RESUMO
Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment of PC. Moreover, many PC patients suffer from glucocorticoid overproduction, and importantly mutated androgen receptors can be stimulated by glucocorticoids. In this study, the first dual inhibitor of CYP17 and CYP11B1 (the enzyme responsible for the last step in glucocorticoid biosynthesis) is described. A series of biphenylmethylene pyridines has been designed, synthesized, and tested as CYP17 and CYP11B1 inhibitors. The most active compounds were also tested for selectivity against CYP11B2 (aldosterone synthase), CYP19 (aromatase), and hepatic CYP3A4. In detail, compound 6 was identified as a dual inhibitor of CYP17/CYP11B1 (IC(50) values of 226 and 287 nM) showing little inhibition of the other enzymes as well as compound 9 as a selective, highly potent CYP17 inhibitor (IC(50) = 52 nM) exceeding abiraterone in terms of activity and selectivity.
Assuntos
Antagonistas de Androgênios/química , Compostos de Bifenilo/química , Imidazóis/química , Neoplasias da Próstata/tratamento farmacológico , Piridinas/química , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Humanos , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Testículo/efeitos dos fármacos , Testículo/enzimologiaRESUMO
CYP17 inhibition is a promising therapy for prostate cancer (PC) because proliferation of 80% of PC depends on androgen stimulation. Introduction of isopropylidene substituents onto the linker of biphenylmethylene 4-pyridines resulted in several strong CYP17 inhibitors, which were more potent and selective, regarding CYP 11B1, 11B2, 19 and 3A4, than the drug candidate abiraterone.
Assuntos
Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/metabolismo , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Masculino , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteroide 17-alfa-Hidroxilase/metabolismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Complexes of the natural melophlins A and C with Mg, Zn, Ga, La and Ru were prepared, characterized and tested for antimicrobial and cytotoxic effects. The lanthanum complex La(melophlinato C)(3) and the ruthenium complex chlorido(eta(6)-p-cymene)(melophlinato C)ruthenium(II) inhibited cells of human A-498 kidney cancer at IC(50)=0.54 microM and 1.0 microM, respectively, and so distinctly better than free melophlin C. Another synergistic effect of coordinating melophlins to bioactive metals was found in the growth inhibition of the melophlin C-resistant bacterium Micrococcus luteus by Ga, La and Ru complexes of melophlin C.
Assuntos
Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Metais/química , Compostos Organometálicos/química , Pirrolidinas/química , Pirrolidinonas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Micrococcus luteus/efeitos dos fármacos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologiaRESUMO
The marine tetramic acid (=1,5-dihydro-4-hydroxy-2H-pyrrol-2-ones) derivatives melophlin P, Q, and R (1p-1r, resp.) were synthesized for the first time in only four steps. Together with the congenerous melophlins A-C and G, they were also tested for antimicrobial and cytotoxic effects. Melophlins B, C, P, Q, and R, which share a 5-Me residue, showed some antibacterial activity, mainly in Gram-positive bacteria. Melophlins B, C, and R, which have Me-branched 3-acyl side chains in common, inhibited the growth of cells of human KB-3-1 cervix carcinoma, A-498 kidney carcinoma, and U-937 leukemia with IC(50) values <10 muM. They were similar in activity to cisplatin. Melophlin Q, also Me-branched, was astoundingly specific in inhibiting A-498 kidney cancer cells, while melophlin P inhibited U-937 leukemia cells particularly well. The position of the Me branch is decisive for the magnitude of the antiproliferative effect of the melophlin couples B/C and R/Q.
Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Pirrolidinonas/química , Células Tumorais CultivadasRESUMO
Abiraterone, a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer. Since steroidal compounds often show side effects attributable to their structure, we have tried to replace the sterane scaffold by nonsteroidal core structures. The design and synthesis of 20 new abiraterone mimetics are described. Their activities have been tested with recombinant human CYP17 expressed in E. coli. Promising compounds were further evaluated for selectivity against CYP11B1, CYP11B2, and the hepatic CYP3A4. Compounds 19 and 20 showed comparable activity to abiraterone (IC50 values of 144 and 64 nM vs 72 nM) and similar or even better selectivity against the other CYP enzymes. Selected compounds were also docked into our homology model, and the same binding modes as for abiraterone were found.
Assuntos
Androstenóis/síntese química , Androstenóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Androstenos , Androstenóis/uso terapêutico , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Modelos Moleculares , Proteínas Recombinantes/efeitos dos fármacosRESUMO
Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.2 and 2 microM, respectively) and 21 (591 nM). Compound 21 showed only weak inhibition of CYP3A4 (32 and 64% at 2 and 10 microM, respectively). Both compounds, however, exhibited moderate to strong inhibition of the glucocorticoid-forming enzyme CYP11B1. The most interesting compounds were docked into our protein model. They bound into one of the modes which we have previously published. New interaction regions were identified.
Assuntos
Compostos de Bifenilo/química , Desenho de Fármacos , Inibidores Enzimáticos , Imidazóis/química , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/biossíntese , Relação Estrutura-AtividadeRESUMO
Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.
Assuntos
Compostos Heterocíclicos/farmacocinética , Imidazóis/farmacocinética , Modelos Moleculares , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Sítios de Ligação , Disponibilidade Biológica , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Concentração Inibidora 50 , Fígado/enzimologia , Hidrocarbonetos Policíclicos Aromáticos/química , Testosterona/sangueRESUMO
Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15 showed a good inhibition of the target enzyme (31% and 66% at 0.2 and 2 microM, respectively), and little inhibition of the most important hepatic enzyme CYP3A4 (6% and 19% inhibition at 0.2 and 2 microM, respectively) and the key enzyme of glucocorticoid biosynthesis CYP11B1 (3% and 23% inhibition at 0.2 and 2 microM, respectively). Docking studies revealed that this compound does not assume the same binding mode as steroidal ligands.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Fígado/enzimologia , Modelos Moleculares , Naftalenos/química , Progesterona/química , Esteroide 17-alfa-Hidroxilase/química , Esteroide 17-alfa-Hidroxilase/metabolismoRESUMO
The enzyme inhibitor RK-682 (5R)-(+)-1 was prepared in solution and on a solid support from (2R)-glycerates in five steps and ca. 40% overall yield. Key steps were a ring-closing tandem addition-Wittig alkenation reaction of the respective protected or immobilized glycerates with the ylide Ph(3)PCCO and the 3-acylation of the tetronic acids thus obtained with palmitic acid. A similar route extended by a mesylation-elimination sequence led to antibiotic agglomerins A-C 2 featuring 3-acyl-5-methylidenetetronic acid structures.
Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Fosfoproteínas Fosfatases/antagonistas & inibidores , 4-Butirolactona/análogos & derivados , Acilação , Furanos/química , Ácidos Glicéricos/química , Estrutura Molecular , Ácido Palmítico/química , Fosfoproteínas Fosfatases/síntese químicaRESUMO
Polystyrene-bound cumulated ylide Ph3PCCO was prepared on a large scale in two steps. It reacts with Grignard compounds, amines and alcohols to give immobilized acyl, amide and ester ylides, respectively. Their Wittig reactions lead to alkenes free of phosphane oxide. Optically pure 5-substituted tetramates were obtained from reactions of resin-bound Ph3PCCO with alpha-ammonium esters in one step. The mycotoxin (-)-tenuazonic acid was accordingly prepared in just three steps.