- Heterocyclic steroids: Synthesis of androsteno[17,16-d]pyrazoles and androsteno[17,16-e]pyrimidines
-
The Vilsmeier-Haack reaction of 3β-acetoxyandost-5-en-17-one (1) with phosphorous oxychloride and dimethylformamide gave 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2). Reaction of 2 with hydrazine and phenylhydrazine provided substituted 5-androst
- Siddiqui,Rao,Maimirani,Siddiqui
-
-
Read Online
- Access to steroidal pyridazines via modified thiohydrazides
-
An approach to steroids annulated with pyridazines via cascade imination/electrocyclization of chlorovinyl aldehydes with oxamic acid thiohydrazides is disclosed. A mechanistic rationalization was performed using real-time 1H NMR spectroscopy a
- Volkova,Antonov,Komkov,Scherbakov,Shashkov,Menchikov,Chernoburova,Zavarzin
-
-
Read Online
- Discovery and development of galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer
-
In our effort to discover potent and specific inhibitors of 17α-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes the biosynthesis of androgens from progestins, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate which modulates multiple targets in the androgen receptor (AR) signaling pathway. This drug annotation summarizes the mechanisms of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for galeterone, which has successfully completed phase II clinical development in men with castration resistant (advanced) prostate cancer (CRPC). Phase III clinical studies in CRPC patients are scheduled to begin in early 2015.
- Njar, Vincent C. O.,Brodie, Angela M. H.
-
-
Read Online
- Synthesis of Heterocyclic-Substituted Novel Hydroxysteroids with Regioselective and Stereoselective Reactions
-
Polyhydroxy steroids bearing the 3β,5α,6β-trihydroxy pattern were synthesized from different heterocyclic-substituted unsaturated steroid by an easy and simple method with high yields. The endocyclic double bond of thiophene-substituted and quinoline-substituted steroids were converted to the trans-diaxial diol by the regioselective and stereoselective reactions with m-chloroperoxybenzoic acid in the basic medium.
- Kolo, Abubakar Mohammed,?pek, Emine,?apan, ?rfan,Servi, Süleyman
-
-
Read Online
- Novel steride androgen receptor antagonist, preparation method and medical application thereof
-
The invention relates to the field of medicinal chemistry, in particular to a series of steride androgen receptor antagonist, and a preparation method and medical application thereof, and particularlyrelates to a medicine for treating androgen receptor related diseases, such as cell proliferation depending on androgens, hirsutism, acnes and androgen alopecia. The general molecular formula of thecompound is shown as follows, and groups in the formula are specified in the specification.
- -
-
Paragraph 0016; 0018; 0019; 0021; 0022; 0024; 0054-0056
(2018/04/21)
-
- PROCESS FOR THE PREPARATION OF GALETERONE
-
A process for the synthesis of 3β-hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene is described, a compound also known as Galeterone and used in the treatment of prostate cancer, having the formula (I) given below.
- -
-
Page/Page column 11-12
(2018/01/17)
-
- Efficient synthesis of 4- And 5-substituted 2-aminopyrimidines by coupling of β-Chlorovinyl Aldehydes and Guanidines
-
A general, practical, and simple synthesis of functionalized 2-aminopyrimidines starting from β-chlorovinyl aldehydes and amidines is reported. In the presence of potassium carbonate, various ketones have been efficiently transformed into the pyrimidine derivatives by a two-step sequence involving the Vilsmeier-Haack reaction followed by a condensation reaction with guanidines. The protocol is distinguished by operational simplicity, inexpensive reagents, and functional-group tolerance. In many cases, pure solid products can be obtained in high to excellent yields without using column chromatography. The synthetic value of the method was demonstrated by the efficient synthesis of steroidal pyrimidines and a precursor of the antitumor agents Imatinib and Mocetinostat.
- Komendantova, Anna S.,Komkov, Alexander V.,Volkova, Yulia A.,Zavarzin, Igor V.
