RESUMO
The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.
Assuntos
Inibidores Enzimáticos/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Administração Oral , Androstenos , Androstenóis/farmacologia , Animais , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Hormônio Luteinizante/sangue , Masculino , Microssomos/enzimologia , Tamanho do Órgão , Ratos , Ratos Wistar , Estereoisomerismo , Testículo/enzimologia , Testosterona/sangueRESUMO
The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.
Assuntos
Arilsulfatases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Estrogênios/metabolismo , Animais , Aromatase/metabolismo , Cumarínicos/farmacologia , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Esteril-Sulfatase , Sulfatases/metabolismo , Sulfonamidas/farmacologia , Ácidos Sulfônicos , Células Tumorais Cultivadas , Útero/enzimologia , Útero/metabolismoRESUMO
A series of novel, highly potent alpha(v)beta(3) antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and beta-amino acids were explored with respect to inhibition of alpha(v)beta(3) mediated cell adhesion and selectivity versus alpha(IIb)beta(3) binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.
Assuntos
Osteoporose/prevenção & controle , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Receptores de Vitronectina/antagonistas & inibidores , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Carbamatos/química , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Guanidina/química , Paratireoidectomia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Ratos , Receptores de Vitronectina/metabolismo , Sensibilidade e Especificidade , Sulfonamidas/química , Tiofenos/síntese química , Tiofenos/farmacologia , TireoidectomiaRESUMO
The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.
Assuntos
Hidantoínas/síntese química , Oligopeptídeos/síntese química , Fibrinogênio/metabolismo , Humanos , Imidazóis/síntese química , Estrutura Molecular , Peptídeos/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica/efeitos dos fármacos , Receptores de Vitronectina/antagonistas & inibidoresAssuntos
Sistemas de Informação em Laboratório Clínico/organização & administração , Redes de Comunicação de Computadores/organização & administração , Laboratórios Hospitalares/organização & administração , Confidencialidade , Documentação , Competição Econômica , Marketing de Serviços de Saúde , New York , Consultórios Médicos , Técnicas de PlanejamentoRESUMO
DL-(1-Amino-2-propenyl)phosphonic acid was synthesized through the sequential oxidation, sulfoxide elimination, and deprotection of diphenyl [1-[(benzyloxycarbonyl)amino]-3-(phenylthio)propyl] phosphonate. This analogue of vinylglycine is a strong inhibitor of the alanine racemases from Pseudomonas aeruginosa and Streptococcus faecalis and of the D-Ala:D-Ala ligase from this latter species. This molecule is ineffective against the whole bacterial cells. Unlike vinylglycine, this unsaturated phosphonate does not inhibit the following mammalian enzymes: aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase, which indicates its specificity. Thus, its incorporation in a peptide structure could induce interesting antimicrobial properties.
Assuntos
Alanina Racemase/antagonistas & inibidores , Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/farmacologia , Compostos Organofosforados/farmacologia , Alanina Transaminase/antagonistas & inibidores , Antibacterianos/síntese química , Aspartato Aminotransferases/antagonistas & inibidores , Bactérias/efeitos dos fármacos , D-Aminoácido Oxidase/antagonistas & inibidores , Compostos Organofosforados/síntese química , Peptídeo Sintases/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The (beta-chloro-, (beta, beta-dichloro-, and (beta, beta, beta-trichloro-alpha-aminoethyl)phosphonic acids have been synthesized and their inhibitory properties on the alanine racemases [EC 5.1.1.1] and the D-Ala:D-Ala ligases [EC 6.3.2.4] from Pseudomonas aeruginosa and Streptococcus faecalis have been evaluated. The monochloro and the dichloro derivatives of Ala-P exhibit a strong inhibition on the racemases of the two species tested but do not behave as suicide substrates. Only the D-Ala:D-Ala ligase of S. faecalis is inhibited by these compounds. The poor antibacterial activity observed with beta-chloro- and beta, beta-dichloro-Ala-P might be enhanced by the peptide-transport strategy.