RESUMO
N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (-78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates.
Assuntos
Aziridinas/química , Cetonas/química , Lítio/química , Metanol/química , Estrutura Molecular , Compostos Organometálicos/química , EstereoisomerismoRESUMO
Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.
Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Benzoquinonas/química , Benzoquinonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico/metabolismo , Helicobacter pylori/química , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Estrutura Molecular , Streptomyces/química , Relação Estrutura-AtividadeRESUMO
Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/química , Streptomyces/metabolismo , Antineoplásicos/metabolismo , Calorimetria/métodos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fluorbenzenos/metabolismo , Fluorbenzenos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Modelos Moleculares , Quinonas/química , Streptomyces/genética , meta-Aminobenzoatos/metabolismo , meta-Aminobenzoatos/farmacologiaRESUMO
Supplementing a culture of a mutant strain of Actinosynnema pretiosum that is unable to biosynthesize aminohydroxy benzoic acid (AHBA), with 3-azido-5-hydroxy-benzoic acid and 3-azido-5-amino-benzoic acid, unexpectedly yielded anilino ansamitocins instead of the expected azido derivatives. This is the first example of the bioreduction of organic azides. The unique nature of these results was demonstrated when 3-azido-5-amino-benzoic acid was fed to the corresponding AHBA blocked mutant of Streptomyces hygroscopicus, the geldanamycin producer. This mutasynthetic experiment yielded the fully processed azido derivative of geldanamycin.
