyl-1-propanols with TiCl3 /LiAlH4 and separation of the meso diastereomers, while 4-15 were obtained by substitution of metahexestrol . The binding affinity of these compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. The test compounds showed relative binding affinity (RBA) values between 15 and less than 0.01% that of estradiol. Only compound 21 showed an estrogen receptor binding affinity exceeding that of metahexestrol (15 and 10%, respectively). Compounds exhibiting RBA values of greater than 0.5% were evaluated in the mouse uterine weight test. They showed a similar (2 and 12), slightly increased (19 and 21), or strongly enhanced (7 and 20) estrogenicity compared to that of metahexestrol . Compounds 1, 2, 7, 12, and 21 exhibited antiestrogenic activity inhibiting the estrone-stimulated uterine growth (24 to 60% inhibition).

Acetoxy-substituted 1,1,2-triphenylbut-1-enes with antiestrogenic and mammary tumor inhibiting properties.

1,1,2-Triphenylbut-1-enes (E- and Z-10-12), which are substituted with one p- and one m-acetoxy group in two different aromatic rings, were synthesized. The E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study of the structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties (mouse), inhibition of the hormone-dependent human MCF7 breast cancer cell line in vitro, and the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, (E)- and (Z)-1-(3-acetoxyphenyl)-1-(4-acetoxyphenyl)-2-phenylbut-1-enes+ ++ (E-10 and Z-10) and (Z)-1-(3-acetoxyphenyl)-1-phenyl-2-(4-acetoxyphenyl)-but-1-ene (Z-12) proved to be partial antiestrogens, which lead to an inhibition of the MCF7 cell line. They exert a growth-inhibiting activity on the hormone-dependent MXT mammary carcinoma of the mouse. In the case of E-10 and Z-10, this effect is only slightly weaker than that of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene (13) and tamoxifen. Under the applied experimental conditions, there were no significant changes of uterine weight as an indicator of estrogenic side effects.

Aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2- phenylethylenediamine](sulfato)platinum-(II) complexes with variable substituents in the 2-phenyl ring. 1. Synthesis and antitumor and estrogenic properties.

Erythro- and threo-configurated aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2- phenylethylenediamine](sulfato)platinum(II) complexes with variable substituents in the 2-phenyl ring (2-PtSO4 to 9-PtSO4: H, 4-F, 3-OH, 4-OH, 2,6-F2, 2,6-Cl2, 2-F/4-OH, 2-Cl/4-OH) were synthesized and tested for estrogenic and antitumor activities. The ligands were obtained by a three-step reaction. The stilbenes were reacted with a mixture of IN3 and NaN3 to yield the respective 1,2-diazido-1,2-diphenylethanes. The subsequent reduction with LiAlH4 led to the corresponding 1,2-diphenyl-ethylenediamines. The (sulfato)platinum(II) complexes were synthesized by reaction of Ag2SO4 with the diiodo complexes, which had been obtained by coordination of the diamines with K2PtI4. Two complexes, erythro-8-PtSO4 and erythro-9-PtSO4, possess antitumor and estrogenic effects and are therefore of interest for the therapy of breast cancer.

Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 1. Synthesis and estrogen receptor binding affinity of 2,2'- and 3,3'-disubstituted hexestrols.

The syntheses of symmetrically 3,3'- and 2,2'-disubstituted meso hexestrol derivatives are described [3,3'-substituents: OH (1), F (2), Cl (3), Br (4), I (5), CH2N(CH3)2 (6), CH3 (7), CH2OCH3 (8), CH2OC2H5 (9), CH2OH (10), NO2 (11), NH2 (12), N(CH3)2 (13), COCH3 (14), and C2H5 (15); 2,2'-substituents: OH (16), F (17), Cl (18), Br (19), CH3 (20), and C2H5 (21)]. The synthesis of 1-3 was accomplished by reductive coupling of the propiophenones with TiCl4/Zn and subsequent hydrogenation of the cis-3,4-diphenylhex-3-enes. Compounds 4-15 were obtained by substitution of hexestrol, while compounds 16-21 were synthesized by coupling the 1-phenyl-1-propanols with TiCl3/LiAlH4 and separation of the meso diastereomers. The binding affinity of these compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. All test compounds showed relative binding affinity (RBA) values between 32 and less than 0.01% that of estradiol. Only meso-3,4-bis(2,4-dihydroxyphenyl)hexane (16) showed an estrogen receptor binding affinity comparable to that of hexestrol (32 and 27%, respectively). Compounds exhibiting RBA values of greater than 5% were evaluated in the mouse uterine weight test. All of them showed uterotrophic activity. Compounds 2, 7, 16, 17, and 20 were strongly active in very small doses (1 microgram per animal per day), while 1 and 12 produced full uterotrophic effects only in high doses and inhibited the estrone-stimulated uterine growth strongly in small doses (59 and 78% inhibition, respectively).

