- The effects of DHEA, 3β-hydroxy-5α-androstane-6,17-dione, and 7-amino-DHEA analogues on short term and long term memory in the mouse
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Neurosteroids have been reported to modulate memory processes in rodents. Three analogues of dehydroepiandrosterone (DHEA), two of them previously described (7β-aminoDHEA and 7β-amino-17-ethylenedioxy-DHEA), and a new one (3β-hydroxy-5α-androstane-6,17-dione) were synthesized, and their effects were evaluated on memory. This study examined their effects on long term and short term memory in male (6 weeks old) NMRI mice in comparison with the reference drug. Long term memory was assessed using the passive avoidance task and short term memory (spatial working memory) using the spontaneous alternation task in a Y maze. Moreover, the effects of DHEA and its analogues on spontaneous locomotion were measured. In all tests, DHEA and analogues were injected at three equimolar doses (0.300-1.350-6.075 μM/kg). DHEA and its three analogues administered immediately post-training at the highest doses (6.075 μM/kg, s.c.) improved retention in passive avoidance test. Without effect per se in the spatial working memory task, the four compounds failed to reverse scopolamine (1 mg/kg, i.p.)-induced deficit in spontaneous alternation. These data suggested an action of DHEA and analogues in consolidation of long term memory particularly when emotional components are implied. Moreover, data indicated that pharmacological modulation of DHEA as performed in this study provides derivatives giving the same mnemonic profile than reference molecule.
- Bazin, Marc-Antoine,Kihel, La?la El,Boulouard, Michel,Bou?t, Valentine,Rault, Sylvain
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Read Online
- Facile synthesis of novel D-ring modified steroidal dienamides via rearrangement of 2H-pyrans
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A simple and practical method for synthesis of the D-ring modified steroidal dienamides (4a-k) from the steroidal α,α-dicyanoalkene 3 and aldehydes via vinylogous aldol reaction was first reported. By using NaOAc as a base, the desired products were obtained in moderate to good yields in ethanol under mild conditions. All the synthesized steroidal dienamides are new and are currently being evaluated for their biological activities.
- Yu, Bin,Zhang, En,Sun, Xiao-Nan,Ren, Jing-Li,Fang, Yuan,Zhang, Bao-Le,Yu, De-Quan,Liu, Hong-Min
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Read Online
- 86. Lipase-catalysed regioselective deacetylation of androstane derivatives
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A series of acetoxy derivatives of androstane was deacetylated in organic solvents by several lipases. The most satisfactory results were obtained with lipase from Candida cylindracea (CCL) and Candida antarctica (CAL). In some derivatives, CCL and CAL showed an overwhelming regioselectivity towards the removal of the 3β - or the 17β-acetyl group (see Table 2). Three new steroid derivatives were obtained through this approach. A hypothetical rationale for the behaviour of these enzymes is given.
- Baldessari, Alicia,Bruttomesso, Andrea C.,Gros, Eduardo G.
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Read Online
- Synthesis of steroid compounds containing a pyridazinone moiety
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The reaction of 17-ketosteroids and glyoxylic acid followed by treatment with hydrazine affords steroid compounds condensed in the 16 and 17 positions with the pyridazin-3(2H)- one ring.
- Cherkalin,Kolobov,Chernoburova,Shchetinina,Zavarzin
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Read Online
- Design, synthesis, brine shrimp lethality and cytotoxicity of some novel 17a-aza-D-homo-androster-17-one derivatives
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In this work, twenty-eight novel 17a-aza-D-homo-androster-17-one derivatives, which divided into two categories, were synthesized with commercial available starting material (dehydroepiandrosterone) via oximation reaction, Beckmann rearrangement, hydroxyl protection, N-alkylation and deprotection. All compounds were characterized by 1H NMR, 13C NMR and HRMS. The structure of 14 g was also identified by X-ray single crystal diffraction. The bioactivities, brine shrimp toxicity and cytotoxicity, of all derivatives were tested. The results indicated that compounds 11 h, 11i, 11 m, 11 s, 14 b and 14 g exhibited excellent toxicity against brine shrimp with LC50 values ranging from 5.34 to 16.89 μg/mL, and compounds 11 s and 14 g displayed significant cytotoxicity against HT29 cells and A549 cells with IC50 values of 9.70 μM and 8.85 μM, respectively. Structure-activity relationships are discussed based on the results obtained from our research, and some important determinants for further modification of steroids towards the development of novel drug candidates are identified.
- Hong, Dongfeng,Ma, Yiming,Song, Siyao,Li, Na,Wang, Junru
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supporting information
p. 3985 - 3991
(2020/04/27)
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- Preparation method of 3beta-acetoxyandrostane-5-ene-17-one
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The invention discloses a method for preparationof 3beta-acetoxyandrostane-5-ene-17-one by utilizing androstane-3-beta hydroxyl-17-one-6alpha-boric acid separated from androstane-5-ene-17-one chemicalreduction reaction solid waste through the four steps of reactions of esterification, oxidation, sulfonic acid esterification and elimination. According to the method, the steroid solid waste can beeffectively recycled, the synthesis method is efficient, the reaction conditions are mild, and the cost of related products is correspondingly reduced while the environmental pollution is reduced.
