32138-69-5Relevant articles and documents
N-substituted piperazinopyridylsteroid derivatives as abiraterone analogues inhibit growth and induce pro-apoptosis in human hormone-independent prostate cancer cell lines
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
, p. 620 - 629 (2013)
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.
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
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.
, p. 2972 - 2984 (2005)
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.
17-Iodoandrosta-5,16-dien-3beta-ol preparation method
-
Paragraph 0020; 0021; 0022; 0023; 0024, (2019/01/23)
The invention discloses a 17-Iodoandrosta-5,16-dien-3beta-ol preparation method. The 17-Iodoandrosta-5,16-dien-3beta-ol preparation method takes dehydroeopiandrosterone-17-hydrazone, trichloroisocyanuric acid (TCCA), tetramethyl guanidine (TMG) and elemental iodine as raw materials to react at 0-90 DEG C with existence of solvent and then performing treatment to obtain the 17-Iodoandrosta-5,16-dien-3beta-ol. According to the 17-Iodoandrosta-5,16-dien-3beta-ol preparation method, the TCCA serves as oxidizing agent, the elemental iodine serves as iodinating agent, an oxidizing iodination methodis applied to iodinating dehydroeopiandrosterone-17-hydrazone, so that, compared with traditional methods, the 17-Iodoandrosta-5,16-dien-3beta-ol preparation method can reduce consumption of the elemental iodine by a half and is simple in operation of reaction processes and easy to control, thereby having a good industrialized application prospect.
A method for preparing abiraterone acetate (by machine translation)
-
, (2017/02/09)
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)
