Search

Your search keyword '"Hartmann R"' showing total 28 results
Start Over Author "Hartmann R" Journal journal of medicinal chemistry
28 results on '"Hartmann R"'

1. Enantioselective Nonsteroidal Aromatase Inhibitors Identified through a Multidisciplinary Medicinal Chemistry Approach

Author

Cavalli, A., Bisi, A., Bertucci, C., Rosini, C., Paluszcak, A., Gobbi, S., Giorgio, E., Rampa, A., Belluti, F., Piazzi, L., Valenti, P., Hartmann, R. W., and Recanatini, M.

Abstract

To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinal chemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med. Chem. 1998, 6, 377−388] was extended taking purposely into account previously discovered enantioselective aromatase inhibitors. The 3D QSAR model was then exploited to design chiral ligands, whose configurational assignment was obtained, after HPLC separation, by means of a combination of circular dichroism measurements and time dependent density functional calculations. Finally, the new enantiomeric inhibitors were separately tested to ascertain both their potency against the cytochrome P450 aromatase (CYP19; EC 1.14.14.1), and their selectivity relative to another enzyme of the P450 family. A satisfactory agreement between experimental and predicted data allowed us to assert that a properly built “enantioselective CoMFA model” might constitute a useful tool for addressing enantioselective ligands design.

Published
2005

2. Heteroaryl-Substituted Naphthalenes and Structurally Modified Derivatives:  Selective Inhibitors of CYP11B2 for the Treatment of Congestive Heart Failure and Myocardial Fibrosis

Author

Voets, M., Antes, I., Scherer, C., Muller-Vieira, U., Biemel, K., Barassin, C., Marchais-Oberwinkler, S., and Hartmann, R. W.

Abstract

Recently we proposed inhibition of aldosterone synthase (CYP11B2) as a novel strategy for the treatment of congestive heart failure and myocardial fibrosis. In this study the synthesis and biological evaluation of heteroaryl-substituted naphthalenes and quinolines (1−31) is described. Key step for the preparation of the compounds was a Suzuki cross-coupling. Activity of the compounds was determined in vitro using human CYP11B2 and selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. A large number of highly active and selective inhibitors of CYP11B2 was identified. The most active inhibitor was the 6-cyano compound 8 (IC50 = 3 nM) showing a competitive type of inhibition (Ki value = 1.9 nM). The 6-ethoxy derivative 5 was found to be the most selective CYP11B2 inhibitor (IC50 = 12 nM; Ki value = 8 nM; CYP11B1 IC50 = 5419 nM; selectivity factor = 451), showing no inhibition of human CYP3A4 (50 nM) and CYP2D6 (20 nM). Docking and molecular dynamics studies using our homology modeled CYP11B2 structure with selected compounds were performed. Caco-2 cell experiments revealed a large number of medium and highly permeable compounds and metabolic studies with 2 using rat liver microsomes showed sufficient stability.

Published
2005

3. Synthesis and Evaluation of (Pyridylmethylene)tetrahydronaphthalenes/-indanes and Structurally Modified Derivatives:  Potent and Selective Inhibitors of Aldosterone Synthase

Author

Ulmschneider, S., Muller-Vieira, U., Klein, C. D., Antes, I., Lengauer, T., and Hartmann, R. W.

Abstract

Elevated aldosterone levels are key effectors for the development and progression of congestive heart failure and myocardial fibrosis. Recently, we proposed inhibition of aldosterone synthase (CYP11B2) as an innovative strategy for the treatment of these diseases. In this study, the synthesis and biological evaluation of E- and Z-(pyridylmethylene)tetrahydronaphthalenes and -indanes (1a,b−38a) is described. The activity of the compounds was determined using human CYP11B2, and the selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. The biological results revealed a few rather selective inhibitors of CYP11B1, some compounds inhibiting both CYP11B1 and CYP11B2, and a large number of highly selective inhibitors of CYP11B2. The most active inhibitor was the 3-pyridyl compound 5a (IC50 = 7 nM). The pyrimidyl-substituted derivative 28a was found to be the most selective CYP11B2 inhibitor (IC50 = 27 nM) in this series, showing a 120-fold selectivity for CYP11B1 (IC50 = 3179 nM). Molecular modeling, i.e., examination of the electronic and steric features of selected compounds and homology modeling and docking, was used to understand the structure−activity/−selectivity relationships.