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Paragraph 0019; 0056-0057
(2021/02/24)
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- Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
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Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.
- Cheong, Eleanor Jing Yi,Nair, Pramod C.,Neo, Rebecca Wan Yi,Tu, Ho Thanh,Lin, Fu,Chiong, Edmund,Esuvaranathan, Kesavan,Fan, Hao,Szmulewitz, Russell Z.,Peer, Cody J.,Figg, William D.,Chai, Christina Li Lin,Miners, John O.,Chan, Eric Chun Yong
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supporting information
p. 438 - 451
(2020/09/04)
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- Novel steroidal 5α,8α-endoperoxide derivatives with semicarbazone/thiosemicarbazone side-chain as apoptotic inducers through an intrinsic apoptosis pathway: Design, synthesis and biological studies
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A series of novel steroidal 5α,8α-endoperoxide derivatives bearing semicarbazone (7a-g) or thiosemicarbazone (7h-k) side chain were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, HCT-116, MCF-7, and A549) using the MTT assay in vitro. The results showed that compound 7j exhibited significant cytotoxic activity against HepG2 cells (IC50 = 3.52 μM), being more potent than ergosterol peroxide. Further cellular mechanism studies in HepG2 cells indicated that compound 7j triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential (MMP), which was associated with up-regulation of Bax, down-regulation of Bcl-2, activation levels of the caspase cascade, and formation of reactive oxygen species (ROS). The above findings indicated that compound 7j may be used as a promising skeleton for antitumor agents with improved efficacy.
- Bu, Ming,Liu, Lei,Ma, Liwei,Wang, Haijun,Wang, Jing,Zhang, Song
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- Synthesis and cytotoxic evaluation of steroidal endoperoxide derivatives with hydrazide side chain as anticancer agents
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– A series of novel steroidal 5α,8α-endoperoxide derivatives bearing hydrazide side chain were synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, HCT-116, MCF-7, and A549) using the MTT assay in vitro. The results showed that compound 6k exhibited significant cytotoxic activity against HepG2 cells (IC50 = 5.60 μM). Further cellular mechanism studies in HepG2 cells indicated that compound 6k triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential (MMP) which was associated with up-regulation of Bax, down-regulation of Bcl-2.
- Bu, Ming,Han, Yinglong,Li, Hongling,Lin, Yu,Ma, Yukun,Wang, Haijun,Wang, Jing,Wang, Yongmei
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p. 790 - 801
(2020/07/13)
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- Design, synthesis and biological evaluation of novel 5α, 8α-endoperoxide steroidal derivatives with hybrid side chain as anticancer agents
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A series of novel 5α, 8α-endoperoxide steroidal hybrid derivatives containing isatin or indole substituents on the C-17 side chain were synthesized and characterized. The preliminary anti-proliferative activity of the compounds against HepG2, MCF-7, HT-29 and HeLa cell lines were investigated. Compounds 7g and 7l displayed significant anti-proliferative activity in vitro against HepG2 and Hela cells, with IC50 values lower than 8 μM. Furthermore, the biological functions of 7g were examined by flow cytometry and colony analysis. The results showed that 7g could induce HepG2 cell apoptosis, inhibited cell cycle progression, and colony growth. The studies indicated that structural modification at C-17 position could be a promising launch point for design steroidal anticancer agents.
- Li, Hongling,Wang, Haijun,Wang, Jing,Lin, Yu,Ma, Yukun,Bu, Ming
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- Method for preparing abiraterone acetate intermediate from dehydroepiandrosterone mother liquor
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The synthesis method of the dehydroepiandrosterone acetate, comprises the following steps :A. adding toluene to the ethyl acetate; heating warm water to wash the toluene layer and separating the toluene layer ;B. by suction filtration, to remove the dehydroepiandrosterone acetate product, to obtain dehydroepiandrosterone acetate as crude product of the dehydroepiandrosterone acetate product at a reflux, temperature and refluxing, cooling crystallization; and drying, to obtain the dehydroepiandrosterone acetate crude product to obtain the dehydroepiandrosterone acetate crude product with the dehydroepiandrosterone acetate as crude product at the near-drying, The invention discloses a dehydroepiandrosterone acetate crude product obtained by distillation . The invention, is suitable for dehydroepiandrosterone acetate production,C. The invention, discloses a dehydroepiandrosterone acetate crude product and, a dehydroepiandrosterone acetate crude product obtained, below ≥ 90%, through ≥ 99.0%, suction; filtration of toluene to near. dry, to obtain dehydroepiandrosterone acetate [, ].
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Paragraph 0014; 0015
(2020/03/29)
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- Synthesis and Biological Evaluation of Novel Steroidal 5α,8α-Endoperoxide Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents
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Abstract: Seven new steroidal 5α,8α-endoperoxide derivatives with C-17 aromatic hydrazone side chain were synthesized. Structures of the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometry. Anti-proliferative activities of the synthesized compounds were evaluated in vitro by the MTT method. Among the seven compounds, 5α,8α-epidioxy-17-(4-chloro-benzylidene)-hydrazonoandrost-3β-ol showed the strongest anti-proliferative activity against three human cancer cell lines (MCF-7, HepG2, and SK-Hep1).
