Ushikulides A and B, Immunosuppressants Produced by a Strain of Streptomyces sp.

Abstract

Novel immunosuppressants, ushikulides A and B, were isolated from the culture broth of Streptomyces sp. IUK-102. Ushikulides A and B both have the same molecular formula, determined as C 40 H 68 O 10 . The structures of both compounds were elucidated to be novel 22-membered macrolides. Both compounds showed immunosuppressive activity for murine splenocyte proliferation in vitro. Binding of each of these drug-protein complexes to a catalytic subunit of carcineurin causes inhibition of signal transduction in T cell activation [3]. However, these agents have some adverse side-effects such as nephrotoxicity and chronic rejection [4,5]. Another potent immunosuppressive agent is desired to develop a safer medical treatment. During our screening for immunosuppressants from microbial products, novel immunosuppressants ushikulides A (1) and B (2) were found in the culture broth of Streptomyces sp. IUK-102 (Fig. 1). This paper describes the isolation, structure elucidation, and biological activities of these compounds.The producing strain, Streptomyces sp. IUK-102, was isolated from a soil sample collected in Ibaraki prefecture, J. Antibiot. 58 (6)

Exploiting Orthogonally Reactive Functionality: Synthesis and Stereochemical Assignment of (−)-Ushikulide A

“…Upon isolation, this compound exhibits identical 1 H, 13 C, IR, HRMS & HPLC properties when compared to the same authentic sample. Measurement of the optical rotation {[α]24 D = −12° ( c 0.28, MeOH)} confirms that the absolute stereochemistry also matches that of natural ushikulide A1 {[α]25 D = −13° ( c 0.50, MeOH)}. In total, these data prove our tentative assignment to be correct and lead us to assign the complete structure of (−)-ushikulide A as depicted below.…”

“…IUK-102 (Figure 1). 1 This compound exhibits potent activity against murine splenic lymphocyte proliferation (IC 50 = 70 nM), rivaling that of the well-known cyclosporin A2 and FK506,3 which revolutionized organ transplant therapy by suppressing rejection. Takahashi’s structural assignment dealt with connectivity, not stereochemistry, as analysis of 1 by X-ray diffraction proved untenable in this particular case 4.…”

Atacamycins A–C, 22-membered antitumor macrolactones produced by Streptomyces sp. C38

“…From ushikulides which were isolated from a Streptomyces strain, an immunosuppressant activity was reported. 26 To the best of our knowledge, this is the first study describing an inhibitory effect of 22-membered macrolactones on the activity of the enzyme phosphodiesterase 4. In this context, the atacamycins and other compounds belonging to the 22-membered macrolactones could be considered as the drug candidates for the treatment of inflammatory diseases, such as chronic obstructive pulmonary diseases.…”

Progress towards the Synthesis of (‐)‐Ushikulide A: Synthesis of C1‐C15 Aliphatic and C17‐C31 Spiroketal Fragments by an Aldol Approach

“…(‐)‐Ushikulide A (1), is a 22‐membered spiroketal containing macrolide, isolated from the culture broth of Stryptomyces sp. IUK‐102 by Takashi and co‐worker in 2005, and known to have immunosuppressant activities for murine splenocyteproliferation in vitro (IC 50 76 μM) ,. Immunosuppression is the reduction of efficiency of the immune system, which helps to prevent organ rejection during organ transplants.…”