Published
2005

4. Synthesis and Evaluation of Imidazolylmethylenetetrahydronaphthalenes and Imidazolylmethyleneindanes:  Potent Inhibitors of Aldosterone Synthase

Author

Ulmschneider, S., Muller-Vieira, U., Mitrenga, M., Hartmann, R. W., Oberwinkler-Marchais, S., Klein, C. D., Bureik, M., Bernhardt, R., Antes, I., and Lengauer, T.

Abstract

Elevated plasma aldosterone levels play a detrimental role in certain forms of congestive heart failure and myocardial fibrosis. We proposed aldosterone synthase (CYP11B2) as a novel target for the treatment of these diseases. In this study, the synthesis and biological evaluation of substituted E- and Z-imidazolylmethylenetetrahydronaphthalenes and E- and Z-imidazolylmethyleneindanes (compounds 1a,b−9a,b) is described. The compounds were prepared by a Wittig-like reaction. They were tested for activity using bovine CYP11B and human CYP11B2 expressed in fission yeast and V79 MZh cells. Selectivity was determined toward human CYP11B1, CYP19, and CYP17. Especially in the case of CYP11B1 (steroid 11β-hydroxylase), selectivity is a crucial issue, since sequence homology between this enzyme and the target enzyme is very high (93%). On the basis of the X-ray structure of human CYP2C9, a protein model of CYP11B2 was developed and docking experiments with the title compounds were performed. The biological results revealed highly potent inhibitors of CYP11B2 (IC50 = 4−93 nM). The Z-isomers usually were more active than the corresponding E-isomers. Different inhibitory profiles could be observed:  rather selective inhibitors of CYP11B1, dual inhibitors of both enzymes, and rather selective inhibitors of CYP11B2. The chloro derivative 8b was found to be a highly potent CYP11B2 inhibitor (IC50 = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC50 = 20 nM). This compound could be an interesting lead for further optimization as a therapeutic agent. It also could be used as well as the CYP11B1 selective compounds as a pharmacological tool.

Published
2005

5. Design, Synthesis, and 3D QSAR of Novel Potent and Selective Aromatase Inhibitors

Author

Leonetti, F., Favia, A., Rao, A., Aliano, R., Paluszcak, A., Hartmann, R. W., and Carotti, A.

Abstract

The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17−20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r2 = 0.949, s = 0.216, and q2 = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.

Published
2004

6. Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy

Author

Clement, O. O., Freeman, C. M., Hartmann, R. W., Handratta, V. D., Vasaitis, T. S., Brodie, A. M. H., and Njar, V. C. O.

Abstract

We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17α-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3β-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads.

Published
2003

7. Synthesis and Evaluation of 2‘-Substituted 4-(4‘-Carboxy- or 4‘-carboxymethylbenzylidene)-N-acylpiperidines: Highly Potent and in Vivo Active Steroid 5α-Reductase Type 2 Inhibitors

Author

Picard, F., Barassin, S., Mokhtarian, A., and Hartmann, R. W.

Abstract

Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4‘-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5α-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC50 values:  15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.

Published
2002
Full Text
View/download PDF

8. A New Class of Nonsteroidal Aromatase Inhibitors:  Design and Synthesis of Chromone and Xanthone Derivatives and Inhibition of the P450 Enzymes Aromatase and 17α-Hydroxylase/C17,20-Lyase

Author

Recanatini, M., Bisi, A., Cavalli, A., Belluti, F., Gobbi, S., Rampa, A., Valenti, P., Palzer, M., Palusczak, A., and Hartmann, R. W.

Abstract

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site − a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO2, Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair − were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1β,2β-3H]testosterone as the labeled substrate. All the compounds were also tested on 17α-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC50 values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g−i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC50 values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.

Published
2001

9. Synthesis and Evaluation of 17-Aliphatic Heterocycle-Substituted Steroidal Inhibitors of 17α-Hydroxylase/C17−20-Lyase (P450 17)

Author

Hartmann, R. W., Hector, M., Wachall, B. G., Palusczak, A., Palzer, M., Huch, V., and Veith, M.

