- Synthesis, characterization and antitumor activities of some steroidal derivatives with side chain of 17-hydrazone aromatic heterocycle
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Here a series of dehydroepiandrosterone-17-hydrazone and estrone-17-hydrazone derivatives possessing various aromatic heterocycle structures in 17-side chain of their steroidal nucleus were synthesized and their structures were evaluated. The antiproliferative activity of synthesized compounds against some cancer cells was investigated. The results have demonstrated that some dehydroepiandrosterone-17-hydrazone derivatives show distinct antiproliferative activity against some cancer cells through inducing cancer cell apoptosis, and compound 8 with a quinoline structure in 17-side chain displays excellent antiproliferative activity in vitro against SGC 7901 cancer cell (human gastric carcinoma) with an IC50 value of 1 μM. In addition, estrone-17-hydrazone derivatives having a key feature of indole group in the structure showed a special obvious cytotoxicity against HeLa cells, but almost inactive against other cells. The information obtained from the studies is valuable for the design of novel steroidal chemotherapeutic drugs.
- Cui, Jianguo,Liu, Liang,Zhao, Dandan,Gan, Chunfang,Huang, Xin,Xiao, Qi,Qi, Binbin,Yang, Lei,Huang, Yanmin
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- Intramolecular sensitization within steroids: Excited-state interaction of C-17 α and β carbon-bromine bonds with a C-6 carbonyl group
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The synthesis, photochemistry, and photophysics of 17α-bromo-3α -(triphenylsilyloxy)-5α-androstan-6-one (1) and 17β-bromo-3β -(triphenylsilyloxy)-5α-androstan-6-one (2) have been studied in aqueous tetrahydrofuran. The 17α-bromo isomer gives evidence (red
- Li, Wen-Shan,Torun, Lokman,Morrison, Harry
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Read Online
- Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents
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A series of isatin-dehydroepiandrosterone hybrids were synthesised via a convenient condensation procedure, and which were evaluated for their potential anticancer activities. The preliminary assays indicated that some of the newly obtained compounds exhi
- Ke, Shaoyong,Shi, Liqiao,Yang, Ziwen
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- Synthetic method of abiraterone acetate and intermediate thereof (by machine translation)
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The invention relates to a synthesis method of abiraterone acetate and a dragon intermediate thereof. In the synthesis method of abiraterone acetate intermediate, a compound of formula (I), a chloro reagent and a base are chlorinated to obtain the abiraterone acetate intermediate of formula (II). The mass ratio of the compound of the formula (I) to the base is 1: (1.5 -3). The structure of the compound of formula (I) and abiraterone acetate is as follows. To the synthesis method, the occurrence probability of side reactions in the chlorination reaction process can be reduced while the high reaction activity is maintained, so that the yield and purity of the abiraterone acetate intermediate can be improved, and the process is simple. (by machine translation)
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Paragraph 0093-0095; 0102-0128
(2021/01/04)
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- Dimerization androst compound and its preparation method, pharmaceutical composition and application
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Dimeric androstane type compounds shown as the formula (I) are disclosed. Definitions of R1 and R2 are described in the specification. A preparing method, a pharmaceutical composition and applications of the dimeric androstane type compounds are further disclosed.
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Paragraph 0060; 0062
(2018/04/20)
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- A method for preparing abiraterone acetate (by machine translation)
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The invention relates to a method for preparing abiraterone acetate, the method is to dehydrogenation epandrosterone as raw materials, with hydrazine hydrate, iodine response, to obtain 17-iodo-androst -5,16-diene -3 β-ol, then the under the catalysis of palladium benzene phosphine base43 with 3-pyridine zinc halide occurs arab League bit dragon Negishi coupling reaction, the final with acetyl chloride or acetic anhydride esterification, to obtain the target product abiraterone acetate. (by machine translation)
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Paragraph 0026; 0027
(2017/02/09)
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- Compound with anti-tumor activity and application of compound
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The invention discloses an amino-acid-oriented steroid small peptide compound with anti-tumor activity.The structure of the compound is shown in the general formula I.Corresponding hydrazone and oxime are synthesized with dehydroepiandrosterone (DHEA), DHEA and an amino acid derivative are then condensed, and the compound is obtained.The compound has a remarkable inhibiting effect on growth of tumor cells especially human hepatoma cells, human lung cancer cells and human melanoma cells, and can serve as an active ingredient for anti-tumor medicine to be applied to prevention and treatment of cancer.
