5α-reductase Inhibitory Activity Research Articles

Formulation and Evaluation of Herbal Cream for the Management of Androgenetic Alopecia

The current study aimed to develop a herbal hair cream formulation including plant extracts traditionally used for hair growth, and further research was conducted to understand the hair growth capability better using the 5 alpha reductase inhibitory model. 5 alpha reductases, an enzyme confined to the nuclear membrane, converts testosterone into dihydrotestosterone. The 5 alpha-reductase and its metabolite dihydrotestosterone influence various human disorders, including male pattern baldness, benign prostatic hyperplasia (BPH), and prostate cancer. Finasteride and alfatradiol are examples of synthetic medications; however, because of their negative impacts, researchers are currently focused on creating safer 5α-reductase inhibitors from plants. The hair cream formulation contained 0.5% extracts of Hibiscus rosa sinensis flower, Eclipta alba whole plant, and Solanum nigrum plant berries in a ratio of 1:1:1. Plant extracts used in the formulation were characterized by chemical biomarkers. The cream formulation was developed, and the quality control parameters were examined. Furthermore, the produced formulation's 5α-reductase inhibitory activity was tested using finasteride as a positive control. H. rosa sinensis, E. alba, and S. nigrum extracts, which comprise 0.35% oleanolic acid, 4.65% β-sitosterol, and 31.18% linoleic acid, were used in the formulation. HPTLC data revealed that each 10 gm of cream formulation contains 16.68 ± 0.21 mg of linoleic acid, 3.61 ± 0.18 mg of β-sitosterol and 0.380 ± 0.11 mg oleanolic acid. In-vitro results showed a good 5α-reductase inhibitory potential. The IC50 value of the developed formulation was 85.254 ± 0.888 μg/ml, whereas finasteride (positive control) was 223.039 ± 1.367 ng/ml. Thus, the herbal hair cream composition benefits alopecia therapy by inhibiting the 5α- reductase enzyme. In addition, the formulation might be a potential option for further research into its antiandrogenic properties.

5α-Reductase Inhibitory Potential of <i>Hibiscus rosa sinensis</i>: Effective for the Management of Alopecia

The condition known as male pattern hair loss and benign prostatic hyperplasia are both treated with a family of drugs known as 5 alpha reductase (5α-reductase) inhibitors. This study shows that the flower of Hibiscus rosa sinensis has 5α-reductase inhibitory action that is helpful in the treatment of androgenic diseases. Phytochemical screening was done using petroleum ether, methanol, and water extracts to identify the phytochemical group present. Then, using quercetin as a reference flavonoid component, the Total Flavonoid Content (TFC) was assessed using a colorimetric technique. The 5α-reductase inhibitory activity was evaluated using several extracts and compared to the well-known 5α-reductase inhibitor finasteride. Finally, the inhibition of different extracts to the enzyme was assessed using a biochemical approach to measure the activity of 5α-reductase. It was determined that the IC<sub>50</sub> value of Hibiscus rosa sinensis methanolic extract, 146.048 ± 0.453 (μg/mL) and quercetin (a chemical biomarker of the plant material) 141.426 ± 1.578 (μg/mL), were promising candidates for future investigation into their antiandrogenic activities.

PROCESS VALIDATION OF BETA-SITOSTEROL HAIR GEL FORMULATION AND EVALUATION OF 5 ALPHA REDUCTASE INHIBITION IN VITRO FOR THE TREATMENT OF ANDROGENETIC ALOPECIA

Objective: The present study was aimed to develop topical gel containing β-sitosterol using carbopol 940 as a gelling agent and to investigate 5 alpha reductase (5α-reductase) inhibitory activity of suitable gel formulation and compare it with a commercial product used topically for alopecia. Methods: Three different batches of β-sitosterol hair gel formulation were manufactured and evaluated. Additionally, the 5α-reductase inhibitory activity of the prepared formulation, finasteride as a positive control, was evaluated and compared to the commercial herbal formulation used. Results: According to the analytical findings of three different batches, the gel formulation is good in appearance, homogeneous, and easily spreadable. Based on findings from HPLC and HPTLC, the amount of β-sitosterol in those formulations complies with the label claim. By checking different critical parameters of those batches, we established the manufacturing process method validation and the process reproducibility. In vitro results showed the good 5α-reductase inhibitory potential of prepared gel formulation and then commercial product. The IC50 value of the prepared formulation was 118.960±0.634 (µg/ml) and standard beta-sitosterol 88.854±0.70 (µg/ml), whereas Finasteride (positive control) 224.372±3.103 (ng/ml). Conclusion: Thus, β-sitosterol formulation utilises a straightforward, low-cost production, less time-consuming process with minimal facility and equipment requirements. The formulation may be a promising candidate for future investigation into their antiandrogenic activities.