Abstract

In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17β-position of anstrost-5-en-3β-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC50 rat:  0.21 μM, Ki = 3 nM; IC50 human:  0.54 μM, Ki = 8 nM), 5 (IC50 rat:  0.43 μM, Ki = 7 nM; IC50 human:  0.29 μM, Ki = 4 nM), and 8 (21R:21S = 1:1; IC50 rat:  0.53 μM, Ki = 9 nM; IC50 human:  0.40 μM, Ki = 6 nM) which were more potent than the reference ketoconazole (IC50 rat:  67 μM; IC50 human: 0.74 μM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA2, and 5α-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.

Published
2000

10. Synthesis and Evaluation of Novel Steroidal Oxime Inhibitors of P450 17 (17α-Hydroxylase/C17−20-Lyase) and 5α-Reductase Types 1 and 2

Author

Hartmann, R. W., Hector, M., Haidar, S., Ehmer, P. B., Reichert, W., and Jose, J.

Abstract

17α-Hydroxylase/C17−20-lyase (P450 17, CYP 17) and 5α-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17−20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5,17(20)-dien-3β-ol (9) showing Ki values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5α-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5α-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA2. Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9−11 strongly inhibited P450 17 being coexpressed with NADPH−P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5α-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.

Published
2000

11. 1-Imidazolyl(alkyl)-Substituted Di- and Tetrahydroquinolines and Analogues:  Syntheses and Evaluation of Dual Inhibitors of Thromboxane A<INF>2</INF> Synthase and Aromatase

Author

Jacobs, C., Frotscher, M., Dannhardt, G., and Hartmann, R. W.

Abstract

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A2 synthase (P450 TxA2) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA2:  IC50 = 0.29 μM; P450 arom:  IC50 = 0.50 μM) and its 5,6-saturated analogue 30 (P450 TxA2:  IC50 = 0.68 μM; P450 arom:  IC50 = 0.38 μM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben:  IC50 = 1.1 μM; aminoglutethimide:  IC50 = 18.5 μM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB2 concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB2 serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben:  60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25 μM). Compound 31 did not affect cyclooxygenase and lipoxygenase.

Published
2000

12. Tetrahydronaphthalenes:  Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Author

Wachter, G. A., Hartmann, R. W., Sergejew, T., Grun, G. L., and Ledergerber, D.

Abstract

In search of new leads for selective inhibition of estrogen and androgen biosynthesis, respectively, heterocyclic substituted 2-(arylmethylene)-1-tetralones (1−4, 9−17), 2-(arylhydroxymethyl)-1-tetralones (5−8), exo-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalenes (18−24), and 3-alkyl substituted 4,5-dihydronaphtho[1,2-c]pyrazoles (25−27) were synthesized and tested for inhibitory activity toward four steroidogenic enzymes, P450 arom, P450 17, P450 18, and P450 scc, as well as another P450 enzyme, thromboxane A2 (TXA2) synthase. The test compounds inhibited human placental P450 arom, showing a wide range of inhibitory potencies. (Z)-4-Imidazolyl compound 17 was the most potent inhibitor, with a relative potency (rp) of 110 [rp of aminoglutethimide (AG) ≡ 1, rp of fadrozole = 359]. A competitive type of inhibition was shown by the (E)-4-imidazolyl compound 16 (rp = 71). On the other hand some of these compounds inhibited rat testicular P450 17. Maximum activity was shown by the 3-pyridyl compound 20 (rp = 10, rp of ketoconazole ≡ 1). 20 was the only compound which exhibited a marked inhibition of TXA2 synthase (IC50 = 14.5 μM; IC50 of dazoxiben = 1.1 μM). Regarding selectivity toward the steroidogenic enzymes, compound 16 was relatively selective toward P450 arom, whereas compound 20 was relatively selective toward P450 17. (P450 arom:  Km testosterone = 42 nM, Ki 16 = 33 nM, Ki 20 = 3 μM. P450 17:  Km progesterone = 7 μM, Ki 16 = 9 μM, Ki 20 = 80 nM). 17 and 24 were not selective since they showed strong inhibition of P450 arom (Ki 17 = 26 nM, Ki 24 = 0.12 μM) and P450 17 (Ki 17 = 0.7 μM, Ki 24 = 0.11 μM).