Influence of alkyl-chain fluorination on the action of mammary tumor inhibiting 2,3-bis(hydroxyphenyl)butanes and 2,3-bis(hydroxyphenyl)but-2-enes.

trans-1,2-Bis(trifluoromethyl)-1,2-bis(4- and 3-hydroxyphenyl)ethenes 2 and 4 were prepared by reductive coupling (TiCl4/Zn/pyridine) of the methoxy-substituted alpha, alpha, alpha-trifluoroacetophenones, separation of the resulting cis- and trans-stilbene derivatives, and ether cleavage with BBr3. The cis-stilbenes were catalytically hydrogenated to give meso-1,1,1,4,4,4-hexafluoro-2,3-bis(4- and 3-hydroxyphenyl)butanes 6 and 8. Compounds 2, 4, 6, and 8 showed 2- to 10-fold increased binding affinities for the estradiol receptor (E2R) and enhanced estrogenicity in the uterine weight test of the immature mouse compared to their unfluorinated analogues. Compound 8 exhibited a 46% inhibition of the estrone-stimulated uterine growth. Antitumor activity was evaluated with use of the transplantable, hormone-dependent MXT mammary tumor of the BD2F1 mouse. All compounds showed tumor growth inhibitory activity corresponding to their RBA values. The most interesting compound 8 led to a significant inhibition of the tumor growth on the DMBA-induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat.

Ring-substituted 1,1,2,2-tetraalkylated 1,2-bis(hydroxyphenyl)ethanes. 4. Synthesis, estrogen receptor binding affinity, and evaluation of antiestrogenic and mammary tumor inhibiting activity of symmetrically disubstituted 1,1,2,2-tetramethyl-1,2-bis(hydroxyphenyl)ethanes.

The syntheses of symmetrically 2,2'-disubstituted derivatives of 1,1,2,2-tetramethyl-1,2-bis(4-hydroxyphenyl)ethane (1) and of 5,5'-, and 6,6'-disubstituted derivatives of 1,1,2,2-tetramethyl-1,2-bis(3-hydroxyphenyl)ethane (6) are described (1 and 6 are strong antiestrogens with mammary tumor inhibiting activity exhibiting only slight estrogenic properties): (2,2'-substituents) F (2), Cl (3), OCH3 (4), CH3 (5); (5,5'-substituents) Cl (7); (6,6'-substituents) F (8), Cl (9), OCH3 (10), CH3 (11). The synthesis of 1-11 was accomplished by reductive coupling of the corresponding 2-phenyl-2-propanols with TiCl3 and LiAlH4. The binding affinity of the compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. With the exception of 7 and 10 all other compounds showed relative binding affinity (RBA) values between 0.5 and 6.4% that of estradiol, 2 (RBA value 6.4), and 8 and 9 (4.0 and 3.5), exceeding those of the corresponding unsubstituted 1 and 6 (3.6 and 3.0). Compounds exhibiting RBA values of greater than 2.5% were evaluated in the mouse uterine weight test. The substituted derivatives showed an increase in uterotrophic and a decrease in antiuterotrophic activity compared to 1 and 6. Compound 2 showed a strong, dose-dependent inhibition on the DMBA-induced hormone-dependent mammary tumor of the SD-rat, exceeding that of the parent compound 1. At a dose of 5 mg/kg per day, 2 reduced total tumor area by 47% and caused a complete remission in 74% of the tumors.

Benzylamines: synthesis and evaluation of antimycobacterial properties.

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.

Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 3. Synthesis, estrogen receptor binding affinity, and evaluation of antiestrogenic and mammary tumor inhibiting activity of 2,2'-disubstituted butestrols and 6,6'-disubstituted metabutestrols.

The synthesis of symmetrically 2,2'-disubstituted butestrols [meso-2,3-bis(4-hydroxyphenyl)butanes] and of 6,6'-disubstituted metabutestrols [meso-2,3-bis(3-hydroxyphenyl)butanes] are described [2,2'-substituents: H (1), OH (2), F (3), Cl (4), Br (5), CH3 (6), and C2H5 (7); 6,6'-substituents: H (8), OH (9), Cl (10), and CH3 (11)]. Compounds 1-11 were obtained by reductive coupling of the corresponding 1-phenylethanols with TiCl3/LiAlH4 and separation of the meso diastereomers. The binding affinity of the test compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. With the exception of 9, all other compounds showed remarkably high relative binding affinity (RBA) values between 1.0 and 29% that of estradiol. Compounds 3 and 6 (RBA values: 15 and 29), as well as 10 and 11 (1.7 and 5.2), exceeded those of the corresponding unsubstituted compounds 1 and 8 (12 and 1.0). The compounds exhibited strong (3, 4, 6, and 7), moderate (1, 2, and 10), weak (11), or no (8) estrogenic activity in the uterine weight test of the immature mouse. Compounds 1, 2, 8, 10, and 11 showed antiestrogenic activity inhibiting the estrone-stimulated uterine growth (25-35% inhibition). Compound 11 led to a significant inhibition of the tumor growth when tested on the 9,10-dimethyl-1,2-benzanthracene induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat.

