Five new derivatives of nonactic and homo-nonactic acids from Streptomyces globisporus Toma ´s ˇR ˇ ezanka, a, * Jaroslav Spı ´z ˇek, a Ve ˇra Pr ˇikrylova ´, a Ales ˇ Prell a and Valery M. Dembitsky b a Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic b Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel Received 10 February 2004; revised 12 March 2004; accepted 1 April 2004 Abstract—In addition to the known compounds of the type of nonactic and homononactic acids and their lactones, dilactones and tetralactones, five new compounds, namely homononactyl-nonactoate, a dilactone consisting of nonactic and homononactic acids and three cyclic trimers with nonactic and homononactic acids, were isolated from a strain of Streptomyces globisporus. Their structures, including the absolute configurations of the hydroxyl and methyl groups, were determined by extensive spectroscopic techniques such as UV, IR, MS, 1D and 2D NMR. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction Macrotetrolides exhibit a very wide range of effects, ranging from antimicrobial to insecticidal, acaricidal (miticidal), antiprotozoan (coccidiostatic) and antiparasitic (anthel- minthic). 1 Their newly described immunosuppressive activity 2 has important consequences for medicine (trans- plantations, treatment of autoimmune diseases). Nonactin, monactin, dinactin, trinactin and tetranactin isolated from a variety of Streptomyces species are cyclotetralactones derived from nonactic (1) acid and homononactic (2) acid as building units of ionophoretic character. With the exception of nonactin, they exhibit, in addition to antibacterial and antifungal activity, also remarkable acaricidal, insecticidal, coccidiostatic and anthelminthic effects. 1 Nonactic and homononactic acids are plant growth stimulators and exhibit specific insecticidal effects. 3 There are reports in the literature on the biological effects of a mixture of macrotetrolides (polynactin) or their components (especially tetranactin). The biological activity of nonactic acids has been reported only infrequently, whereas that of their homologs (macrotetrolides G, D, C, and E and isodinactin or isotrinactin) was not tested at all. This work is part of an on going study 4 performed concerned with the isolation and identification of new antibiotics produced in cultures of different species of the genus Streptomyces. In our screening studies for new products of pesticidal compounds 1 we isolated soil micro- organisms S. globisporus and S. griseus from which we obtained the macrotetrolides—nonactin, monactin, dinactin and trinactin by HPLC on normal phase. 5,6 Free nonactic and homononactic acids were isolated from the strain S. griseus by RP-HPLC. 7 For the identification of metabolites containing nonactic and homonactic acids we employed LC-MS/APCI, as described previously. 8 By using gradient elution and highly effective column (,26,500 plates/25 cm), we could separate and identify five new compounds (homononactyl-nonactoate, bilactone consisting of nonactic and homononactic acids and three cyclic trimers with nonactic and homononactic acids), in addition to 12 compounds that had been described previously. 2. Results and discussion A mixture of antibiotics were isolated from a strain of S. globisporus. 6 After repeated crystallization of the major part of the nonactin, monactin, dinactin, and trinactin mixture, the mother liquors were separated by means of semipreparative HPLC on normal phase and two main fractions were obtained. One of them contained compounds without a free carboxyl group (lactones), whereas the other group included compounds with a single free carboxyl group. By further chromatography on RP-HPLC it was possible to obtain a total of 12 compounds. Of them lactone 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.04.006 Tetrahedron 60 (2004) 4781–4787 * Corresponding author. Tel.: þ420-241-062-300; fax: þ420-241-062-347; e-mail address: rezanka@biomed.cas.cz Keywords: Streptomyces globisporus; Nonactic acid; Homo-nonactic acid; Dilactone; Trilactones.