Published
1996

13. A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase.

Author

Recanatini M, Bisi A, Cavalli A, Belluti F, Gobbi S, Rampa A, Valenti P, Palzer M, Palusczak A, and Hartmann RW

Subjects
Chromones chemistry, Chromones pharmacology, Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, In Vitro Techniques, Male, Microsomes drug effects, Microsomes enzymology, Models, Molecular, Placenta ultrastructure, Structure-Activity Relationship, Testis ultrastructure, Xanthenes chemistry, Xanthenes pharmacology, Aromatase Inhibitors, Chromones chemical synthesis, Enzyme Inhibitors chemical synthesis, Steroid 17-alpha-Hydroxylase antagonists & inhibitors, Xanthenes chemical synthesis, Xanthones
Abstract

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.

Published
2001
Full Text
View/download PDF

14. Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17).

Author

Hartmann RW, Hector M, Wachall BG, Palusczak A, Palzer M, Huch V, and Veith M

Subjects
Androstenols chemistry, Androstenols pharmacology, Animals, Chromatography, High Pressure Liquid, Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Imines chemistry, Imines pharmacology, In Vitro Techniques, Male, Microsomes enzymology, Pregnenolone analogs & derivatives, Pregnenolone chemistry, Pregnenolone pharmacology, Radioimmunoassay, Rats, Rats, Sprague-Dawley, Spectrophotometry, Ultraviolet, Stereoisomerism, Structure-Activity Relationship, Testis ultrastructure, Testosterone blood, Androstenols chemical synthesis, Enzyme Inhibitors chemical synthesis, Imines chemical synthesis, Pregnenolone chemical synthesis, Steroid 17-alpha-Hydroxylase antagonists & inhibitors
Abstract

In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.

Published
2000
Full Text
View/download PDF

15. Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2.

Author

Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, and Jose J

Subjects
3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics, Animals, Cell Line, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Escherichia coli cytology, Escherichia coli drug effects, Escherichia coli enzymology, Humans, Male, Microsomes drug effects, Microsomes enzymology, Oximes chemistry, Oximes pharmacology, Pregnenolone chemistry, Pregnenolone pharmacology, Progesterone chemistry, Progesterone pharmacology, Rats, Rats, Sprague-Dawley, Steroid 17-alpha-Hydroxylase genetics, Testis ultrastructure, Testosterone blood, 5-alpha Reductase Inhibitors, Enzyme Inhibitors chemical synthesis, Oximes chemical synthesis, Pregnenolone analogs & derivatives, Pregnenolone chemical synthesis, Progesterone analogs & derivatives, Progesterone chemical synthesis, Steroid 17-alpha-Hydroxylase antagonists & inhibitors
Abstract

17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.

Published
2000
Full Text
View/download PDF

16. Pyridyl-substituted tetrahydrocyclopropa[a]naphthalenes: highly active and selective inhibitors of P450 arom.

Author

Hartmann RW, Bayer H, Grün G, Sergejew T, Bartz U, and Mitrenga M

Subjects
Adrenal Glands drug effects, Adrenal Glands enzymology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cattle, Female, Humans, Liver drug effects, Liver enzymology, Male, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental pathology, Naphthalenes chemistry, Naphthalenes therapeutic use, Ovary drug effects, Ovary enzymology, Placenta drug effects, Placenta enzymology, Rats, Testis drug effects, Testis enzymology, Antineoplastic Agents pharmacology, Aromatase Inhibitors, Naphthalenes pharmacology, Pyridines chemistry
Abstract

