The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Eugenio Flores - One of the best experts on this subject based on the ideXlab platform.
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recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5α reductase inhibitors
Current Medicinal Chemistry, 2005Co-Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio FloresAbstract:The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity.
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steroid 5α reductase inhibitors
Mini-reviews in Medicinal Chemistry, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Alexandra Quiroz, Ivonne HeuzeAbstract:The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5α-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 55α-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 55α-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 55α-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 165β-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16β-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16β-phenylpregnatriene- 3,17a-diones, 30, 31 (Fig. (7)) and 16β-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5α-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5α-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5α-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.
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effect of a novel steroid pm 9 on the inhibition of 5α reductase present in Penicillium crustosum broths
Steroids, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Alexandra Quiroz, Genoveva García, Elena RamirezAbstract:The conversion of testosterone (T) to 5-dihydrotestosterone (DHT) has been demonstrated in Penicillium crustosumbroth obtained from fermented pistachios, lemons and corn tortillas. Furthermore, the presence of 5-reductase enzyme, which is responsible for this conversion, has been established by electrophoretical techniques in these cultures. 5-Reductase enzyme is also present in animal and human androgen-dependent tissues as well as in prostate and seminal vesicles. The increase of the conversion of T to DHT in prostate gland, has been related to some illnesses such as benign prostate hyperplasia and prostate cancer. Furthermore, treatment with 5-reductase inhibitors such as finasteride reduces the prostate growth. These data have stimulated research for the synthesis of new molecules with antiandrogenic activity, whose biological effect needs to be demonstrated. The purpose of this study is to determine the inhibition pattern of 5-reductase in P. crustosum by finasteride and the new steroidal compound PM-9. Km and Vmax values for T, were determined in the broths by Lineweaver–Burk plots using different testosterone concentrations. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver–Burk using different concentrations of T and inhibitors. Results show that finasteride and PM-9 inhibit 5 -reductase present in the broth in a competitive manner. © 2002 Elsevier Science Inc. All rights reserved.
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5 alpha-reductase inhibition by a new synthetic steroid (PM-9) in cultures of Penicillium crustosum.
Proceedings of the Western Pharmacology Society, 2002Co-Authors: Marisa Cabeza, Eugene Bratoeff, Elena Ramirez, Alexandra Quiroz, Genoveva García, Eugenio FloresAbstract:The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 alpha-reductase enzyme, which is responsible for this reduction, had been demonstrated in P. crustosum broth. This enzyme is also present in androgen-dependent animal and human tissues such as prostate and seminal vesicles. The increase in the conversion of T to DHT has been implicated in androgen-dependent diseases such as benign prostate hyperplasia and prostate cancer. The use of 5 alpha-reductase inhibitors could mitigate these illnesses by inhibiting the DHT-receptor complex formation. The purpose of this study is to determine the inhibition pattern of 5 alpha-reductase by finasteride and PM-9 in P. crustosum broth. Km and Vmax values were determined in the broth by Lineweaver-Burk plots using different testosterone concentrations. The Km value was 0.22 microM and Vmax 0.833 pmol of DHT/mg of mycelium/day. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver-Burk plot, using different concentrations of T and inhibitors. The results of this study show that both finasteride and PM-9 inhibit 5 alpha-reductase in a competitive manner.
Zhenggang Han - One of the best experts on this subject based on the ideXlab platform.
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aromatic amino acids in the cellulose binding domain of Penicillium crustosum endoglucanase egl1 differentially contribute to the cellulose affinity of the enzyme
PLOS ONE, 2017Co-Authors: Jiangke Yang, Wei Xiong, Fangyuan Chen, Zhenggang HanAbstract:The cellulose binding domain (CBD) of cellulase binding to cellulosic materials is the initiation of a synergistic action on the enzymatic hydrolysis of the most abundant renewable biomass resources in nature. The binding of the CBD domain to cellulosic substrates generally relies on the interaction between the aromatic amino acids structurally located on the flat face of the CBD domain and the glucose rings of cellulose. In this study, we found the CBD domain of a newly cloned Penicillium crustosum endoglucanase EGL1, which was phylogenetically related to Aspergillus, Fusarium and Rhizopus, and divergent from the well-characterized Trichoderma reeseis cellulase CBD domain, contain two conserved aromatic amino acid-rich regions, Y451-Y452 and Y477-Y478-Y479, among which three amino acids Y451, Y477, and Y478 structurally sited on a flat face of this domain. Cellulose binding assays with green fluorescence protein as the marker, adsorption isotherm assays and an isothermal titration calorimetry assays revealed that although these three amino acids participated in this process, the Y451-Y452 appears to contribute more to the cellulose binding than Y477-Y478-Y479. Further glycine scanning mutagenesis and structural modelling revealed that the binding between CBD domain and cellulosic materials might be multi-amino-acids that participated in this process. The flexible poly-glucose molecule could contact Y451, Y477, and Y478 which form the contacting flat face of CBD domain as the typical model, some other amino acids in or outside the flat face might also participate in the interaction. Thus, it is possible that the conserved Y451-Y452 of CBD might have a higher chance of contacting the cellulosic substrates, contributing more to the affinity of CBD than the other amino acids.