Characterization of carotenoids in Lycium barbarum fruit by using UPC2-PDA-Q-TOF-MSE couple with deep eutectic solvents extraction and evaluation of their 5α-reductase inhibitory activity.

Carotenoids from Lyciu m barbarum fruits have possessed pharmacological efficacy against eye diseases, cardiovascular disorders, cancer, and benign prostatic hyperplasia. However, the efficient extraction, rapid characterization and activities evaluation of Lycium carotenoids remains a challenge. To concentrate and characterize Lycium carotenoids, we have developed ultrasound-assisted extraction methods with different deep eutectic solvents (DESs) and analyzed carotenoids by ultra-performance convergence chromatography coupled with photo diode array detector and quadrupole time-of-flight mass spectrometry (UPC2-PDA-Q-TOF-MSE). DESs containing choline chloride and malonic acid presented better extraction efficiency and were more environmentally friendly than other extraction methods. Carotenoids were more quickly profiled (in 11min) by UPC2 compared to by UPLC (in 35min), with seventeen main peaks were characterized in the MS fragmentation patterns. The in vitro 5α-reductase inhibitory activity of DESs extracts, fractions and components were subsequently assessed, and the predominant component zeaxanthin dipalmitate (ZD) exhibited potent inhibitory activity. Our study provides a chemical and pharmacological basis for the further development of potential new drugs based on Lycium carotenoids.

Health Benefits and Safety of Red Pigmented Rice (Oryza sativa L.): In Vitro, Cellular, and In Vivo Activities for Hair Growth Promoting Treatment

The hair growth-promoting activities of Thai native red (Sang-Yod-SY and Mun-Poo-MP) and black (Black glutinous-BG and Hom-Nil-HN) pigmented rice (Oryza sativa L.) extracts, including in vitro 5α-reductase inhibition, hair growth-promoting activity on human hair germinal matrix cells, and in vivo hair-cycle-converting activity in C3H/HeMlac mice, were investigated. Moreover, these extracts were determined to be safe via cytotoxicity (HaCaT cell) and in vivo irritation tests. The results showed that SY red rice extract with high contents of proanthocyanidin (1.50 ± 0.16 mgECE/g extract) exhibited significantly higher 5α-reductase inhibitory activity (18.5 ± 9.0 mgFEA/g extract) (p < 0.05). The maximum growth-promoting activity for human matrix cells treated with SY extract reached about 216.2 ± 0.7% (1 mg/mL) relative to control (100%) after 3 days culture (p < 0.05). Moreover, topical application of 1 mg/mL SY red pericarp rice extracts on shaven C3H skin in telogen phase led to significant hair regeneration (97.2 ±1.3%) based on the shaven area, while vehicle application only tended to yield a regeneration of 50.9 ± 11.7%. Red rice extracts were found to be safe, without signs of cytotoxicity and irritation. This research demonstrates the health benefits and safety of SY red pericarp extract when used for hair growing activity and its potential for use as a natural hair growth promoter and 5α-reductase inhibitor.

Synthesis, Characterization and Evaluation of 5α, 6β-Dihalo Androsterone Derivatives as 5α-Reductase Inhibitors

Background and Objective: Testosterone under the influence of 5α-reductase enzyme gets converted to dihydrotestosterone and high levels are found to be causative for androgen dependent disease like benign prostatic hyperplasia. Thus, 5α-reductase has been recognised as an important target for discovering new drugs against Benign Prostatic Hyperplasia and Prostate Cancer. Methods: In the present study, a series of 5α, 6β-Dichloro-17-Oxoandrostan-3β-yl esters (7a-7f) were synthesized and characterized by analytical and spectroscopic methods. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen level. Results: The target compounds (7a-7f) showed increased anti-androgenic activity as compared to finasteride and control, which implies that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 7b showing highest inhibitory activity and noteworthy D-Score was further sorted by performing solubility and dissolution studies. Results of these studies when compared with finasteride showed increased solubility and dissolution of target compound 7b. Conclusion: These results demonstrated that enhancement of activity by the presence of electronegative group at position 3 of the steroidal nucleus makes 7b a lead compound for further exploration and optimal formulation.