- Wang,Bu,Wang,Liu,Zhang
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p. 585 - 590
(2020/01/21)
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- Recycling method of positional isomer in preparation of 3beta-acetoxy-5alpha-chloro-6beta-hydroxyandrost-17-one
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The invention discloses a recycling method for forming 3beta-acetoxyandrost-5-en-17-one by performing a cyclization elimination reaction by utilizing solid waste 3beta-acetoxy-6beta-chloro-5alpha-hydroxyandrost-17-one obtained in the process of an addition reaction of preparing 3beta-acetoxy-5alpha-chloro-6beta-hydroxyandrost-17-one from 3beta-acetyloxyandrost-5-en-17-one as a raw material, and performing a reduction elimination reaction. The method provided by the invention can effectively recover and reuse the by-product obtained in the preparation process of the 3beta-acetoxy-5alpha-chloro-6beta-hydroxyandrost-17-one, and the synthetic method is simple and convenient to operate, has mild reaction conditions, is environmentally friendly, and reduces the production costs of preparing the3beta-acetoxy-5alpha-chloro-6beta-hydroxyandrost-17-one from the 3beta-acetyloxyandrost-5-en-17-one.
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Paragraph 0037; 0038
(2019/07/16)
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- Synthesis of Heterocyclic-Substituted Novel Hydroxysteroids with Regioselective and Stereoselective Reactions
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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
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p. 492 - 497
(2018/01/10)
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- 3beta-hydroxy-5alpha, 8alpha-peroxoandrost-6-en-17-(arring substituted) hydrazone derivative and preparation and application thereof
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The invention discloses a 3beta-hydroxy-5alpha, 8alpha -Peroxyandrost-6-en-17-(aromatic ring substituted) hydrazone derivative, preparation and application thereof, and belongs to the technical fieldof medicine chemistry. The structural formula of the 3beta-hydroxy-5alpha, 8alpha -Peroxyandrost-6-en-17-(aromatic ring substituted) hydrazone derivative is shown in the description, wherein R1 represents -CH3, -F, -Cl, -C(CH3)3, -CN, -OCH3, -OH or -H; R2 represents -OC, -H3, -CF3, or -H. Dehydroepiandrosterone is used as the starting material to prepare 3beta -Acetoxy-5-Androstene-17-ketones, followed by bromination and debromination to obtain 3beta-Hydroxyl-5alpha, 8alpha -Peroxyandrost-6-en-17-a hydrazine intermediate , hydrolysis to reduce hydroxyl groups, and then the light is constructed by 5alpha, 8alpha- peroxy bridge which then reacts with hydrazine hydrate to obtain 3beta-Hydroxyl-5alpha, 8alpha -Peroxyandrost-6-en-17-a hydrazine intermediate, and then reacted with hydrazine hydrate to obtain 3beta-Hydroxyl-5alpha, 8alpha -Peroxyandrost-6-en-17-a hydrazine intermediate, and finally the aldehyde amine condensation reaction is carried out to generate 3beta-hydroxyl-5alpha, 8alpha -Peroxyandrost-6-ene-17-(aromatic ring substituted) hydrazone derivatives. The compound has the effects of preventing and treating cancers such as liver cancer, breast cancer and the like.
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Paragraph 0036; 0038; 0039; 0040
(2018/10/11)
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- 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof
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The invention discloses a 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof, belonging to the technical field of medicinal chemistry. The structural formula of the 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative is as shown in the description, wherein R1 represents -H, -F, -Cl, -Br, -I, -NO2, -OCH3, -OCF3 or -CH3; R2 represents -H, -Cl or -Br. The preparation comprises the following steps: preparing 3beta-acetoxyl-5-androstene-17-ketone by using dehydroepiandrosterone as a raw material; performing bromination reaction and debromination reaction to obtain 3beta-acetoxyl-5,7-diene androstane-17-ketone intermediate, and hydrolyzing to reduce hydroxyl; constructing a 5alpha, 8alpha-peroxide bridge by illuminating; reacting with hydrazine hydrate to prepare 3beta-hydroxyl-5alpha, 8alpha-peroxy-androstane-6-alkene-17-hydrazine intermediate; and finally performing a condensation reaction to generate the 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative. The compound has an effect of preventing and treating cancers such as liver cancer, breast cancer and the like.
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Paragraph 0036; 0038; 0039; 0040
(2018/11/22)
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- Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A "visible Light" Approach
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In our continued effort to address the challenges of selective sp3 C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.
- Bume, Desta Doro,Harry, Stefan Andrew,Pitts, Cody Ross,Lectka, Thomas
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p. 1565 - 1575
(2018/02/09)
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- Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2
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Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.
