CHIBA Kenji Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Team Leader, 創薬第一研究所, 主任研究員
SASAKI Shigeo Research Laboratory, Taito Co., Ltd., Senior Researcher, 研究員
HAMAMAMICHI Norimitsu Kyoto Pharmaceutical University, Researcher, 研究員 (60054011)
NISHIDE Kiyoharu Kyoto Pharmaceutical University, Assistant Professor, 助教授 (10237711)
|Budget Amount *help
¥11,600,000 (Direct Cost : ¥11,600,000)
Fiscal Year 1996 : ¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1995 : ¥8,400,000 (Direct Cost : ¥8,400,000)
Immunosuppressants are clinically important for organ transplantations and the treatment of autoimmune diseases. Since cyclosporin A (CsA) and FK-506 were introduced, the success rate in organ transplantations has increased remarkably. These compounds have very similar mechanisms of action, inhibiting the production of interleukin-2 (IL-2), but higher doses of both compounds induce renal dysfunction and other side effects. Therefore, less toxic drugs for the prevention of graft rejection are needed.
Several immunosuppressants, ISP-I [myriocin=thermozymocidin] and mycestericin A-G,were isolated from culture broths of Isaria sinclairii and Mycelia sterilia, respectively. In order to investigate structure-activity relationships, extensive modification 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. Among them, 2-amino-2-tetradecylpropane-1,3-diol hydrochloride, ISP-I-55
, showed the lowest toxicity. ISP-I-55 was developed to FTY720 by incorporation of a phenyl ring into the side chain. FTY720 is expected as a powerful candidate for safer immunosuppresant for organ transplantations and for the treatment of autoimmune diseases.
Mycestericins F and G were identical with dihydro-mycestericins 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. The first total synthesis of four new immunosuppressants, mycetericins D-G,has been accomplished.
ISP-I was found to suppress the proliferation of an interleukin-2-dependent cytotoxic T cell line, CTLL-2, through the inhibition of serine palmitoyltransferase, which catalyzes the committed step of sphingolipid biosynthesis.
FTY720 indicated an oral synergistic effect in combination with a subtherapeutic dose of CsA. Less