-
supporting information
p. 4247 - 4254
(2018/08/24)
-
- Synthesis and biological evaluation of esters of 16-formyl-17-methoxy-dehydroepiandrosterone derivatives as inhibitors of 5α-reductase type 2
-
In this study, we investigated the in vitro effect of 16-formyl-17-methoxy dehydroepiandrosterone derivatives on the activity of 5α-reductase type 2 (5α-R2) obtained from human prostate. The activity of different concentrations of these derivatives was de
- Sánchez-Márquez, Araceli,Arellano, Yazmín,Bratoeff, Eugene,Heuze, Yvonne,Córdova, Karen,Nieves, Gladys,Soriano, Juan,Cabeza, Marisa
-
p. 1170 - 1176
(2016/10/09)
-
- Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17 β-hydroxysteroid dehydrogenase
-
The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy.
- Cabeza, Marisa,Posada, Alejandro,Snchez-Mrquez, Araceli,Heuze, Yvonne,Moreno, Isabel,Soriano, Juan,Garrido, Mariana,Corts, Francisco,Bratoeff, Eugene
-
-
- Novel dehydroepiandrosterone benzimidazolyl derivatives as 5α-reductase isozymes inhibitors
-
5α-R isozymes (types 1 and 2) play an important role in prostate gland development because they are responsible for intraprostatic dihydrotestosterone (DHT) levels when the physiological serum testosterone (T) concentration is low. In this study, we synthesized seven novel dehydroepiandrosterone derivatives with benzimidazol moiety at C-17, and determined their effect on the activity of 5α-reductase types 1 and 2. The derivatives with an aliphatic ester at C-3 of the dehydroepiandrosterone scaffold induced specific inhibition of 5α-R1 activity, whereas those with a cycloaliphatic ester (cyclopropyl, cyclobutyl, or cyclopentyl ring) or an alcohol group at C-3 inhibited the activity of both isozymes. Derivatives with a cyclohexyl or cycloheptyl ester at C-3 showed no inhibitory activity. In pharmacological experiments, derivatives with esters having an alcohol or the aliphatic group or one of the three smaller cycloaliphatic rings at C-3 decreased the diameter of male hamster flank organs, with the cyclobutyl and cyclopentyl esters exhibiting higher effect. With exception of the cyclobutyl and cyclopentyl esters, these compounds reduced the weight of the prostate and seminal vesicles.
- Arellano, Yazmín,Bratoeff, Eugene,Segura, Tania,Mendoza, Maria Eugenia,Sánchez-Márquez, Araceli,Medina, Yesica,Heuze, Yvonne,Soriano, Juan,Cabeza, Marisa
-
p. 908 - 914
(2016/10/09)
-
- A Straightforward Approach toward Multifunctionalized Pyridazines via Imination/Electrocyclization
-
A facile synthesis of functionalized 3-carbamide pyridazines starting from readily available chlorovinyl aldehydes and oxamic acid thiohydrazides via cascade imination/electrocyclization is reported. In the presence of p-toluenesulfuric acid, various ketones have been efficiently incorporated into the pyridazine derivatives through a two-step sequence involving a Vilsmeier-Haack reaction and imination. The synthetic value of this method has been demonstrated by efficient synthesis of steroidal pyridazines.
- Komkov, Alexander V.,Komendantova, Anna S.,Menchikov, Leonid G.,Chernoburova, Elena I.,Volkova, Yulia A.,Zavarzin, Igor V.
-
supporting information
p. 3734 - 3737
(2015/08/18)
-
- Microwave-Assisted Synthesis of Fused and Substituted 2-Aminopyridines from β-Halo α,β-Unsaturated Aldehydes
-
2-Aminopyridines were synthesized from β-halo α,β-unsaturated aldehydes by a microwave-assisted Knoevenagel reaction. The β-halo-α,β-unsaturated aldehydes were, in turn, efficiently synthesized from the corresponding ketones by a Vilsmeier formylation reaction. The protocol was used to synthesize several novel steroidal and nonsteroidal fused 2-aminopyridine derivatives.
- Gogoi, Junali,Gogoi, Pranjal,Goswami, Limi,Boruah, Romesh C.