- Fehl, Charlie,Vogt, Caleb D.,Yadav, Rahul,Li, Kelin,Scott, Emily E.,Aubé, Jeffrey
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p. 4946 - 4960
(2018/06/20)
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- Steroid compound 3-site hydroxyl configuration inversion method
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The invention discloses a steroid compound 3-site hydroxyl configuration inversion method. The method specifically comprises the following steps that (1) a steroid compound containing a 3-site hydroxyl reacts with an acyl chloride compound; (2) the product obtained in the step (1) and a substituting agent are subjected to SN2 nucleophilic substitution reaction under existing of a phase transfer catalyst; and (3) the product obtained in the step (2) is subjected to a hydrolysis reaction. Compared with a Mitsunobu method, the method does not need to use triphenylphosphine and azodiformate pricedhigher, and accordingly the production cost is greatly lowered; meanwhile, a p-nitrobenzoic acid derivative which seriously affects the water environment does not need to be used, and therefore the method is more environmentally friendly. The method adopts cesium acetate/18-crown ether-6 system to conduct 3-site hydroxyl configuration inversion, can remarkably reduce occurrence of side reactions,accordingly a higher reaction yield is obtained, and the method is finally applicable to industrialized production.
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- Synthesis and biological evaluation of novel steroidal 5α,8α-endoperoxide derivatives with aliphatic side-chain as potential anticancer agents
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By inspiration of significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP), a series of novel steroidal 5α,8α-endoperoxide derivatives 5a–d and 14a–f were designed, synthesized, and biologically evaluated for their in vitro anti-proliferative inhibitory and cytotoxic activity. The results revealed that most of these compounds showed moderate-to-excellent anti-proliferative effects against the tested cancer cell lines (i.e. HepG2, SK-Hep1, MDA-MB-231 and MCF-7). Among them, compound 5b and 14d exhibited preferable inhibitory activities (IC50 of 5b and 14d are 8.07 and 9.50?μM against HepG2, respectively). The structure-activity relationships indicated that incorporation the peroxidic bridge to the steroid scaffolds at C-5 and C-8 positions together with the aliphatic side-chain at the C-17 position would provide synergistic effect for the bioactivity.
- Bu, Ming,Cao, Tingting,Li, Hongxia,Guo, Mingzhou,Yang, Burton B.,Zhou, Yue,Zhang, Na,Zeng, Chengchu,Hu, Liming
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- Synthesis and biological evaluation of novel steroidal 5α,8α-epidioxyandrost-6-ene-3β-ol-17-(O-phenylacetamide)oxime derivatives as potential anticancer agents
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Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5α,8α-epidioxyandrost-3β-ol-17-(O-phenylacetamide)oxime derivatives (9a–o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC50??20?μM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure.
- Bu, Ming,Cao, Tingting,Li, Hongxia,Guo, Mingzhou,Yang, Burton B.,Zeng, Chengchu,Zhou, Yue,Zhang, Na,Hu, Liming
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supporting information
p. 3856 - 3861
(2017/07/27)
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- Synthesis and antitumor activities of steroidal 5α,8α-endoperoxide derivatives with side chain of 17-hydrazone aromatic heterocycle
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Here a series of novel 5α,8α-epidioxyandrostan-3β-ol-17-hydrazone derivatives possessing various aromatic heterocycle structures in 17-side chain of their steroidal nucleus were synthesized and characterized. The antiproliferative activity of synthesized compounds against some cancer cells was investigated. The results have demonstrated that compound 8b with quinoline and 8c with indole structure in side chain display excellent anti-proliferative activity in vitro against tested cancer cell lines.
- Bu, Ming,Wang, Yujie,Cao, Tingting,Li, Hongxia,Guo, Mingzhou,Zhou, Yue,Zhang, Na,Zeng, Chengchu,Hu, Liming
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p. 691 - 701
(2017/05/02)
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- Synthesis and antiproliferative activity of 3-aza steroids as 5α-reductase inhibitors
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Background: Dihyrdotestosterone (DHT), the most potent circulating androgen hormone, is produced by stereoselective reduction of testosterone (T) under catalysis of NADPH dependent enzyme steroid 5α-reductase (5AR). The DHT production is related to many pathological conditions and endocrine diseases such as Benign Prostatic Hyperplasia (BPH). Many years ago, the use of 5AR inhibitors for the possible control or suppression of DHT formation has become years ago a therapeutic target for the treatment of BPH. During last two decades, several non steroidal and steroidal compounds have been synthesized as reversible and irreversible 5AR inhibitors. Methods: Present study describes the synthesis of 17β-substituted amides of 3-aza-A-homo-4a-androsten-4-one starting from 16-Dehydropregnelone acetate (16-DPA). The structure of newly synthesized compounds was established on the basis of TLC and various spectroscopic studies and compounds were subjected for their in vitro cytotoxicity studies using prostate cancer cell lines PC-3. Results and Conclusion: Synthesized compounds (13a to 13h) showed better cytotoxicity as compared to reference drug and 3-Aza-A-homo-17β-(4-nitrobenzamido)-4a-androsten-4-one (13b) showed an excellent antiproliferative activity as compared to Dutasteride.
- Kaur, Milanpreet,Dhingra, Richa,Bhardwaj,Dhingra, Neelima
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p. 1335 - 1346
(2017/11/14)
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- Development of a Chemoenzymatic Process for Dehydroepiandrosterone Acetate Synthesis
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Dehydroepiandrosterone (DHEA, 2) is an important endogenous steroid hormone in mammals used in the treatment of a variety of dysfunctions in female and male health,1 as well as an intermediate in the synthesis of steroidal drugs, such as abiraterone acetate which is used for the treatment of prostate cancer.2-4 In this manuscript we describe a novel, concise, and cost-efficient route toward DHEA (2) and DHEA acetate (3) from 4-androstene-3,17-dione (4-AD, 1). Crucial to success was the identification of a ketoreductase from Sphingomonas wittichii for the highly regio- and stereoselective reduction of the C3-carbonyl group of 5-androstene-3,17-dione (5) to the required 3β-alcohol (2, >99% de). The enzyme displayed excellent robustness and solvent stability under high substrate concentrations (up to 150 g/L).
