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.