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Paragraph 0030; 0031; 0032
(2016/10/10)
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- Dehydro epandrosterone aromatic aldehyde azine steroid compound and its synthetic method and application in the preparation of antineoplastic
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The invention relates to a dehydroepiandrosterone aromatic aldehyde azine steroidal compound with an azine structure. The chemical structural formula is as shown by dehydroepiandrosterone acetone azine (1), dehydroepiandrosterone benzaldehyde azine (2), dehydroepiandrosterone-3-pyridylaldehyde azine (3), dehydroepiandrosterone-3-thiophenecarboxaldehyde azine (4), dehydroepiandrosterone-3-hydroxybenzaldehyde azine (5), dehydroepiandrosterone-2-naphthaldehyde azine (6), dehydroepiandrosterone-4-quinolinecarboxaldehyde azine (7) and dehydroepiandrosterone-6-methoxy-naphthaldehyde azine (8) described in the specification. Experiments prove that the dehydroepiandrosterone aromatic aldehyde azine steroidal compound has an obvious inhibitory effect on various tumor cell strains, and can be applied to preparation of drugs for treating cancers.
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Paragraph 0025-0026
(2017/02/28)
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- A-ring modified steroidal azoles retaining similar potent and slowly reversible CYP17A1 inhibition as abiraterone
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Abiraterone acetate is a potent inhibitor of human cytochrome P450c17 (CYP17A1, 17α-hydroxylase/17,20-lyase) and is clinically used in combination with prednisone for the treatment of castration-resistant prostate cancer. Although many studies have documented the potency of abiraterone (Abi) in a variety of in vitro and in vivo systems for several species, the exact potency of Abi for human CYP17A1 enzyme has not yet been determined, and the structural requirements for high-potency steroidal azole inhibitors are not established. We synthesized 4 Abi analogs differing in the A-B ring substitution patterns: 3α-hydroxy-Δ4-Abi (13), 3-keto- Δ4-Abi (11), 3-keto-5α-Abi (6), and 3α-hydroxy- 5α-Abi (5). We measured the spectral binding constants (Ks) using purified and modified human CYP17A1 along with the determination constants (Ki) applying a native human CYP17A1 enzyme in yeast microsomes for these compounds as well as for ketoconazole. For Abi, 3-keto- Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi, the type 2 spectral changes gave the best fit for a quadratic equation, since in these experiments Ks values were 0.1-2.6 nM, much lower than that for ketoconazole and 3α-hydroxy-Δ4-Abi (Ks values were 140 and 1660 nM, respectively). Inhibition experiments showed mixed inhibition patterns with Ki values of 7-80 nM. Abi dissociation from the CYP17A1-Abi complex was incomplete and slow; the t1/2 for dissociation was 1.8 h, with 55% of complex remaining after 5 h. We conclude that Abi and the 3 related steroidal azoles (3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi), which also mimic natural substrates, are extraordinarily potent inhibitors of human CYP17A1, whereas the 3α-hydroxy-Δ4-Abi is moderately potent and comparable to ketoconazole.
- Garrido, Mariana,Peng, Hwei-Ming,Yoshimoto, Francis K.,Upadhyay, Sunil K.,Bratoeff, Eugene,Auchus, Richard J.
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- SYNTHESIS OF ABIRATERONE AND RELATED COMPOUNDS
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The present invention relates to processes for obtaining abiraterone and derivatives thereof, such as abiraterone acetate, by means of a Suzuki coupling through a steroid borate of general formula (IV) or a C—C coupling through a steroid hydrazone of general formula (II), as well as to intermediates useful in said processes.
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Paragraph 0181; 0182
(2014/02/15)
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- PROCESS FOR THE PREPARATION OF (3β)-17-(3-PYRIDINYL)ANDROSTA-5,16-DIEN-3-YL ACETATE AND POLYMORPH THEREOF
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The present invention relates to a process for the preparation of (3β)-17-(3- pyridinyl)androsta-5,16-dien-3-yl acetate compound of formula- 1. The present invention also relates to a novel polymorph of compound of formula- 1 and process for its preparation.