-
p. 1905 - 1912
(2015/06/30)
-
- One-pot stereoselective synthesis of (Z)-β-ketoenamides from β-halo α,β-unsaturated aldehydes
-
A series of steroidal and non-steroidal β-ketoenamides have been synthesized from their corresponding β-halo α,β-unsaturated aldehydes. This synthetic methodology provides efficient access to (Z)-β-ketoenamides. The structures of these products have been
- Gogoi, Junali,Gogoi, Pranjal,Boruah, Romesh C.
-
supporting information
p. 3483 - 3490
(2014/06/09)
-
- ANDROGEN RECEPTOR DOWN-REGULATING AGENTS AND USES THEREOF
-
The present disclosure provides the design and synthesis of novel steroidal compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant. The compounds are potential agents for the treatment of all forms of prostate cancer and other diseases that depend on functional AR.
- -
-
Paragraph 0071
(2014/10/04)
-
- Effect of dehydroepiandrosterone derivatives on the activity of 5α-reductase isoenzymes and on cancer cell line PC-3
-
It is well known that testosterone (T) under the influence of 5α-reductase enzyme is converted to dihydrotestosterone (DHT), which causes androgen-dependent diseases. The aim of this study was to synthesize new dehydroepiandrosterone derivatives (3a-e, 4a
- Bratoeff, Eugene,Garrido, Mariana,Ramrez-Apan, Teresa,Heuze, Yvonne,Snchez, Araceli,Soriano, Juan,Cabeza, Marisa
-
p. 6233 - 6241
(2015/01/09)
-
- Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer
-
As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl) androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5, 16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5, 16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.
- Purushottamachar, Puranik,Godbole, Abhijit M.,Gediya, Lalji K.,Martin, Marlena S.,Vasaitis, Tadas S.,Kwegyir-Afful, Andrew K.,Ramalingam, Senthilmurugan,Ates-Alagoz, Zeynep,Njar, Vincent C. O.
-
p. 4880 - 4898
(2013/07/26)
-
- Design and synthesis of novel D-ring fused steroidal heterocycles
-
Using dehydroepiandrosterone as the starting material, we have synthesized a series of steroid analogs possessing a D-ring fused with heterocycles which are pyridine, imidazo [2,1-b]thiazoles or substituted thiazole imines. All the final structures are first reported and identified by NMR and MS spectroscopys, the yields of these products are moderate to good and the reaction conditions are mild. The cytotoxicity of the synthesized compounds against EC-109(human esophageal carcinoma), EC-9706(human esophageal carcinoma), MGC-803(human gastric carcinoma) were investigated.
- Zhang, Bao-Le,Zhang, En,Pang, Lu-Ping,Song, Li-Xing,Li, Ya-Fei,Yu, Bin,Liu, Hong-Min
-
p. 1200 - 1208
(2013/10/22)
-
- CYP11B, CYP17, AND/OR CYP21 INHIBITORS
-
Provided herein are inhibitors of CYP11B, CYP17, and/or CYP21 enzymes of Formula (Z), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), or (XVII). Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat androgen-dependent diseases, disorders and conditions. Formula (Z)
- -
-
Page/Page column 181
(2012/06/30)
-
- Synthesis of a novel class of steroidal tetrazolo[1,5-a]pyridines via intramolecular 1,3-dipolar cycloadditions
-
A facile synthesis of a novel class of steroidal A/B/D-ring annulated tetrazolo[1,5-a]pyridine derivatives has been accomplished via intramolecular 1,3-dipolar cycloaddition reaction of azide with nitrile in aprotic solvent. The synthesis of D-ring annulated tetrazolo[1,5-a]pyridine in alcohol showed incorporation of an alcohol molecule into the heterocyclic system.