Diamine ligand release from the cisplatin analogue [meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]dichloroplatinum(II) in cell culture medium.

The stability of the five-membered chelate ring of the cisplatin analogue [meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]dichloroplatinum(II) was investigated under typical cell culture conditions (IMEM-Richter's medium with 10% fetal calf serum, 37 degrees C). For this purpose, the platinum compound was radiolabeled with tritium in the meta position of the aromatic ring by an acid-catalyzed tritium-exchange reaction, and a reversed-phase HPLC assay with radiochemical detection was developed to monitor for the presence of the free diamine ligand in the cell culture medium. A gradual increase in radioactivity attributed to the free diamine was found in medium containing the dichloroplatinum(II) complex (ca. 25% after 24 h), indicating that the diamine ligand was being released from the metal atom. When 1 mM glutathione (GSH) was included in the incubation medium, the amount of free diamine nearly doubled after 24 h, while the amount of radioactivity attributed to serum protein-platinum adducts decreased relative to incubations without GSH. On the other hand, the omission of serum from the incubations resulted in a dramatic decrease in the amount of radioactivity eluting under the diamine peak, while the concentrations of the two methionine-Pt adducts, which formed in a 1:1 ratio, rose. Through the use of liquid secondary ion mass spectroscopy, the two methionine-Pt adducts were identified as monomethionine metabolites of the title compound, whereby the two chloride ligands have been replaced by the amino acid. These compounds are probably diastereomers since the sulfur of methionine can coordinate to platinum with equal probability either cis or trans to the R-configured benzylamine carbon. On the basis of the chemical shifts of the MeS groups in the 250-MHz 1H NMR, it is concluded that a S,N-five-membered chelate ring is present in these methionine-Pt adducts.

Mammary tumor inhibiting effect of 3,3'-diacetoxy-alpha, beta-dialkylstilbenes and of related stilbene oxides.

3,3'-Diacetoxy-alpha, beta-dialkylstilbenes (alkyl = CH3 to C4H9, 1-4) 3,3'-dihydroxy-alpha, beta-diethylstilbene (5), and their corresponding stilbene oxides (6-10) were synthesized. Compounds 1-10 competitively antagonized in vitro the interaction of [3H]estradiol with its receptor. 3,3'-Diacetoxy-alpha, beta-diethylstilbene (2), 3,3'-diacetoxy-alpha, beta-diethylstilbene oxide (7), and their phenolic analogues (5 and 10) were most effective. Shortening or lengthening the alkyl side chains led to a decrease in receptor affinity. Among the stilbenes and epoxides, those with C2H5 and C3H7 groups (2, 3, 5 and 7, 8, 10) caused the strongest inhibition of the growth of a hormone-dependent postmenopausal human mammary carcinoma serially implanted in nude mice. The strong antitumor activity of 5 and 10 was confirmed by experiments on the 9,10-dimethyl-1,2-benzanthracene-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat.

N,N'-Dialkylbis(dichlorophenyl)ethylenediamines and -imidazolidines: relationship between structure and estradiol receptor affinity.

Diastereomeric N,N'-dialkylbis(dichlorophenyl)ethylenediamines and the corresponding imidazolidines with chlorine in the 2,4, 2,6, 3,4, and 3,5 positions were synthesized. Only the stereoisomers of the 2,6-dichloro-substituted compounds exhibit for N-CH3 (2e, 3e), N-C2H5 (2f, 3f), and N-C3H7 (2g, 3g) an affinity to the estradiol receptor (Ka values ranging from 9.1 X 10(4) to 9.1 X 10(6)), because the nitrogen atoms are shielded by the ortho-located chlorine atoms; therefore, a binding interaction with hydrophobic receptor areas is possible. These substances show weak uterotrophic activity and no significant effect on the growth of the DMBA-induced hormone-dependent mammary adenocarcinoma of the rat.

Potential antiestrogens. Synthesis and evaluation of mammary tumor inhibiting activity of 1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes.