The synthesis and biological evaluation of substituted exo-1-(4-pyridyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene s as inhibitors of estrogen biosynthesis is described [H (1); 4-OCH3 (2); 5-OCH3 (3); 6-OCH3 (4); 1-CH3, 6-OCH3 (5); 4-OCH3, 7-Br (6); 6-OCH3, 5-Br (7); 4-OH (8); 5-OH (9); 6-OH (10)]. The synthetic key step--the formation of the cyclopropyl ring--was accomplished using the conditions of a modified Wolff-Kishner reduction (N2H5OH/KOH; delta T) and yielded exclusively the exo-configurated diastereomers. The racemic compounds 1-10 showed an inhibition of human placental aromatase (P450 arom) exhibiting relative potencies (rp) from 3.7 to 303 (compounds 8 and 4, respectively; rp of aminoglutethimide (AG) identical to 1, fadrozole = 359). The enantiomers of 4 and 7 were separated by LPLC on tribenzoyl cellulose and by crystallization of the diastereomeric tartrates (4). (1aS,2S,7bS)-(+)-4 (absolute configuration determined by X-ray crystallographic analysis) is the active P450 arom inhibiting enantiomer of 4 and shows a rp value of 617. Compound 4 is a reversible inhibitor showing a competitive type of inhibition and a type II difference spectrum. In vitro 4 influenced other steroidogenic P450 enzymes either not at all (bovine adrenal P450 scc) or only marginally (rat testicular P450 17, bovine adrenal P450 18). In ACTH-stimulated rat adrenal tissue, 4 was less active, inhibiting corticosterone and aldosterone formation compared to AG and fadrozole, respectively. In vivo 4 was not superior to AG as far as the inhibition of the uterotrophic activity of androstenedione (juvenile SD rats) and the reduction of the plasma estradiol concentration (pregnant mares' serum gonadotropin-primed SD rats) are concerned. Compound 4 shows marked antitumor activity in the dimethylbenzanthracene-induced mammary carcinoma of the SD rat: in the postmenopausal model it is at least as active as AG; in the premenopausal experiment it is clearly superior to AG. No induction of hepatic P450 enzymes was observed in the latter experiment. The rp value of 4 toward rat ovarian P450 arom, i.e., 23 (rp of AG identical to 1), is markedly decreased compared to the human enzyme (rp value of 303). From this fact it must be concluded that 4 should be more active in the human than in the rat.

Published
1995
Full Text
View/download PDF

17. Aromatase inhibitors. Syntheses and structure-activity studies of novel pyridyl-substituted indanones, indans, and tetralins.

Author

Hartmann RW, Bayer H, and Grün G

Subjects
Androstenedione pharmacology, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use, Aromatase metabolism, Cattle, Female, Humans, Indans pharmacology, Mammary Neoplasms, Experimental chemically induced, Mammary Neoplasms, Experimental drug therapy, Microsomes enzymology, Molecular Structure, Organ Size drug effects, Placenta enzymology, Placenta ultrastructure, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Testosterone metabolism, Tetrahydronaphthalenes pharmacology, Tetrahydronaphthalenes therapeutic use, Uterus anatomy & histology, Aromatase Inhibitors, Indans chemical synthesis, Indans chemistry, Tetrahydronaphthalenes chemical synthesis
Abstract

The (E)-2-(4-pyridylmethylene)-1-indanones(E)-1-(E)-5[(E)-1,H;(E)-2,4- OCH3; (E)-3,5-OCH3; (E)-4,4-OH;(E)-5,5-OH] were obtained by aldol condensation of the corresponding 1-indanones with 4-pyridinecarboxaldehyde, and in case of the OH compound (E)-4 subsequent ether cleavage of (E)-2. The synthesis of the (Z)-isomers (Z)-1-(Z)-3[(Z)-1,H;(Z)-2,4-OCH3; (Z)-3,5-OCH3] was accomplished by UV irradiation of the corresponding (E)-isomers. Catalytic hydrogenation of (E)-1-(E)-3 gave the 2-(4-pyridylmethyl)-1-indanones 6-8 (6, H; 7,4-OCH3; 8,5-OCH3). The 2-(4-pyridylmethyl)-substituted indans 11-13 (11,H; 12,4-OCH3; 13,5-OCH3) and the tetralins 16-19 (16,H;17,5-OCH3;18,6-OCH3;19,7-OCH3) were obtained by reduction of the corresponding ketones using N2H4/KOH. The 2-(4-pyridylmethyl)-substituted indanones 9 (4-OH) and 10 (5-OH), indans 14 (4-OH) and 15 (5-OH), and tetralins 20-22 (20,5-OH; 21,6-OH; 22,7-OH) were synthesized by ether cleavage of the corresponding OCH3 compounds. All compounds showed inhibition of human placental aromatase exhibiting relative potencies from 0.9 [(E)-4] to 163 [18; aminoglutethimide (AG) potency identical to 1]. Compounds 13 and 18 showed competitive type of inhibition and a type II difference spectrum, indicating the interaction of the pyridyl-N with the central Fe(III) ion of the cytochrome P450 heme component.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1994
Full Text
View/download PDF

18. Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones.

