RESUMO
Several immunosuppressants, ISP-I [(2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoeicos++ +-6-enoic acid, myriocin = thermozymocidin] and mycestericins A-G, were isolated from culture broths of Isaria sinclairii and Mycelia sterilia, respectively. In order to investigate structure-activity relationships, extensive modifications of ISP-I were conducted, and it was established that the fundamental structure possessing the immunosuppressive activity is a symmetrical 2-alkyl-2-aminopropane-1,3-diol. The tetradecyl, pentadecyl, and hexadecyl derivatives prolonged rat skin allograft survival in the combination of LEW donor and F344 recipient and were more effective than cyclosporin A. Among them, 2-amino-2-tetradecylpropane-1,3-diol hydrochloride, ISP-I-55, showed the lowest toxicity. ISP-I-55 is a promising lead compound for the development of effective immunosuppressants for organ transplantations and for the treatment of autoimmune diseases.
Assuntos
Ácidos Graxos Monoinsaturados/química , Imunossupressores/síntese química , Propilenoglicóis/química , Aciltransferases/metabolismo , Alquilação , Animais , Ascomicetos , Ácidos Eicosanoicos/química , Ácidos Graxos Insaturados/química , Interleucina-2/biossíntese , Camundongos , Ratos , Serina C-Palmitoiltransferase , Pele/efeitos dos fármacos , Baço/efeitos dos fármacosRESUMO
In order to investigate the structure-activity relationships, fourteen derivatives of myriocin ((2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14-oxoeicos- 6-enoic acid) were prepared and examined for immunosuppressive activity on mouse allogeneic mixed lymphocyte reaction in vitro. Among them, 14-deoxomyriocin ((2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2- hydroxymethyleicos-6-enoic acid) was the most potent. It also suppressed the generation of allo-reactive cytotoxic T lymphocytes in mice upon intraperitoneal administration, with a potency 10-fold greater than that of myriocin.
Assuntos
Antifúngicos/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Imunossupressores/farmacologia , Animais , Antifúngicos/síntese química , Ácidos Graxos Monoinsaturados/síntese química , Fungos/metabolismo , Imunossupressores/síntese química , Teste de Cultura Mista de Linfócitos , Camundongos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Mycestericins D, E, F and G were isolated from the culture broth of Mycelia sterilia ATCC 20349 as potent immunosuppressants. Mycestericins F and G were identical with dihydromycestericins D and E, respectively. Their absolute configurations were determined by use of the modified MOSHER'S method and by comparison of the CD spectra of their benzoate derivatives with those of synthetic analogs. Mycestericins D, E, F and G suppressed the proliferation of lymphocytes in the mouse allogeneic mixed lymphocyte reaction.