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Page/Page column 18
(2014/12/12)
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- SYNTHESIS OF ABIRATERONE AND RELATED COMPOUNDS
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The present invention relates to processesfor obtaining abirateroneand derivatives thereof, such as abiraterone acetate, by means of a Suzuki coupling through a steroid borate of general formula (IV) or a C-C coupling through a steroid hydrazone of general formula (II), as well as to intermediates useful in said processes.
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Page/Page column 28
(2013/03/28)
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- N-substituted piperazinopyridylsteroid derivatives as abiraterone analogues inhibit growth and induce pro-apoptosis in human hormone-independent prostate cancer cell lines
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Nine new 17-(piperazin-1-yl)pyridin-5-yl)steroids as abiraterone analogues were synthesized. Compounds 5d and 5g showed selective activities against 17α-hydroxylase/C17,20-lyase (CYP17A1) and aromatase (CYP19), respectively. IC50 values of 5d were 5.09 and >50 μm, whereas these values for 5g were >50 μm and 7.40 μm, respectively, for CYP17A1 and CYP19. Molecular modelling highlighted that the inhibitor designed to bind cytochrome P450 haem iron is a necessary condition but not the only rationale to explain inhibitory activity. These abiraterone analogues were then evaluated on hormone-independent prostate cancer cell lines DU-145 and PC-3 and on hormone-dependent breast and prostate cancer cell lines MCF-7 and LNCaP, respectively. Compounds 5e, 5g and 5i have showed potent activities only on hormone-independent prostate cancer cell lines DU-145 and PC-3 with 60-85% inhibition of both cell viability and growth at 10 nm with pro-apoptotic mechanism as illustrated in PC-3 cells by DNA ladder assay and Western blotting of Bax, Casp-3 and its substrate, the poly (ADP-ribose) polymerase. We conclude that hybrid heterocycle steroids could be good lead compounds in the drug design especially against hormone-independent prostate cancer. Three derivatives showed potent activities only on hormone-independent prostate cancer cell lines DU-145 and PC-3 with 60-85% inhibition of both cell viability and growth at 10 nm with pro-apoptotic mechanism.
- Brossard, Dominique,Zhang, Ying,Haider, Shozeb M.,Sgobba, Miriam,Khalid, Mohamed,Legay, Remi,Duterque-Coquillaud, Martine,Galera, Philippe,Rault, Sylvain,Dallemagne, Patrick,Moslemi, Safa,El Kihel, Laila
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p. 620 - 629
(2013/11/06)
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- NOVEL PRODRUGS OF STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS
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Prodrugs of C-17-heterocyclic- steroidal drugs providing improved oral bioavailability and phamacokinetics are described. The drugs are inhibitors of human CYP 17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR), and are useful for the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions, such as human prostate cancer, breast cancer, and prostate hyperplasia. The disclosure describes methods of synthesizing and using the prodrugs in cancer therapy.
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Page/Page column 15; 16
(2010/08/18)
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- NOVEL PRODRUGS OF C-17-HETEROARYL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS: SYNTHESIS, IN VITRO BIOLOGICAL ACTIVITIES, PHARMACOKINETICS AND ANTITUMOR ACTIVITY
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Prodrugs of steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods of synthesis are also described, whereby a prodrug group is substituted for a functional group at A ring portion of the ABC ring structure of the steroid. Suitable prodrug groups include amino acid groups, succinate groups, phosphate groups, or sulfamate groups. The prodrugs of the disclosed compounds allow for improved oral bioavailability of the compounds that are inhibitors of human CYP 17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds and the corresponding prodrugs are useful for the treatment of conditions such as human prostate cancer, breast cancer, and prostate hyperplasia.
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Page/Page column 11; 35
(2009/10/22)
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- One-pot/four-step/palladium-catalyzed synthesis of indole derivatives: The combination of heterogeneous and homogeneous systems
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One-pot, four-step syntheses of indoles using both solid-supported heterogeneous and homogeneous palladium catalysts and reagents were carried out. Such a combination of these two-phase catalysts and reagents causes a dramatic increase in yield, and it is a simple process. The presented methodology is effective for four-step reactions to provide various functionalized indoles.