Author

Hartmann RW, Batzl C, Pongratz TM, and Mannschreck A

Subjects
Aminoglutethimide pharmacology, Cholesterol Side-Chain Cleavage Enzyme antagonists & inhibitors, Chromatography, High Pressure Liquid, Circular Dichroism, Crystallization, Female, Humans, Molecular Conformation, Piperidones chemistry, Piperidones pharmacology, Placenta enzymology, Stereoisomerism, Aromatase Inhibitors, Piperidones chemical synthesis
Abstract

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.

Published
1992
Full Text
View/download PDF

19. New aromatase inhibitors. Synthesis and biological activity of pyridyl-substituted tetralone derivatives.

Author

Bayer H, Batzl C, Hartmann RW, and Mannschreck A

Subjects
Animals, Chromatography, High Pressure Liquid, Female, Humans, Lyases antagonists & inhibitors, Magnetic Resonance Spectroscopy, Mammary Neoplasms, Experimental drug therapy, Mice, Ovary drug effects, Ovary metabolism, Placenta enzymology, Pregnancy, Pyridines chemical synthesis, Rats, Tetrahydronaphthalenes chemical synthesis, Aromatase Inhibitors, Pyridines pharmacology, Tetrahydronaphthalenes pharmacology
Abstract

The (E)-2-(4-pyridylmethylene)-1-tetralones 1-7 (1, H; 2, 5-OCH3; 3, 6-OCH3; 4, 7-OCH3; 5, 5-OH; 6, 6-OH; 7, 7-OH) were obtained by aldol condensation of the corresponding 1-tetralones with 4-pyridinecarboxaldehyde, and in the case of the OH compounds 5 and 7 subsequent ether cleavage of the OCH3-substituted 2-(4-pyridylmethylene)-1-tetralones. Catalytic hydrogenation of 1-4 gave the 2-(4-pyridylmethyl)-1-tetralones 8-11 (8, H; 9, 5-OCH3; 10, 6-OCH3; 11, 7-OCH3). Subsequent ether cleavage of 9-11 led to the corresponding OH compounds 12-14 (12, 5-OH; 13, 6-OH; 14, 7-OH). The enantiomers of 11 and 12 were separated semipreparatively by HPLC on triacetylcellulose. All compounds (1-14) showed an inhibition of human placental aromatase exhibiting relative potencies from 2.2 to 213 [compounds 6 and (+)-12, respectively; aromatase inhibitory potency of aminoglutethimide (AG) = 1]. The compounds exhibited no or only a weak inhibition of desmolase [cholesterol side chain cleavage enzyme; maximum activity shown by 12, 23% inhibition (25 microM); AG, 53% inhibition (25 microM)]. In vivo, however, the compounds were not superior to AG as far as the reduction of the plasma estradiol concentration and the mammary carcinoma (MC) inhibiting properties are concerned (PMSG-primed SD rats as well as DMBA-induced MC of the SD rat, pre- and postmenopausal experiments, and the transplantable MXT-MC of the BD2F1 mouse). This is due to a fast decrease of the plasma E2 concentration inhibiting effect as could be shown by a kinetic experiment. In addition, select compounds inhibited rat ovarian aromatase much less than human placental aromatase (12, factor of 10). Estrogenic effects as a cause for the poor in vivo activity of the test compounds could be excluded, since they did not show affinity for the estrogen receptor.

Published
1991
Full Text
View/download PDF

20. Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)piperidine-2,6-diones.