- Fryszkowska, Anna,Peterson, Justine,Davies, Nichola L.,Dewar, Colin,Evans, George,Bycroft, Matthew,Triggs, Neil,Fleming, Toni,Gorantla, Srikanth Sarat Chandra,Hoge, Garrett,Quirmbach, Michael,Timmanna, Upadhya,Reddy Poreddy, Srinivas,Kumar Reddy, D. Naresh,Dahanukar, Vilas,Holt-Tiffin, Karen E.
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p. 1520 - 1528
(2016/08/30)
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- D ring modified steroid β-lactam compound, its preparation process and its application (by machine translation)
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The invention belongs to the technical field of medicinal chemistry and medicine and discloses a steroid beta-lactam compound and a preparation method and application of the steroid beta-lactam compound. The steroid beta-lactam compound is represented by the formula I. In-vitro antineoplastic activity experiments show that the compound has broad-spectrum antineoplastic activity, plays a good role in inhibiting various human cancer cells such as EC-109. MGC-803, GES-1 and U-87, and is suitable for researches on antineoplastic lead compounds or preparation of novel antineoplastic drugs. The synthetic method of the steroid beta-lactam compound is easy and suitable for industrial production.
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Paragraph 0018; 0019; 0020; 0021
(2016/12/01)
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- Green Suzuki coupling reaction for synthesis of abiraterone acetate and its analogues
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An eco-friendly efficient method was developed for the synthesis of abiraterone acetate and analogues in water-PEG-400 (6:1; v/v) at 75°C from various arylboronic acids and 17-(trifluoromethanesulfonyl)oxy-3β-acetoxylandrosta-5,16-diene obtained from the 3-acetate of dehydroepiandrosterone.
- Bian, Xiaoqin,Wang, Lizhong,Liu, Jinliang,Wang, Cunde
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p. 289 - 292
(2016/07/06)
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- ALTERING STEROID METABOLISM FOR TREATMENT OF STEROID-DEPENDENT DISEASE
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A method of treating steroid-dependent disease such as prostate cancer in a subject is described that includes administering a therapeutically effective amount a CYP17A inhibitor and an effective amount of a 5- -reductase inhibitor to the subject.
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Page/Page column 43
(2016/09/26)
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- Synthesis and biological evaluation of D-ring fused 1,2,3-thiadiazole dehydroepiandrosterone derivatives as antitumor agents
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A series of D-ring fused 1,2,3-thiadiazole DHEA derivatives were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. It is amazing that for these compounds, T47D cell line was much more sensitive than other tumor cell lines. The most potent saturated N-heterocyclic derivatives showed similar antitumor effect with the positive control compound ADM (adriamycin) on T47D cells, that was 44–60 folds more potent than the lead compound DHEA. Most compounds with potent antitumor activity displayed low toxicity on normal human fibroblasts (HAF). Especially compound 25 (CH33) showed an IC50 of 0.058 μM on T47D cells and its selectivity index (SI) between HAF and T47D was 364, which was 214 folds better than ADM (SI = 1.7). The apoptosis, colony formation and transwell migration assays of 25 were performed on T47D cell line. The primary mechanism study showed that 25 caused a dose-dependent induction of apoptosis, and induced phosphorylation of EphA2 and EphB3 in T47D cells. The in vivo antitumor effect of 25 was also observed in T47D tumor-bearing mice without obvious toxicity.
- Cui, Hai-Wei,Peng, Shihong,Gu, Xiang-Zhong,Chen, Huang,He, Yuan,Gao, Wei,Lv, Fang,Wang, Jin-Hua,Wang, Yan,Xie, Jia,Liu, Ming-Yao,Yi, Zhengfang,Qiu, Wen-Wei
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p. 126 - 137
(2017/12/26)
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- INHIBITORS OF CYP17A1
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Compounds according to formula I or II are provided. Such compounds are useful in treating cancers, such as leukemia, colon cancer, breast cancer, or prostate cancer by beneficially inhibiting CYP17A1. Pharmaceutical compositions and methods including the compounds are also provided.
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Paragraph 0096
(2016/04/05)
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- Novel dehydroepiandrosterone benzimidazolyl derivatives as 5α-reductase isozymes inhibitors
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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
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p. 908 - 914
(2016/10/09)
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- Regioselective and Stereospecific Copper-Catalyzed Deoxygenation of Epoxides to Alkenes
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Two copper salts (Cu(CF3CO2)2 and IMesCuCl) were identified as earth-abundant, inexpensive, but effective metal catalysts together with diazo malonate for chemo-/regioselective and stereospecific deoxygenation of various epoxides with tolerance of common functional groups (alkene, ketone, ester, p-methoxybenzyl, benzyl, tert-butyldimethylsilyl, and triisopropylsilyl). In particular, the unprecedented regioselectivity allowed for the first time monodeoxygenation of diepoxides to alkenyl epoxides. Density functional theory mechanistic studies showed that the deoxygenation occurred by collapsing the free ylide, unfavoring the possible intuitive pathway via cycloreversion of possible oxetane.