- Sakai, Hayato,Tsutsumi, Ken,Morimoto, Tsumoru,Kakiuchia, Kiyomi
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supporting information; experimental part
p. 2498 - 2502
(2009/08/14)
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- NOVEL C-17-HETEROARYL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS: SYNTHESIS, IN VITRO BIOLOGICAL ACTIVITIES, PHARMACOKINETICS AND ANTITUMOR ACTIVITY
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Described are steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods for their synthesis are also described, which include methods having a step of nucleophilic vinylic "addition-elimination" substitution reaction of 3F-acetoxy-17-chloro-16-formylandrosta-5,16-diene or analogs thereof and benzoazole or pyrimidinoazole nucleophiles and methods having a palladium catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3F-ol or analogs thereof with tributylstannyl diazines. The compounds are potent inhibitors of human CYP 17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds are useful for the treatment of human prostate cancer. "
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Page/Page column 31; 45
(2008/06/13)
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- Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: Synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model
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New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic "addition-elimination" substitution reaction of 3β-acetoxy-17- chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3β-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3β-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (5, code named VN/124-1), 3β-hydroxy-17-(5 1-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl) androsta-4,16-dien-3-one (6), with IC50 values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing binding of 3H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists. The cell growth studies showed that 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC 50 values in the low micromolar range (i.e., 10 μM). Their inhibitory potencies were comparable to that of casodex but remarkably superior to that of flutamide. The pharmacokinetics of compounds 5 and 6 in mice were investigated. Following s.c. administration of 50 mg/kg of 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 min, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively), and neither was detectable at 8 h. Remarkably, compound 5 was rapidly converted into a metabolite tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer.
- Handratta, Venkatesh D.,Vasaitis, Tadas S.,Njar, Vincent C. O.,Gediya, Lalji K.,Kataria, Ritesh,Chopra, Pankaj,Newman Jr., Donnell,Farquhar, Rena,Guo, Zhiyong,Qiu, Yun,Brodie, Angela M. H.
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p. 2972 - 2984
(2007/10/03)
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- Syntheses of Δ16-17(Trialkylstannyl)steroids from 17-Ketosteroids. II
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The oxidation of the hydrazones of 17-ketosteroids by iodine yields Δ16-17-iodosteroids (2, 4).Starting with 2 or 8 (the 3-tetrahydropyranylether of 4) and lithium(tributyl)stannate, Δ16-17(tributylstannyl)steroids (5, 9) are synthesized.The reaction is catalyzed by electronrich complexes of nickel and palladium.In the course of side reactions Δ16-olefines (6, 10) and the "dimers" 7 and 11, the products of a cross coupling of the Δ16-17-iodosteroids, and the Δ16-17-tributylstannylsteroids are obtained.The mechanisms of these side-reaction and the influence of the solvent (THF, HMPA) are discussed.The tributylstannylsteroids are to be used as intermediates for the syntheses of steroid hormones from the 17-ketosteroids.
- Schweder, Bernd,Uhlig, Egon
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p. 223 - 228
(2007/10/02)
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- STUDIES ON THE OXIDATION OF HYDRAZONES WITH IODINE AND WITH PHENYLSELENENYL BROMIDE IN THE PRESENCE OF STRONG ORGANIC BASES; AN IMPROVED PROCEDURE FOR THE SYNTHESIS OF VINYL IODIDES AND PHENYL-VINYL SELENIDES
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The oxidation of hydrazones by iodine in the presence of strong organic bases (guanidines) has been studied.Improved yields of vinyl iodides can be obtained by inverse addition using dry solvents and with a final heating period where appropriate.The reaction has been extended to various dihydrazones with interesting results.In complementary studies hydrazones have been oxidized by phenylselenyl bromide in the presence of strong organic bases to give the corresponding phenyl vinyl selenides in good yield.
- Barton, Derek H. R.,Bashiardes, George,Fourrey, Jan-Louis
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p. 147 - 162
(2007/10/02)
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