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the catalytic domain of Penicillium crustosum endoglucanase egl1 has cellulose binding capacity and cellulolytic activity
Enzyme and Microbial Technology, 2017Co-Authors: Wei Xiong, Jiangke Yang, Fangyuan Chen, Zhenggang HanAbstract:The cellulase-mediated degradation of cellulosic materials, which is initiated by endoglucanases by the random cleavage of the glycosidic bonds between glucose units to break long cellulose molecules into shorter ones, represents a major carbon flow in the global carbon cycle. The structure of a typical endoglucanase contains a classical (α/β)8 barrel fold catalytic domain, a linker region and a cellulose-binding domain. In this study, we found that both the full-length enzyme and the catalytic domain of endoglucanase EGL1 cloned from Penicillium crustosum strain 601 have CMCase and FPase activity. A cellulose-binding assay using green fluorescent protein as a marker further showed that the catalytic domain could also bind the cellulose substrate. The three-dimensional structure of the catalytic domain of EGL1 revealed that this cellulose substrate-binding capacity of the catalytic domain may come from the hydrophobic core formed by aromatic amino acids distributed in or outside the (α/β)8 barrel fold. A glycine scanning mutagenesis assay further found that the aromatic amino acids at the bottom of the barrel fold and those adjacent to the catalytic site significantly affect the cellulolytic activity and the cellulose binding affinity of the catalytic domain. Thus, it could be speculated that the aromatic amino acids in the bottom of the barrel fold might be the main contributors in the binding capacity of the catalytic domain with the cellulose substrate, and those distributed around the active sites on the top of the enzyme might participate in moving the cellulose substrate to the active site in the barrel fold or releasing the hydrolysis products.
Elena Ramirez - One of the best experts on this subject based on the ideXlab platform.
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recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5α reductase inhibitors
Current Medicinal Chemistry, 2005Co-Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio FloresAbstract:The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity.
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steroid 5α reductase inhibitors
Mini-reviews in Medicinal Chemistry, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Alexandra Quiroz, Ivonne HeuzeAbstract:The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5α-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 55α-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 55α-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 55α-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 165β-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16β-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16β-phenylpregnatriene- 3,17a-diones, 30, 31 (Fig. (7)) and 16β-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5α-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5α-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5α-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.
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effect of a novel steroid pm 9 on the inhibition of 5α reductase present in Penicillium crustosum broths
Steroids, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Alexandra Quiroz, Genoveva García, Elena RamirezAbstract:The conversion of testosterone (T) to 5-dihydrotestosterone (DHT) has been demonstrated in Penicillium crustosumbroth obtained from fermented pistachios, lemons and corn tortillas. Furthermore, the presence of 5-reductase enzyme, which is responsible for this conversion, has been established by electrophoretical techniques in these cultures. 5-Reductase enzyme is also present in animal and human androgen-dependent tissues as well as in prostate and seminal vesicles. The increase of the conversion of T to DHT in prostate gland, has been related to some illnesses such as benign prostate hyperplasia and prostate cancer. Furthermore, treatment with 5-reductase inhibitors such as finasteride reduces the prostate growth. These data have stimulated research for the synthesis of new molecules with antiandrogenic activity, whose biological effect needs to be demonstrated. The purpose of this study is to determine the inhibition pattern of 5-reductase in P. crustosum by finasteride and the new steroidal compound PM-9. Km and Vmax values for T, were determined in the broths by Lineweaver–Burk plots using different testosterone concentrations. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver–Burk using different concentrations of T and inhibitors. Results show that finasteride and PM-9 inhibit 5 -reductase present in the broth in a competitive manner. © 2002 Elsevier Science Inc. All rights reserved.
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5 alpha-reductase inhibition by a new synthetic steroid (PM-9) in cultures of Penicillium crustosum.