- Yu, Jingxun,Zhou, Yu,Lin, Zhenyang,Tong, Rongbiao
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supporting information
p. 4734 - 4737
(2016/09/28)
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- MnO2/TBHP: A Versatile and User-Friendly Combination of Reagents for the Oxidation of Allylic and Benzylic Methylene Functional Groups
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In the presence of activated MnO2, tert-butyl hydroperoxide (TBHP) in CH2Cl2 is able to oxidize the allylic and benzylic methylene groups of different classes of compounds. I describe a one-pot oxidation protocol based on two sequential steps. In the first step, carried out at low temperature, MnO2 catalyses the oxidation of the methylene group. This is followed by a second step where reaction temperature is increased, allowing MnO2 both to catalyse the decomposition of unreacted TBHP and to oxidize allylic alcohols that could possibly be formed. The proposed oxidation procedure is generally applicable, although its efficiency, regioselectivity, and chemoselectivity are strongly dependent on the structure of the substrate. A simple and user-friendly synthetic procedure for the oxidation of allylic and benzylic methylene groups to the corresponding conjugated carbonyl derivatives is described. The proposed oxidation protocol is based on the combined use of MnO2 and tert-butyl hydroperoxide, and is generally applicable.
- Serra, Stefano
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p. 6472 - 6478
(2015/10/19)
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- PROCESS FOR MAKING THE 17-TRIFLATE INTERMEDIATE OF ABIRATERONE-3-ACETATE
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The present invention relates to a process for making the compound 3β-acetoxy- androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5) and is characterized in that dehydroepiandrosterone-3-acetate of formula (2) is reacted with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.
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Page/Page column 13; 14; 16
(2014/05/24)
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- Protein-binding properties of a designed steroidal lactam compound
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Introducing amide bonds into a steroid nucleus or its side chain may reduce the acute toxicity and enhance the pharmaceutical activity. In this work, a designed steroidal amide compound, named 3β-hydroxy-17-aza-d-homo-5- androsten-17-one (HAAO), was synthesized and identified. The interactions between HAAO and human serum albumin (HSA) were studied by multiple spectroscopic methods and molecular modeling procedures. It was found that HAAO locates in Sudlow's site I in subdomain IIA of HSA molecules, relying on hydrogen bonds and van der Waals power to form HAAO-HSA complexes at ground state. The number of binding sites, binding constants, enthalpy change (ΔHθ), Gibbs free energy change (ΔG θ) and entropy change (ΔSθ) were calculated at different temperatures based on fluorescence quenching theory and classical thermodynamic equation. The percentages content of the HSA's secondary structures in presence of HAAO were detected by circular dichroism (CD) spectra and compared with those in no presence of HAAO. In addition, the experimental results of both binding site and conformational change were further confirmed by molecular modeling investigation, in which more details of the binding were visually unfolded. The information provided by the study may be useful for designing novel chemotherapeutic drugs and be helpful both in the early stages of drug discovery and in clinical practice.
- Zhang, Hua-Xin,Liu
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- Discovery of novel steroidal pyran-oxindole hybrids as cytotoxic agents
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A series of novel steroidal pyran-oxindole hybrids were efficiently synthesized in a single operation through the vinylogous aldol reaction of vinyl malononitrile 3 with substituted isatins involving the construction of C-C and C-O bonds. Some compounds displayed moderate to good cytotoxicity against T24, SMMC-7721, MCF-7 and MGC-803 cells. Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells with the IC50 values of 4.43 and 8.45 μM, respectively. Further mechanism studies indicated that compound 4i induced G2/M arrest and early apoptosis in a concentration- and time-dependent manner.
- Yu, Bin,Qi, Ping-Ping,Shi, Xiao-Jing,Shan, Li-Hong,Yu, De-Quan,Liu, Hong-Min
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- PROCESSES FOR THE PREPARATION OF DEHYDROEPIANDROSTERONE AND ITS INTERMEDIATES
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The present application relates to a regioselective and stereoselective processes for the preparation of dehydroepiandrosterone (DHEA) and processes for its intermediates.
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Page/Page column 21
(2014/12/12)
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- Zinc triflate catalyzed acylation of alcohols, phenols, and thiophenols
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An expedient procedure for the acylation of alcohols, phenols, and thiophenols using catalytic amount of Zn(OTf)2 is described. This procedure is highly suitable for industrial application due to use of less toxic metal as a part of catalyst, short reaction time at ambient temperature, without any racemization of chiral alcohols.
- Kumar, N. Uday,Reddy, B. Sudhakar,Reddy, V. Prabhakar,Bandichhor, Rakeshwar
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supporting information
p. 910 - 912
(2014/02/14)
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- Zinc triflate catalyzed acylation of alcohols, phenols, and thiophenols
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An expedient procedure for the acylation of alcohols, phenols, and thiophenols using catalytic amount of Zn(OTf)2 is described. This procedure is highly suitable for industrial application due to use of less toxic metal as a part of catalyst, short reaction time at ambient temperature, without any racemization of chiral alcohols.
