RESUMO
Carbohydrate moieties are essential for the biological activity of anthracycline anticancer agents such as nogalamycin, which contains l-nogalose and l-nogalamine units. The former of these is attached through a canonical O-glycosidic linkage, but the latter is connected via an unusual dual linkage composed of C-C and O-glycosidic bonds. In this work, we have utilized enzyme immobilization techniques and synthesized l-rhodosamine-thymidine diphosphate (TDP) from α-d-glucose-1-TDP using seven enzymes. In a second step, we assembled the dual linkage system by attaching the aminosugar to an anthracycline aglycone acceptor using the glycosyl transferase SnogD and the α-ketoglutarate dependent oxygenase SnoK. Furthermore, our work indicates that the auxiliary P450-type protein SnogN facilitating glycosylation is surprisingly associated with attachment of the neutral sugar l-nogalose rather than the aminosugar l-nogalamine in nogalamycin biosynthesis.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Enzimas Imobilizadas/metabolismo , Nogalamicina/análogos & derivados , Nogalamicina/metabolismo , Streptomyces/enzimologia , Amino Açúcares/metabolismo , Antraciclinas/metabolismo , Antibióticos Antineoplásicos/síntese química , Biocatálise , Glicosilação , Nogalamicina/síntese química , Streptomyces/metabolismo , Nucleotídeos de Timina/metabolismoRESUMO
A novel reductive Heck cyclization approach was developed in order to construct a model DEF-benzoxocin ring system that is present in nogalamycin, menogaril, and related anthracycline antitumor antibiotics.
Assuntos
Antibióticos Antineoplásicos/síntese química , Menogaril/síntese química , Nogalamicina/síntese química , Antibióticos Antineoplásicos/química , Ciclização , Menogaril/química , Modelos Químicos , Estrutura Molecular , Nogalamicina/química , Streptomyces/químicaRESUMO
Nogalamycin (1) has been modified by changes at C-10 and C-7 and in the dimethylamino group to prepare an extensive series of analogues. The chemistry involved in the modifications and structure--activity relationships among these nogalamycin analogues are discussed, as well as comparisons with previously reported compounds 1, 7-con-O-methylnogarol (2), and disnogamycin (11).
Assuntos
Daunorrubicina/análogos & derivados , Nogalamicina/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Fenômenos Químicos , Química , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Camundongos , Nogalamicina/síntese química , Relação Estrutura-AtividadeRESUMO
Nogalamycin, an antitumor antibiotic, has been converted to a series of analogs by removal of the carbomethoxy group at C-10 and replacement of the neutral sugar at C-7 by other groups. Removal of the carbomethoxy group to give disnogamycin (6) followed by acidic alcoholysis gave pairs of isomeric 7-alkoxy compounds differing in configuration at C-7. Treatment of 6 with trifluoroacetic acid followed by nucleophiles gave a series of analogs having substituents at C-7 with a configuration at C-7 opposite to that of nogalamycin. Among the analogs prepared, 7-con-O-methylnogarol (7) is a highly active antitumor agent.