Proceedings of the Western Pharmacology Society, 2002Co-Authors: Marisa Cabeza, Eugene Bratoeff, Elena Ramirez, Alexandra Quiroz, Genoveva García, Eugenio FloresAbstract:The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 alpha-reductase enzyme, which is responsible for this reduction, had been demonstrated in P. crustosum broth. This enzyme is also present in androgen-dependent animal and human tissues such as prostate and seminal vesicles. The increase in the conversion of T to DHT has been implicated in androgen-dependent diseases such as benign prostate hyperplasia and prostate cancer. The use of 5 alpha-reductase inhibitors could mitigate these illnesses by inhibiting the DHT-receptor complex formation. The purpose of this study is to determine the inhibition pattern of 5 alpha-reductase by finasteride and PM-9 in P. crustosum broth. Km and Vmax values were determined in the broth by Lineweaver-Burk plots using different testosterone concentrations. The Km value was 0.22 microM and Vmax 0.833 pmol of DHT/mg of mycelium/day. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver-Burk plot, using different concentrations of T and inhibitors. The results of this study show that both finasteride and PM-9 inhibit 5 alpha-reductase in a competitive manner.
Tianjiao Zhu - One of the best experts on this subject based on the ideXlab platform.
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secondary metabolites produced by combined culture of Penicillium crustosum and a xylaria sp
Journal of Natural Products, 2019Co-Authors: Zichao Sun, Jixing Peng, Meilin Zhu, Qian Che, Guojian Zhang, Tianjiao ZhuAbstract:Four new alkyl aromatics, penixylarins A-D (1-4), along with the known biogenetically related 1,3-dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3-dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6), were isolated from a mixed culture of the Antarctic deep-sea-derived fungus Penicillium crustosum PRB-2 and the mangrove-derived fungus Xylaria sp. HDN13-249. UPLC-MS data and an analysis of structural features showed that compounds 1 and 2 were produced by collaboration of the two fungi, while compounds 3-6 could be produced by Xylaria sp. HDN13-249 alone, but in noticeably increased quantities by cocultivation. Compounds 2, 3, 5, and 6 showed antibacterial activity against a panel of strains, and compound 3 possessed potential antituberculosis effects (MIC = 6.25 μM against Mycobacterium phlei).
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secondary metabolites produced by combined culture of Penicillium crustosum and a xylaria sp
Journal of Natural Products, 2019Co-Authors: Zichao Sun, Jixing Peng, Meilin Zhu, Qian Che, Guojian Zhang, Tianjiao ZhuAbstract:Four new alkyl aromatics, penixylarins A–D (1–4), along with the known biogenetically related 1,3-dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3-dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6)...
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genomic locus of a Penicillium crustosum pigment as an integration site for secondary metabolite gene expression
ACS Chemical Biology, 2019Co-Authors: Florian Kindinger, Jonas Nies, Anke Becker, Tianjiao ZhuAbstract:Heterologous expression of secondary metabolite genes and gene clusters has been proven to be a successful strategy for identification of new natural products of cryptic or silent genes hidden in the genome sequences. It is also a useful tool to produce designed compounds by synthetic biology approaches. In this study, we demonstrate the potential usage of the gene locus pcr4401 in the fast-growing filamentous fungus Penicillium crustosum as an integration site for heterologous gene expression. The deduced polyketide synthase (PKS) Pcr4401 is involved in the dihydroxynaphthalene (DHN)-melanin pigment formation, and its deletion in P. crustosum PRB-2 led to an albino phenotype. Heterologous expression of pcr4401 in Aspergillus nidulans proved its function as the melanin precursor YWA1 synthase. To ensure gene expression after genomic integration and to easily identify the potential transformants by visualization, the gene locus of pcr4401 was chosen as an integration site. For heterologous expression in P. crustosum, the expression constructs were created by ligation-independent homologous recombination in Escherichia coli or Saccharomyces cerevisiae. A pyrG deficient strain was also created, so that both the pyrG and hph resistance gene can be used as selection markers. Successful expression in P. crustosum was demonstrated by using one uncharacterized PKS gene from Aspergillus and two from Penicillium strains. All three genes were successfully introduced, heterologously expressed, and their biosynthetic products elucidated. The results presented in this study demonstrated that P. crustosum can be used as a suitable host for heterologous expression of secondary metabolite genes.