- Gogoi, Junali,Bezbaruah, Pranjal,Saikia, Pallabi,Goswami, Jonalee,Gogoi, Pranjal,Boruah, Romesh Chandra
-
scheme or table
p. 1497 - 1500
(2012/03/27)
-
- The reaction of azoles with 17-chloro-16-formylandrosta-5,16-dien-3β- yl-acetate: Synthesis and structural elucidation of novel 16-azolylmethylene-17- oxoandrostanes
-
The synthesis and structural elucidation, by 1D and 2D NMR and X-ray diffraction techniques, of novel E/Z 16-azolylmethylene-17-oxoandrostanes 2-9 prepared from the Vilsmeier-Hack reaction product 17-chloro-16-formylandrosta-5, 16-dien-3β-yl acetate 1 is reported. The reaction proceeds with pyrrole and pyrrole-alike nitrogen heterocycles such as 7-azaindole, indole, and 3-methylindole, in DMF, at 80 °C, in the presence of K2CO 3, and allowed the attachment of privileged heterocyclic moieties, through the nitrogen atom to the steroid core at C16 via a methine carbon bridge, which is unprecedented in the literature and of potential synthetic and biological interest. Considerations on the possible reaction mechanism are included. All the synthesized compounds are new and are currently being tested for biological activities.
- Moreira, Vania M.,Salvador, Jorge A.R.,Beja, Ana Matos,Paix?o, José A.
-
scheme or table
p. 582 - 587
(2011/05/14)
-
- NOVEL PRODRUGS OF C-17-HETEROARYL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS: SYNTHESIS, IN VITRO BIOLOGICAL ACTIVITIES, PHARMACOKINETICS AND ANTITUMOR ACTIVITY
-
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.
- -
-
Page/Page column 10; 34
(2009/10/22)
-
- Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors
-
A series of novel 1H- and 2H-indazole derivatives of the commercially available dehydroepiandrosterone acetate have been synthesized and tested for inhibition of human cytochrome 17α-hydroxylase-C17,20-lyase (CYP17), androgen receptor (AR) binding affinity, and cytotoxic potential against three prostate cancer (PC) cell lines.
- Moreira, Vania M.A.,Vasaitis, Tadas S.,Njar, Vincent C.O.,Salvador, Jorge A.R.
-
p. 939 - 948
(2008/03/18)
-
- NOVEL C-17-HETEROARYL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS: SYNTHESIS, IN VITRO BIOLOGICAL ACTIVITIES, PHARMACOKINETICS AND ANTITUMOR ACTIVITY
-
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. "
- -
-
Page/Page column 26; 44
(2008/06/13)
-
- The preparation and crystal structure of 16-acetylandrosta-4,16-dien-3-one
-
Dehydroisoandrosterone was formylated at C-16 by a Vilsmeier reaction and by condensation with methyl formate. The product of the latter reaction was converted to 16-acetylandrosta-4,16-dien-3-one and its X-ray crystal structure was determined.
- Dalmaris, John,Hanson, James R.,Hitchcock, Peter B.,Kiran, Ismail
-
p. 150 - 152
(2007/10/03)
-
- 17-azolyl steroids useful as androgen synthesis inhibitors
-
Androgen synthesis inhibitors, as well as methods for the use of the same to reduce plasma levels of testosterone and/or dyhydrotestosterone, and to treat prostate cancer and benign prostatic hypertrophy, are disclosed.
- -
-
-
- Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17α- hydroxylase-C17,20-lyase (P450(17α)): Potential agents for the treatment of prostate cancer
-
A new synthetic route to a variety of novel Δ16-17-azolyl steroids is described: it involves the nucleophilic vinylic 'addition-elimination' substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel Δ16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17α). They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17α). The most potent compounds are 3β-hydroxy-17-(1H-imidazol-1-yl)androsta- 5,16-diene (17), 3β-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with K(i) values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (K(i) = 38 nM). Spectroscopic studies with a modified form of human P450(17α) indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17α) inhibitors (27-29) are also powerful inhibitors of steroid 5α-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
- Njar, Vincent C. O.,Kato, Katsuya,Nnane, Ivo P.,Grigoryev, Dmitry N.,Long, Brian J.,Brodie, Angela M. H.
-
p. 902 - 912
(2007/10/03)
-