Effects of some medicinal plant extracts on dermal papilla cells.

Miniaturization of the hair follicles is evident on the balding scalp. Approved medications, topical minoxidil, and oral finasteride for the treatment of alopecia sometimes come with undesirable adverse effects. The study was to examine the bioactivity of medicinal plants for finding the promising source of anti-hair loss application. Ten ethanolic extracts were prepared from Acacia concina (Willd.) DC., Acanthus ebracteatus Vahl, Bridelia ovata Decne, Cleome viscosa L., Cocos nucifera L., Hibiscus subdariffla L., Oryza sativa L., Terminalia chebula Retz., Tinospora crispa (L.) Hook. f. & Thomson and cytotoxic tested on dermal papilla cells using MTT assay. The effect of the extracts on cell cycle was also determined using flow cytometry technique. Anti-inflammatory activity was examined by determining IL-1β inhibition in RAW 257.4 cells. In vitro study of androgenic and 5α-reductase inhibitory activities were also determined using MTT assay and enzymatic reaction couple with liquid chromatography-mass spectrometry (LC-MS), respectively. Our results revealed that only A. ebracteatus promoted dermal papilla cell proliferation and the S and G2/M phases in cell cycle. A. ebracteatus also showed inhibitory activity against 5α-reductase and testosterone in reducing cell viability of the dermal papilla. Moreover, A. ebracteatus extract strongly inhibited LPS-stimulating IL-1β production in RAW 264.7 cells in a dose-dependent manner. Our finding indicated that the ethanolic extract of A. ebracteatus is a promising candidate for anti-hair loss treatment.

Isolation and HPLC Quantitative Determination of 5α-Reductase Inhibitors from Tectona grandis L.f. Leaf Extract.

Steroid 5α-reductase plays a crucial role in catalyzing the conversion of testosterone to dihydrotestosterone, which is involved in many androgen-dependent disorders. Leaf-hexane extract from Tectona grandis L.f. has shown promise as a 5α-reductase inhibitor. The objectives of this current study were to isolate and identify 5α-reductase inhibitors from T. grandis leaves and to use them as the bioactive markers for standardization of the extract. Three terpenoid compounds, (+)-eperua-8,13-dien-15-oic acid (1), (+)-eperua-7,13-dien-15-oic acid (2), and lupeol (3), were isolated and evaluated for 5α-reductase inhibitory activity. Compounds 1 and 2 exhibited potent 5α-reductase inhibitory activity, while 3 showed weak inhibitory activity. An HPLC method for the quantitative determination of the two potent inhibitors (1 and 2), applicable for quality control of T. grandis leaf extracts, was also developed. The ethanolic extract showed a significantly higher content of 1 and 2 than found in the hexane extract, suggesting that ethanol is a preferable extraction solvent. This study is the first reported isolation of 5α-reductase inhibitors (1 and 2) from T. grandis leaves. The extraction and quality control methods that are safe and useful for further development of T. grandis leaf extract as an active ingredient for hair loss treatment products are also reported.

Antioxidant and 5α-Reductase Inhibitory Activity of Momordica charantia Extract, and Development and Characterization of Microemulsion