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secondary metabolites from antarctic marine derived fungus Penicillium crustosum hdn153086
Natural Product Research, 2019Co-Authors: Congcong Liu, Zhenzhen Zhang, Yanyan Feng, Tianjiao ZhuAbstract:A new polyene compound (1) and a new diketopiperazine (2), as well as three known compounds (3–5), were isolated from the Antarctic marine-derived fungus Penicillium crustosum HDN153086. The struct...
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penilactones a and b two novel polyketides from antarctic deep sea derived fungus Penicillium crustosum prb 2
Tetrahedron, 2012Co-Authors: Tianjiao ZhuAbstract:Two highly oxygenated polyketides, penilactones A and B (1 and 2), containing a new carbon skeleton formed from two 3,5-dimethyl-2,4-diol-acetophenone units and a γ-butyrolactone moiety, together with five known compounds (3–7) were isolated from an Antarctic deep-sea derived fungus Penicillium crustosum PRB-2. Penilactones A and B possess antipodal absolute stereochemistries. Their structures were elucidated by spectroscopic methods, and their absolute configurations were assigned by single-crystal X-ray diffraction and CD analyses. A plausible biogenetic pathway for 1–2 is proposed.
Eugene Bratoeff - One of the best experts on this subject based on the ideXlab platform.
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recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5α reductase inhibitors
Current Medicinal Chemistry, 2005Co-Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio FloresAbstract:The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity.
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steroid 5α reductase inhibitors
Mini-reviews in Medicinal Chemistry, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Alexandra Quiroz, Ivonne HeuzeAbstract:The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5α-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 55α-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 55α-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 55α-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 165β-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16β-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16β-phenylpregnatriene- 3,17a-diones, 30, 31 (Fig. (7)) and 16β-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5α-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5α-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5α-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.
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effect of a novel steroid pm 9 on the inhibition of 5α reductase present in Penicillium crustosum broths
Steroids, 2003Co-Authors: Eugenio Flores, Eugene Bratoeff, Marisa Cabeza, Alexandra Quiroz, Genoveva García, Elena RamirezAbstract:The conversion of testosterone (T) to 5-dihydrotestosterone (DHT) has been demonstrated in Penicillium crustosumbroth obtained from fermented pistachios, lemons and corn tortillas. Furthermore, the presence of 5-reductase enzyme, which is responsible for this conversion, has been established by electrophoretical techniques in these cultures. 5-Reductase enzyme is also present in animal and human androgen-dependent tissues as well as in prostate and seminal vesicles. The increase of the conversion of T to DHT in prostate gland, has been related to some illnesses such as benign prostate hyperplasia and prostate cancer. Furthermore, treatment with 5-reductase inhibitors such as finasteride reduces the prostate growth. These data have stimulated research for the synthesis of new molecules with antiandrogenic activity, whose biological effect needs to be demonstrated. The purpose of this study is to determine the inhibition pattern of 5-reductase in P. crustosum by finasteride and the new steroidal compound PM-9. Km and Vmax values for T, were determined in the broths by Lineweaver–Burk plots using different testosterone concentrations. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver–Burk using different concentrations of T and inhibitors. Results show that finasteride and PM-9 inhibit 5 -reductase present in the broth in a competitive manner. © 2002 Elsevier Science Inc. All rights reserved.
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5 alpha-reductase inhibition by a new synthetic steroid (PM-9) in cultures of Penicillium crustosum.
Proceedings of the Western Pharmacology Society, 2002Co-Authors: Marisa Cabeza, Eugene Bratoeff, Elena Ramirez, Alexandra Quiroz, Genoveva García, Eugenio FloresAbstract:The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 alpha-reductase enzyme, which is responsible for this reduction, had been demonstrated in P. crustosum broth. This enzyme is also present in androgen-dependent animal and human tissues such as prostate and seminal vesicles. The increase in the conversion of T to DHT has been implicated in androgen-dependent diseases such as benign prostate hyperplasia and prostate cancer. The use of 5 alpha-reductase inhibitors could mitigate these illnesses by inhibiting the DHT-receptor complex formation. The purpose of this study is to determine the inhibition pattern of 5 alpha-reductase by finasteride and PM-9 in P. crustosum broth. Km and Vmax values were determined in the broth by Lineweaver-Burk plots using different testosterone concentrations. The Km value was 0.22 microM and Vmax 0.833 pmol of DHT/mg of mycelium/day. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver-Burk plot, using different concentrations of T and inhibitors. The results of this study show that both finasteride and PM-9 inhibit 5 alpha-reductase in a competitive manner.