RESUMO
Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11-deoxycorticosterone hydroxylation by 11ß-hydroxylase. [(3)H]Metyrapol and 4-[(131)I]iodometomidate bind with high affinity to membranes prepared from bovine and rat adrenals. Here we report inhibitory potencies of several compounds structurally related to one or both of these adrenostatic drugs, against the binding of both radioligands to rat adrenal membranes. While derivatives of etomidate inhibited the binding of both radioligands with similar potencies, derivatives of metyrapone inhibited the binding of 4-[(131)I]iodometomidate about 10 times weaker than the binding of [(3)H]metyrapol. By X-ray structure analysis the absolute configuration of (+)-1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1-propanol [(+)-11, a derivative of metyrapol] was established as (R). We introduce 1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1-propanone (9; Ki = 6 nM), 2-(1-imidazolyl)-2-methyl-1-phenyl-1-propanone (13; 2 nM), and (R)-(+)-[1-(4-iodophenyl)ethyl]-1H-imidazole (34; 4 nM) as new high affinity ligands for the metyrapol binding site on 11ß-hydroxylase and discuss our results in relation to a proposed active site model of 11ß-hydroxylase.
Assuntos
Glândulas Suprarrenais/metabolismo , Membrana Celular/metabolismo , Etomidato/análogos & derivados , Metirapona/química , Animais , Sítios de Ligação , Bovinos , Etomidato/química , Etomidato/metabolismo , Metirapona/metabolismo , RatosAssuntos
Antineoplásicos/síntese química , Paclitaxel/análogos & derivados , Paclitaxel/síntese química , Taxoides , Adenocarcinoma/tratamento farmacológico , Animais , Antineoplásicos/toxicidade , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Macrolídeos , Microtúbulos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/toxicidadeRESUMO
Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.
Assuntos
Antineoplásicos/síntese química , Taxoides/síntese química , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama , Química Orgânica/métodos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Epotilonas/farmacologia , Feminino , Humanos , Indicadores e Reagentes , Macrolídeos , Estrutura Molecular , Paclitaxel/farmacologia , Poríferos/química , Fuso Acromático/efeitos dos fármacos , Estereoisomerismo , Taxoides/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The microtubule-stabilizing antitumor agent laulimalide (1) has been obtained in by new synthetic route. The carbon skeleton was assembled by means of Julia-Kocienski (C16-C17) and Horner-Wadsworth-Emmons (C21-C22) olefinations. Still-Gennari olefination was used for the C2-C3 ring closure. The key step of the synthesis was a regioselective C16-C17 matched Sharpless asymmetric epoxidation.