Momordica charantia (M. charantia) is rich in flavonoids, which possess a strong antioxidant capacity and may help prevent hair loss. This study aims to develop the microemulsion of M. charantia with antioxidant activity and 5α-reductase (5aR) inhibitory activity. The total phenolic content (TPC), antioxidant activity, and 5aR inhibitory activity of ethanolic and aqueous extracts of the fruit were investigated. The preparation of M. charantia extract-loaded microemulsion (MELM) was optimized and characterized the MELM. The aqueous extract of M. charantia fruit flesh displayed a TPC of 780.75 ± 24.82 mg Gallic acid equivalence/g of extract. ABTS (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), DPPH (2,2-diphenyl-1-picrylhydrazyl), and nitric oxide (NO) radical scavenging activities were observed in all the extracts. About 0.461 ± 0.003 mg finasteride equivalence/g of extract of 5aR inhibitory activity was detected in the aqueous extract of the inner tissue of M. charantia fruit. Based on NO radical scavenging and 5aR inhibitory activity, an aqueous extract of the inner tissue (pericarp with seed) of M. charantia fruit was used to prepare the MELM. The MELM was prepared using a different ratio of tween 80 and ethanol as Smix. The results showed that the 1:1 ratio of tween 80: ethanol produced microemulsion of an optimum size, zeta potential, and polydispersity index. The MELM samples were stored at 5, 30, and 40 °C for 12 weeks, and the stability was assessed. The results revealed that the size, zeta potential, and polydispersity index of the formulated MELM remained unchanged during the investigated time. This study primarily reports the 5aR inhibitory activity of M. charantia extract and the development of microemulsion. The prepared MELM could be further developed into cosmetic or pharmacological preparations to manage hair loss.

Target Specific Uptake of a Newly Synthesized Radiolabeled 5α-Reductase Inhibitor "Tc-99m-17-Oxo-17a-Aza-D-Homo-5-Androsten-3β-yl Phenoxyacetate (Tc-99m-17a-Aza Steroid)" in Rat Prostatic Neoplastic Lesions.

Objective:Considering the 5α-reductase (5AR) inhibitory activity of the oximes and the importance of the ester group in increasing the anti-androgenic property, we reasoned to synthesize a compound having a lactam group in ring D and an ester group at the 3 β position of the androsterone nucleus. The study aims to radiolabel 17-oxo-17a-aza-D-homo-5-androsten-3β-yl phenoxyacetate (17a-aza steroid) with Tc-99m to evaluate its targeted uptake in experimentally induced prostate carcinogenesis in rats.Materials and Methods:The prediction of the optimal interaction and binding affinity of Tc-99m-17-oxo-17a-aza-D-homo-5-androsten-3 β-ylphenoxyacetate (Tc-99m-17a-aza steroid) toward 5AR inhibitor was done using Biopredicta Vlife MDS tool. Tc-99m-17a-aza steroid was developed by direct radiolabeling protocol. The radio-pharmacological characteristics (serum stability, plasma protein-binding ability, and lipophilicity) of the complex were evaluated. Further, the bio-distribution studies of the complex were performed in rats with experimentally induced prostate carcinogenesis.Results:The in-silico analysis exhibits favorable binding of Tc-99m-17a-aza toward 5AR with D score-130.97. The radiochemical purity of Tc-99m-17a-aza was 96.79%. The radio-complex maintained stability in the rat serum for a period of 6 h (hours). Plasma protein binding and Log Po/w value were observed to be 86.23 ± 7.08% and 0.118 ± 0.045, respectively. A significantly enhanced percent-specific uptake was observed in the prostate of rats with induced prostate carcinogenesis.Conclusion:The study concludes that Tc-99m-17a-aza exhibits prostate specificity and can be explored further for its potential as a radionuclide imaging probe.

Chemical characterization and 5α-reductase inhibitory activity of phenolic compounds in goji berries

Lycium fruits have a high content of phenolics as bioactive constituents with various pharmacological effects, but there is a lack of comparative analysis and chemical profiling of phenolics in Lycium fruit varieties. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MSE) combined with chemometrics was developed to characterize the phenolics in fruits from four Lycium species, including Lycium barbarum L. (LBL), L. chinense Mill. (LCM), L. barbarum var. auranticarpum (LBA) and L. ruthenicun Murr. (LRM). 63 phenolics were identified according to reported tandem mass fragmentation patterns and the UNIFI scientific informatics platform. Nine phenolics (5, 18, 20, 29, 31, 37, 41, 43, 60) were common and predominant components among four types of Lycium fruit. The partial least squares discriminant analysis (PLS-DA) and the orthogonal partial least squares discriminant analysis (OPLS-DA) were analyzed on the basis of a matrix created from 653 sets of data, and 20 Lycium fruits were classified into four groups. Further analysis identified that phenolics profiles were characteristic for each Lycium species, and five markers (13, 29, 31, 35, 99) could be utilized for fruit identification. Subsequently, inhibitory activity against 5α-reductase of phenolic extracts of Lycium fruits showed that LBL extract was the relative better effective, followed by LCM, whereas LBA and LRM showed no activity, which might be associated with the high contents of marker compounds (29, 31, 35, 43, 71, 99) in LBL. These findings will provide guidance for the development of Lycium phenolics with beneficial properties for the prevention and treatment of Benign prostatic hyperplasia (BPH).