Author

Hartmann RW and Batzl C

Subjects
Adrenal Glands enzymology, Alkylation, Animals, Cattle, Crystallization, Estrogens biosynthesis, Female, Humans, Kinetics, Lyases metabolism, Ovariectomy, Placenta enzymology, Pregnancy, Rats, Rats, Inbred Strains, Aromatase Inhibitors, Mammary Neoplasms, Experimental enzymology
Abstract

The synthesis and biological evaluation of 3-alkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones as inhibitors of estrogen biosynthesis are described [H (1), methyl (2), ethyl (3), n-propyl (4), isopropyl (5), n-butyl (6), isobutyl (7), sec-butyl (8), n-pentyl (9), isopentyl (10), 2-methylbutyl (11), sec-pentyl (12), n-hexyl (13), n-heptyl (14)]. In vitro compounds 4-14 showed a stronger inhibition of human placental aromatase compared to aminoglutethimide (AG, compound 3), which recently has become used for the treatment of hormone-dependent breast cancer. The most active derivative, compound 10, showed a 93-fold stronger inhibition than AG. With the exception of 5, 7, and 8, all other compounds exhibited similar or decreased inhibition of bovine adrenal desmolase compared to AG. Compounds 4 and 6-12 showed a stronger inhibition of the plasma estradiol concentration of pregnant mare serum gonadotropin (PMSG) primed Sprague-Dawley (SD) rats compared to the parent compound. Compounds 4, 6-8, 10, and 12 inhibited the testosterone-stimulated tumor growth of ovariectomized 9,10-dimethyl-1,2-benzanthracene (DMBA) tumor-bearing SD rats more strongly than AG. Being stronger and more selective inhibitors of the estrogen biosynthesis than AG, some of the newly developed derivatives of AG might be better candidates for the treatment of the hormone-dependent human breast cancer.

Published
1986
Full Text
View/download PDF

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

Author

Hartmann RW, Buchborn H, Kranzfelder G, Schönenberger H, and Bogden A

Subjects
Animals, Antineoplastic Agents therapeutic use, Cell Line, Dose-Response Relationship, Drug, Estrogen Antagonists therapeutic use, Female, Hexestrol chemical synthesis, Hexestrol therapeutic use, Humans, Mice, Mice, Inbred Strains, Rats, Rats, Inbred Strains, Uterus drug effects, Antineoplastic Agents chemical synthesis, Estrogen Antagonists chemical synthesis, Hexestrol analogs & derivatives, Mammary Neoplasms, Experimental drug therapy
Abstract

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.

Published
1981
Full Text
View/download PDF

22. 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.

Author

Hartmann RW, Heindl A, and Schönenberger H

Subjects
Aging, Animals, Binding, Competitive, Cattle, Cytosol metabolism, Estradiol metabolism, Female, Hexestrol chemical synthesis, Hexestrol pharmacology, Indicators and Reagents, Mice, Mice, Inbred Strains, Receptors, Estradiol, Receptors, Estrogen drug effects, Structure-Activity Relationship, Uterus drug effects, Uterus growth & development, Uterus metabolism, Estradiol Congeners chemical synthesis, Hexestrol analogs & derivatives, Receptors, Estrogen metabolism
Abstract

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).

Published
1984
Full Text
View/download PDF

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

Author

Hartmann RW, Kranzfelder G, von Angerer E, and Schönenberger H

Subjects
Animals, Cattle, Estradiol metabolism, Estradiol Congeners chemical synthesis, Estrogen Antagonists therapeutic use, Ethane chemical synthesis, Ethane pharmacology, Female, In Vitro Techniques, Mice, Organ Size drug effects, Rats, Receptors, Estrogen metabolism, Uterus drug effects, Estrogen Antagonists chemical synthesis, Ethane analogs & derivatives, Mammary Neoplasms, Experimental drug therapy
Abstract

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).

Published
1980
Full Text
View/download PDF

24. 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.

Author

Hartmann RW, Heindl A, Schneider MR, and Schönenberger H

Subjects
9,10-Dimethyl-1,2-benzanthracene, Animals, Binding, Competitive, Cattle, Estrogen Antagonists chemical synthesis, Estrogens, Non-Steroidal chemical synthesis, Female, Fluorine, Hexestrol chemical synthesis, Hexestrol metabolism, Hexestrol pharmacology, In Vitro Techniques, Mammary Neoplasms, Experimental chemically induced, Mice, Neoplasm Transplantation, Neoplasms, Hormone-Dependent drug therapy, Receptors, Estradiol metabolism, Structure-Activity Relationship, Uterus drug effects, Antineoplastic Agents chemical synthesis, Hexestrol analogs & derivatives, Mammary Neoplasms, Experimental drug therapy
Abstract

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.

Published
1986
Full Text
View/download PDF

25. 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.