- Uday Kumar,Sudhakar Reddy,Prabhakar Reddy,Bandichhor, Rakeshwar
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supporting information
p. 910 - 912
(2015/02/19)
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- Efficient construction of novel D-ring modified steroidal dienamides and their cytotoxic activities
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Two series of steroidal dienamides 4a-q and 5a-f were designed, synthesized and evaluated for cytotoxic activities against five human cancer cell lines (MGC-803, EC109, PC-3, SMMC-7721 and MCF-7). The protocol developed efficiently achieved the construction of carbon ecarbon double bond and selective conversion of nitrile group into carboxamide in one-pot procedure. Besides, compounds 4a-q and 5a-f showed moderate to excellent cytotoxic activities with the IC 50 values ranging from 0.1 to 40 μM and most of them were more potent than 5-fluorouracil. Particularly, four compounds 4d, 4-, 4q and 5a showed excellent selectivity against MGC-803 with the IC50 values less than 1 mM. Flow cytometry analysis demonstrated that compound 4c caused the cellular early apoptosis and cell cycle arrest in G2/M phase in a concentration-independent manner.
- Yu, Bin,Shi, Xiao-Jing,Ren, Jing-Li,Sun, Xiao-Nan,Qi, Ping-Ping,Fang, Yuan,Ye, Xian-Wei,Wang, Meng-Meng,Wang, Jun-Wei,Zhang, En,Yu, De-Quan,Liu, Hong-Min
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p. 171 - 179
(2013/10/01)
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- Design and synthesis of novel D-ring fused steroidal heterocycles
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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
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p. 1200 - 1208
(2013/10/22)
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- CYP11B, CYP17, AND/OR CYP21 INHIBITORS
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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)
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Page/Page column 180-181
(2012/06/30)
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- 17-Oximino-5-androsten-3β-yl esters: Synthesis, antiproliferative activity, acute toxicity, and effect on serum androgen level
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The 17-oximino-5-androsten-3β-yl esters (10a- 10j) were synthesized from commercially available (25R)- 5-Spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against prostate specific cancer cell line DU-145, acute toxicity, and effect on serum androgen level and were compared with Finasteride used as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data, and biological evaluation for the synthesized compounds are reported. Springer Science+Business Media, LLC 2010.
- Dhingra, Neelima,Bhardwaj, Tilak Raj,Mehta, Neeraj,Mukhopadhyay, Tapas,Kumar, Ashok,Kumar, Manoj
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scheme or table
p. 817 - 825
(2012/05/04)
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- Synthesis, antiproliferative activity, acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives
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A number of 17-oxo-5-androsten-3β-yl esters (9a-9f) and 3β-alkoxy-5-androsten-17-ones (11a-11e) were synthesized from commercially available (25R)-5-spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against the prostate-specific cancer cell line DU-145, acute toxicity and effect on serum androgen levels, and compared with finasteride as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and biological activity of the synthesized compounds are reported.
- Dhingra, Neelima,Bhardwaj,Mehta, Neeraj,Mukhopadhyay, Tapas,Kumar, Ashok,Kumar, Manoj
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scheme or table
p. 1055 - 1063
(2012/07/28)
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- Synthesis and cytotoxicity of 17a-aza-d-homo-androster-17-one derivatives
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A series of 17a-aza-D-homo-andrester-17-one derivatives, bearing hydroxyl, hydroximino, carbonyl and thiosemicarbazido groups at the position-3 or position-6 of steroidal nucleus, were prepared and evaluated in vitro against two human cell lines (Hela (human cervical carcinoma) and SMMC 7404 (human liver carcinoma)). The results showed that these compounds could exhibit a high cytotoxicity to Hela tumor cell line, especially for compounds 8 and 12, the IC50 values are 15.1 and 14.0 nmol/mL, respectively. Our findings could provide new evidence showing the relationship between the chemical structure and biological activity and may be useful for the discovery of new anti-cancer drugs.
- Huang, Yanmin,Cui, Jianguo,Zhong, Zhengguo,Gan, Chunfang,Zhang, Wenyan,Song, Huacan
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scheme or table
p. 3641 - 3643
(2011/08/06)
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- Synthesis, antiproliferative, acute toxicity and assessment of antiandrogenic activities of some newly synthesized steroidal lactams
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The 17-oxo-17a-aza-d-homo-5-androsten-3β-yl esters (13-22) were synthesized from commercially available (25R)-5-spirosten-3β-ol (Diosgenin) (6) as starting material. The synthesized compounds were evaluated for their antiproliferative activity, acute toxicity and effect on serum androgen level and were compared with Finasteride as positive controls. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and pharmacological screening for the synthesized compounds were reported.
- Dhingra, Neelima,Bhardwaj,Mehta, Neeraj,Mukhopadhyay, Tapas,Kumar, Ashok,Kumar, Manoj
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scheme or table
p. 2229 - 2236
(2010/06/16)
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- Esters of dehydroepiandrosterone (DHEA) as probes for the active site of type 3 17β-hydroxysteroid dehydrogenase (17β-HSD3)
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We report the use of steroid-based compounds as probes for the active site of 17β-hydroxysteroid dehydrogenase, in particular, type 3 (17β-HSD3). Results suggest that the compounds were good inhibitors of 17β-HSD3 - a number were extremely potent with respect to the standard compounds used.