Estrogenic and antiandrogenic activities of methoxyflavans isolated from the fruit of Mauritia Flexuosa (Moriche Palm).

Moriche palm is consumed as both a fresh fruit and processed food in Peru and Brazil. Although its fruit contains phytoestrogens, the active compounds have not yet been identified. Therefore, we purified moriche palm extract (MPE) and identified compounds exhibiting estrogenic and antiandrogenic activities. Estrogenic activity was assessed by the estrogen-dependent growth of MCF-7 cells and increases in uterine weights in mice. Antiandrogenic activity was evaluated by 5α-reductase inhibitory activity and prostate-specific antigen (PSA) expression in LNCaP cells. In vivo antiestrogenic activity was also assessed based on testosterone-induced prostate growth in castrated mice. Four methoxyflavans were isolated from MPE and all, except for 7,4'-dihydroxy-5-methoxyflavan, promoted MCF-7 cell growth, indicating estrogenic activity. Uterine and ovary weights increased in mice orally administered MPE (400mg/kg) for 2weeks. Regarding antiandrogenic activity, among the four methoxyflavans isolated, 6,7,4'-trihydroxy-5-methoxyflavan (1 µg/ml) suppressed the mRNA and protein expression of PSA in LNCaP cells. Furthermore, prostate growth was suppressed in mice orally administered MPE (200mg/kg) for 2weeks. All methoxyflavans inhibited 5α-reductase activity with IC50 less than 10 µg/ml. Collectively, the present results demonstrated that orally administered MPE exhibited estrogenic and antiandrogenic activities. Methoxyflavans, particularly 6,7,4'-trihydroxy-5-methoxyflavan, appear to be the active compounds for these activities. PRACTICAL APPLICATIONS: The fruit of Mauritia flexuosa (moriche palm) has been used for beverages and processed foods. Although it is said to contain phytoestrogens, the active compounds have not yet been identified. In this study, we isolated and identified methoxyflavans exhibiting estrogenic and antiandrogenic activities. Among them, 6,7,4'-trihydroxy-5-methoxyflavan appeared to be the most effective compounds for these activities.

Synthesis and Study of Some 17a-aza-D-homo Steroids as 5α-Reductase Inhibitors.

Tremendous advances have been made in the development of new pharmacotherapuetic agents and less invasive techniques to help men with lower urinary tract symptoms. The use of 5α-reductase inhibitor (5-ARI) is restricted to the patients with large prostate volumes, whose symptoms are refractory to antiandrogens or α-adrenergic blockers. Out of the various synthesized 5-reductase inhibitors with different substituents on the steroidal nucleus, esters have been found to exhibit high anti-androgenic activity. In our attempt to find new, safer and potent 5-ARI and our continued interest in azasteorids, esters of 17a-Aza-D-homo-5-androsten-3β-ol with synergistic effect were synthesized and characterized using different analytical techniques. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen level by ELISA assay procedure. The interaction with receptors was studied using an advanced docking programme to predict the correlation of the synthesized compounds with actual biological activity. The target compounds (6-12) showed increased anti-androgenic activity as compared to finasteride and control, which imply that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 6 showed the highest inhibitory activity and greater affinity for the 5- AR receptor with the highest dock score. The results of these studies when compared with Finasteride showed increased solubility and dissolution of target compound 6. Compound 6 showed immense potential with improved efficacy and better bioavailability, thus makes it a suitable candidate for further studies and optimal formulation.

Anti-Acne Vulgaris Effects of Pedunculagin from the Leaves of Quercus mongolica by Anti-Inflammatory Activity and 5α-Reductase Inhibition.

Quercus mongolica (QM)—a member of the Fagaceae family—has been used as traditional medicine in Korea, China and Mongolia as a treatment for inflammation of oral, genital or anal mucosa and for external inflammation of skin. To treat acne vulgaris (AV), we evaluated the inhibition of inflammatory cytokines (IL-6 and IL-8) of QM leaf extract (QML) and its main compound, pedunculagin (PD) in vitro and 5α-reductase inhibitory activity by western blotting. As results, QML and PD showed potent NO production inhibitory activity compared with the positive control (PC), NG-monomethyl-L-arginine (L-NMMA). QML and PD was also showed the decreases of IL-6 and IL-8 compared with the PC, EGCG and exhibited potent 5α-reductase type 1 inhibitory activities compared with the PC, dutasteride.

