Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols.
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.
Fujita
T
T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Hirose
R
R
Yoneta
M
M
Sasaki
S
S
Inoue
K
K
Kiuchi
M
M
Hirase
S
S
Chiba
K
K
Sakamoto
H
H
Arita
M
M
D000217:Acyltransferases / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D001203:Ascomycota; D004537:Eicosanoic Acids / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000138:chemical synthesis*; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D011409:Propylene Glycols / Q000737:chemistry*; D051381:Rats; D051102:Serine C-Palmitoyltransferase; D012867:Skin / Q000187:drug effects; D013154:Spleen / Q000187:drug effects
D004537:Eicosanoic Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; C087463:mycestericin B; C087462:mycestericin A; C087465:mycestericin D; C087464:mycestericin C; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; C001996:thermozymocidin