Author

Hartmann RW, Heindl A, Schwarz W, and Schönenberger H

Subjects
Animals, Binding, Competitive, Cattle, Estradiol metabolism, Female, Hexestrol chemical synthesis, Hexestrol therapeutic use, Hexestrol toxicity, Mammary Neoplasms, Experimental drug therapy, Mice, Organ Size drug effects, Rats, Rats, Inbred Strains, Receptors, Estradiol, Uterus metabolism, Antineoplastic Agents chemical synthesis, Estrogen Antagonists chemical synthesis, Hexestrol analogs & derivatives, Receptors, Estrogen metabolism
Abstract

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.

Published
1984
Full Text
View/download PDF

26. 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.

Author

Hartmann RW, Schwarz W, Heindl A, and Schönenberger H

Subjects
Animals, Binding, Competitive, Cattle, Chemical Phenomena, Chemistry, Estradiol metabolism, Female, Hexestrol metabolism, Hexestrol pharmacology, Hexestrol therapeutic use, Mice, Rats, Structure-Activity Relationship, Uterus drug effects, Uterus growth & development, Uterus metabolism, Estrogen Antagonists chemical synthesis, Hexestrol analogs & derivatives, Mammary Neoplasms, Experimental drug therapy, Receptors, Estrogen metabolism
Abstract

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.

Published
1985
Full Text
View/download PDF

27. 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.

Author

Hartmann RW, Schwarz W, and Schönenberger H

Subjects
Animals, Female, Hexestrol chemical synthesis, Hexestrol metabolism, Mice, Structure-Activity Relationship, Hexestrol analogs & derivatives, Receptors, Estrogen metabolism
Abstract

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).

Published
1983
Full Text
View/download PDF

28. Influence of alkyl chain ramification on estradiol receptor binding affinity and intrinsic activity of 1,2-dialkylated 1,2-bis(4- or 3-hydroxyphenyl)ethane estrogens and antiestrogens.

Author

Hartmann RW

Subjects
Animals, Binding, Competitive, Cattle, Chemical Phenomena, Chemistry, Female, Hexestrol chemical synthesis, Hexestrol metabolism, Mice, Structure-Activity Relationship, Uterus drug effects, Uterus metabolism, Estrogen Antagonists metabolism, Hexestrol analogs & derivatives, Receptors, Estradiol metabolism, Receptors, Estrogen metabolism
Abstract

The influence of a symmetrical introduction of CH3 substituents in the alpha or beta positions of the 1,2-dialkyl-1,2-bis(4-hydroxyphenyl)ethane estrogens hexestrol (ethyl, HES) and octestrol (n-propyl, OCES) [isopropyl (1), tert-butyl (2), sec-butyl (3), isobutyl (4)] and the 1,2-dialkyl-1,2-bis(3-hydroxyphenyl)ethane antiestrogens metahexestrol (ethyl, MetaHES) and metaoctestrol (n-propyl, MetaOCES) [isopropyl (5), tert-butyl (6), sec-butyl (7), isobutyl (8)] on estradiol receptor (E2R) binding affinity and intrinsic activity is described. The synthesis of compounds 1-8 was accomplished by reductive coupling of (a) the corresponding alpha-alkylbenzyl alcohols with TiCl3/LiAlH4 and separation of the meso diastereoisomers (compounds 2-4, 7, and 8), (b) alpha-tert-butyl-3-methoxybenzyl chloride with CoCl2/EtMgCl and isolation of the meso configurated isomer (6), and (c) the isopropyl phenyl ketones with TiCl4/Zn and subsequent hydrogenation of the corresponding cis-hex-3-enes (compounds 1 and 5). The binding affinity of 1-8 to the calf uterine E2R was measured relative to that of [3H]E2 by a competitive binding assay. Compounds 1 and 5 showed relative binding affinity (RBA) values exceeding those of HES and MetaHES, respectively. All other derivatives showed RBA values smaller than the corresponding parent compounds. The intrinsic activity was monitored in terms of uterotrophic and antiuterotrophic activity. It is striking that the introduction of a CH3 group in the alpha positions of MetaHES and MetaOCES led to compounds with full intrinsic activity (5-7), i.e., estrogens without antiestrogenic properties. No correlation between E2R binding affinity and intrinsic activity was found.

Published
1986
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results