The syntheses of the meso-1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes [alkyl substituent: CH3 (19), C2H5 (20), C3H7 (22), C4H9 (23), i-C4H9 (24), and C5H11 (25)] and of d,l-3,4-bis(3'-hydroxyphenyl)hexane (21) are described. In vitro these compounds inhibited the [3H]estradiol receptor interaction competitively, exhibiting Ka values between 0.20 x 10(9) (20) and 0.11 x 10(6) M-1 (24). In vivo the meso compounds reduced the estrone-stimulated mouse uterine growth; the most effective compounds were 20, 22, and 23 (53, 50, and 45% inhibition, respectively). Compounds 20 and 22-24 showed weak estrogenic activity in the mouse uterine weight test and in the vaginal cornification test. Compounds 19 (NSC-297169), 20 (NSC-297170), and 22 (NSC-297171) exhibited a dose-dependent growth inhibition on the MCF-7 human breast tumor cell line (10(-6) to 10(-9) M). These compounds also showed a marked dose-dependent inhibition on the DMBA-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat corresponding to their association constants.

Antiestrogens. Synthesis and evaluation of mammary tumor inhibiting activity of 1,1,2,2-tetraalkyl-1,2 -diphenylethanes.

Among the newly synthesized 1,1,2,2-tetraalkyl-1,2-diphenylethanes, 1,1,2,2-tetramethyl-1,2-bis(4'-hydroxyphenyl)ethane (23) and 1,1,2,2-tetramethyl-1,2-bis(3'-hydroxyphenyl)ethane (26) were the most active compounds regarding estradiol receptor affinity, exhibiting Ka values of 0.73 X 10(8) and 0.67 X 10(8) M-1, respectively. In vivo, 23 and 26 showed only very small uterotrophic activity in the mouse. They strongly inhibited (73%) the estrone-stimulated mouse uterine growth. Tested on the 9,10-dimethyl-1,2-benzanthracene induced hormone-dependent mammary adenocarcinoma of the Sprague-Dawley rat, compounds 23 and 26 exhibited a dose-dependent inhibition of the tumor growth, having a strong effect at a dose of 20 (mg/kg)/day (compound 23).

N,N'-Dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines and N,N-dialkyl-4,5-bis(4-hydroxyphenyl)imidazolidines: syntheses and evaluation of their mammary tumor inhibiting activity.

Diastereomeric N,N'-dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines (5) were synthesized and tested for their affinity for the estradiol receptor. Only the (+/-)-1,2-bis(4-hydroxyphenyl)ethylenediamines with the alkyl groups C3H7 [(+/-)-5c, Ka = 1.1 x 19(6))], C4H9 [(+/-)-5e,Ka = 3.6 x 10(6)], and C5H11 [(+/-)-5h, Ka = 2.2 x 10(6)] showed a marked affinity, which is mainly due to the (+) enantiomers [e.g., (+)-5e, Ka = 2.1 x 10(7)]. No enhancement of affinity by cyclization to imidazolidines [e.g., (+/-)-trans-7a, Ka = 1.2 x 10(7)] was observed. These compounds [e.g., (+/-)-, (+)-, and (-)-5e], which did not produce any uterine response in the mouse, were able to inhibit weakly the growth of the DMBA-induced mammary carcinoma of the rat. The inhibitory effect of (+/-)-5e against MCF-7 cells, which can be overcome by hexestrol, makes a direct antiestrogenic mode of action probable, since general cytotoxic effects and a central action could be ruled out.

Dichloro[1,2-bis(4-hydroxyphenyl)ethylenediamine]platinum(II) complexes: an approach to develop compounds with a specific effect on the hormone-dependent mammary carcinoma.

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.

1,1,2-triphenylbut-1-enes: relationship between structure, estradiol receptor affinity, and mammary tumor inhibiting properties.

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.

Ring-substituted [1,2-bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum (II) complexes: compounds with a selective effect on the hormone-dependent mammary carcinoma.

[1,2-Bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum (II) complexes with one substituent in the 2-position (CH3, CF3, F, Cl, Br, I: meso- and d,l-1-PtCl2, meso-(3-5)-PtCl2, meso-(7 and 8)-PtCl2) or two substituents in the 2,6-positions (CH3, Cl: meso-2-PtCl2, meso- and d,l-6-PtCl2) in both benzene rings were synthesized and tested for estrogenic and cytotoxic activities. Two complexes (meso-6-PtCl2 and meso-7-PtCl2) possess both effects. In comparative tests on estrogen receptor positive and negative mammary tumors in cell culture (MCF 7, ER+ and MDA-MB 231, ER-) and in animals (MXT, ER+ and MXT, ER-, mouse), meso-6-PtCl2 shows a selective effect on the estrogen receptor positive mammary carcinoma. A further increase of efficacy was achieved with the water-soluble (sulfato)platinum(II) derivative (meso-6-PtSO4). On the DMBA-induced hormone dependent mammary carcinoma of the SD rat, meso-6-PtSO4 is significantly more active than its ligand (meso-6) and cisplatin.