Quintaquinone, a Merosesquiterpene from the Yellow Sponge Verongula cf. rigida Esper.

A chemical investigation of the sponge Verongula cf. rigida led to the isolation of 13 merosesquiterpenes, among which quintaquinone (2), 5-epi-nakijiquinone L (3), and 3-farnesyl-2-hydroxy-5-methoxyquinone (4) were isolated and reported here for the first time. Particularly, compound 2 is the first member of merosesquiterpenes with a polyketide side chain substituted on C-19. All of the isolated compounds were examined for steroid 5α-reductase inhibitory activity. Cyclospongiaquinone 1 (5) showed a strong activity in the same range as that of standard finasteride.

Synthesis, 17α-hydroxylase-C17,20-lyase Inhibitory and 5AR Reductase Activity of Novel Pregnenolone Derivatives.

The potential of steroids for development into lead pharmacological molecules lies in the regulation of a variety of biological processes by these molecules and also because of these being a fundamental class of signaling molecules. Steroid based scaffolds have been extensively used as active pharmaceutical agents for the treatment of various diseases including the deadly disease of cancer which despite the recent advances in the early diagnosis, prevention and therapy, remains a clinical challenge affecting millions of people world over and is one of the leading causes of death. It thus warrants the development of new drugs against this dreadful disease through exploitation of emerging molecularly defined targets. The present study explores the effect of novel steroidal pyrazolines as presumed inhibitors of 5α- reductase (5AR) and 17α-hydroxylase-C17,20-lyase as a target for treatment of prostate cancer. A series of 1,5- diaryl pyrazoline pregnenolones were synthesized and screened for 5α-reductase inhibitory activities. Synthesis of the analogs is multistep and proceeds in good overall yields. The key step in the synthesis of 1,5- disubstituted pyrazolinyl pregnenolones is the heterocyclization of bezylidine derivatives (3) in presence of phenylhydrazines (4) through the initial formation of the phenylhydrazones, which undergo concomitant cyclization to generate the stable pyrazoline derivatives. All the synthesised D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were screened for prostate cancer cell inhibitory, 5α-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active. Further, compounds 5g and 5h were found to have moderate 17α-hydroxylase-C17,20-lyase inhibitory activities. A series of D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were synthesized and screened for their prostate cancer cell inhibitory, 5a-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active whereas compounds 5g and 5h were found to have moderate 17α- hydroxylase-C17,20-lyase inhibitory activities.

Design, synthesis, and biological evaluation of novel androst-17β-amide structurally related compounds as dual 5α-reductase inhibitors and androgen receptor antagonists

Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17β-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR − cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a–9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC50 lower than 1 μM. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.

Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists

Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.

Design, synthesis and biological evaluation of novel androst-3,5-diene-3-carboxylic acid derivatives as inhibitors of 5α-reductase type 1 and 2

5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25μM and 0.13μM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p<0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.

Health Promotion Potential of Vegetables Cultivated in Northern Thailand: A Preliminary Screening of Tannin and Flavonoid Contents, 5α-Reductase Inhibition, Astringent Activity, and Antioxidant Activities.

Many of scientific evidences suggest that regular consumption of fruits and vegetables can prevent chronic diseases. In Northern Thailand, there are many vegetables that are usually consumed by local people. In this study, 17 local vegetables were selected and extracted with 95% ethanol. The extracts were screened for 5α-reductase inhibitory activity, total tannin and flavonoid contents, astringent and antioxidant activities. The results showed that Spondias pinnata and Ocimum americanum had the highest tannin and flavonoid content, respectively. Neptunia oleracea was the most potent 5α-reductase inhibitor. For antioxidant activities, S pinnata was the most potent ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) radical scavenger and the most potent ferric reducer. Polygonatum odoratum was the most potent hydrogen peroxide scavenger and Leucaena leucocephala was the most potent DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenger among the tested samples. This suggests that local vegetables in Northern Thailand have a health promotion potential, which can be further developed as nutritional supplements, preventive medicines, and topical products for cosmetic purposes.