- Olusanjo, Moniola S.,Owen, Caroline P.,Ahmed, Sabbir
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experimental part
p. 365 - 369
(2011/11/12)
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- First synthesis of 7α- and 7β-amino-DHEA, dehydroepiandrosterone (DHEA) analogues and preliminary evaluation of their cytotoxicity on Leydig cells and TM4 Sertoli cells
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Efficient syntheses of new DHEA analogues, and their apoptotic and necrotic effects on Leydig cells and TM4 Sertoli cells are described. The key step in the synthetic strategy of 7-amino-DHEA derivatives involves a bromination on C-7 position to give an epimeric mixture of bromides which were substituted by azides and reduced to give 7α- and 7β-amino-3β-hydroxyandrost-5-en-17-ones. No cytotoxic effect induced by apoptosis mechanism was observed on Leydig and TM4 Sertoli cells by treatment with these amino-DHEA analogues. A necrotic effect was induced only in TM4 Sertoli cells. The best activity was obtained with 7α,β-amino-androst-5-en-3β-ol and 7β-amino-3β-hydroxy-androst-5-en-17-one.
- Bazin, Marc-Antoine,Travert, Carine,Carreau, Serge,Rault, Sylvain,Kihel, La?la El
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p. 3152 - 3160
(2008/02/07)
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- Structure-activity relationship study of androstene steroids with respect to local anti-inflammatory activity
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A sex hormone, 37β-acetoxy-17β-hydroxy-androst-5-ene (1) (CAS 1639-43-6), was isolated from aerial parts of Acacia nilotica. This compound is reported to have anti-inflammatory activity. In view of this, considering this molecule as a lead molecule different androstene compounds were synthesized to study their potency and structure-activity relationship with respect to local anti-inflammatory activity. The experiments indicated that 17 ketonic compounds were more active towards inflammation than their oxime analogues. Similarly, for the compounds containing an acetyl group fixed at C-3 position a decreasing trend of activity was observed in the order of ketonic, hydroxyl, oxime and acetyl group, respectively, when these groups are at C-17 position. ECV · Editio Cantor Verlag, Aulendorf.
- Chaubal, Rohini,Mujumdar, Arvind M.,Misar, Ashwini,Deshpande, Vishnu H.,Deshpande, Nirmala R.
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p. 394 - 398
(2007/10/03)
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- Preparation of 3β-acetoxy-17a-oxo-androst-5-ene-7,17-dione, a biologically active impurity isolated from the production of 3β-acetoxyandrost-5-ene-7,17-dione
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An impurity isolated during the kilo-lab preparation of 3β-acetoxyandrost-5-ene-7,17-dione was identified as 3β-acetoxy-17a- oxo-androst-5-ene-7,17-dione. This novel D-ring secosteroid was postulated to be a Baeyer-Villiger oxidation by-product of the preparation reaction. A genuine sample was prepared by the selective peracid-mediated Baeyer-Villiger reaction on 3β-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA acetate), confirming the novel structure.
- Coutts, Lisa D.,DeOrazio, Russell J.,Meckler, Harold
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p. 979 - 985
(2007/10/03)
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- Microwave induced selective enolization of steroidal ketones and efficient acetylation of sterols in semisolid state
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Under microwave irradiation steroidal enones, more specifically, position three carbonyls were efficiently and selectively converted to the corresponding enol acetates in the presence of additional enolizable carbonyl functions at other positions, using acetic anhydride and a catalytic amount of toluene-p-sulfonic acid. Acetylation of hydroxyl groups of the sterols, including those at the hindered positions, was near quantitative. Strictly anhydrous conditions were not a pre-requisite for acetylation and the reaction system easily tolerated up to 10% (v/v) moisture.
- Marwah, Padma,Marwah, Ashok,Lardy, Henry A.
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p. 2273 - 2287
(2007/10/03)
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- Electrostatic catalysis by ionic aggregates: Scope and limitations of Mg(ClO4)2 as acylation catalyst
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Alkali and alkaline earth metal perchlorates exhibit electrostatic catalysis in the activation of anhydrides for the acylation reaction. Perchlorates with higher values of the charge-size function of the metal ion exhibit better catalytic activity following the order Mg(ClO4) 2>Ba(ClO4)2>LiClO4. Acylation of structurally diverse phenols, thiols, alcohols, and amines have been carried out with stoichiometric amounts of anhydride at room temperature under solvent free conditions in the presence of catalytic amount of Mg(ClO4) 2. Sterically hindered and electron deficient phenols are efficiently acylated. Acylation with sterically hindered anhydrides such as iso-butyric, pivalic, and benzoic anhydrides are carried out with phenols and alcohols in excellent yields. Acid-sensitive alcohols are acylated in excellent yields without any competitive side reactions.
- Chakraborti, Asit K.,Sharma, Lalima,Gulhane, Rajesh,Shivani
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p. 7661 - 7668
(2007/10/03)
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