The structures of premithramycinone and demethylpremithramycinone, plausible early intermediates of the aureolic acid group antibiotic mithramycin

Abstract

The structures of premithramycinone and its demethyl analogue suggest that the aureolic acid antibiotics are biosynthetically formed via a tetracycline-type, and not a tetracenomycin-type, folded decaketide.

References

1. The structure elucidation on mithramycin by Thiem et al.(ref. 4), lead to a different sequence of the sug moieties. We reinvestigated the structure of the mithramycin, produced by S. argillaceus ATCC 12956, because of contradictions to the compounds found in our glycosyltransferase inhibition studie (ref. 21). The structure of mithramycin, produced by S. argillaceus, is definitely 1: E. Künzel, S.-E. Wohlert, R. Machinek, C. Méndez, J. A. Salas and J. Rohr, J. Org. Chem., submitted.
2. The Merck Index, ed. S. Budavari, M. J. O'Neil, A. Smith, P. E. Heckelman and J. F. Kinneary, Merck & Co., Whitehouse Station, NJ, 12th edn., number 7696, 1996, pp. 1298–1299.
3. J. D. Skarbek and M. K. Speedie, in Antitumor Compounds of Natural Origin, ed. A. Aszalos, CRC Press, Boca Raton, FL, 1981, vol. 1, pp. 191–235.
4. J. Thiem, G. Schneider and V. Sinnwell, Liebigs Ann. Chem., 1986, 814 and references cited therein.
5. W. A. Remers, in The Chemistry of Antitumor Antibiotics, Wiley-Interscience, New York, 1979, vol. 1, pp. 133–175.
6. H. Nakano, H. Ogawa, Y. Yamashita, R. Katahira, S. Chiba, T. Iwasaki and T. Ashizawa, WO 95 06054, JP Appl. 93/211572, 2.5. 1995(Chem. Abstr., 1995, 123, 8030p).
7. B. J. Kennedy, J. W. Yarbo, V. Kickertz and M. Sandberg Wollheim, Cancer Res., 1968, 28, 91.
8. E. G. Elias and J. T. Evans, J. Bone Jt. Surg., Am. Vol., 1972, 54-A, 1730.
9. M. Sastry and D. J. Patel, Biochemistry, 1993, 32, 6588.
10. A. Montanari and J. P. N. Rosazza, J. Antibiot., 1990, 43, 883.
11. G. Blanco, H. Fu, C. Mendez, C. Khosla and J. A. Salax, Chem. Biol., 1996, 3, 193.
12. E. Künzel, S.-E. Wohlert, C. Beninga, S. Haag, H. Decker, C. R. Hutchinson, G. Blanco, C. Mendez, J. A. Salas and J. Rohr, Chem. Eur. J., 1997, 3, 1675.
13. J. Rohr, J. Org. Chem., 1992, 57, 5217.
14. B. Shen, R. G. Summers, E. Wendt-Pienkowski and C. R. Hutchinson, J. Am. Chem. Soc., 1995, 117, 6811.
15. P. J. Kramer, R. J. X. Zawada, R. McDaniel, C. R. Hutchinson, D. A. Hopwood and C. Khosla, J. Am. Chem. Soc., 1997, 119, 635.
16. F. Lombó, K. Siems, A. F. Brana, C. Méndez, K. Bindseil and J. A. Salas, J. Bacteriol., 1997, 179, 3354.
17. F. Lombó, G. Blanco, E. Fernández, C. Mendez and J. A. Salas, Gene, 1996, 172, 87.
18. Selected data for 2: m/z(EI-MS) 414 (M⁺, 64%), 258 (100), 241 (25), 229 (22), 216 (20), 156 (72); λ(MeOH)/nm (ε) 230 (27 400), 276 (49 700), 323 (7700), 411 (13 100); λ_extr(MeOH)/nm (θ) 232 (–15 400), 284 (158 000), 412 (–23 800); ν_max(KBr)/cm^–1 3408, 2923, 1672, 1636, 1449, 1401, 1343, 1161, 1096, 1013, 996, 873, 743, 609. For 3: m/z(EI-MS) 400 (M⁺, 8%), 259 (61), 241 (48), 230 (100), 133 (90).
19. Yu. A. Berlin, M. N. Kolosov, I. V. Vasina and I. V. Yartseva, J. Chem. Soc., Chem. Commun., 1968, 762.
20. Y.-Z. Shu, J. Q. Cutrone, S. E. Klohr and S. Huang, J. Antibiot., 1995, 48, 1060.
21. Inactivation of a mithramycin-glycosyltransferase gene in the mithramycin producer S. argillaceus resulted in four different glycosylated compounds containing one, two or all three sugars of the mithramycin trisaccharide chain, and premithramycinone (for one monosaccharide) and its 9-methyl analogue (for the other mono-, di- and tri-saccharide), respectively, as aglycon moiety: E. Fernández, A. F. Braña, C. Méndez, J. A. Salas, U. Weiβbach, J. Rohr, unpublished results.
22. M. Gerlitz, G. Udvarnoki and J. Rohr, Angew. Chem., Int. Ed. Engl., 1995, 34, 1617.
23. This mechanistically interesting alternative to the Baeyer–Villiger oxidation was suggested by one of the referees.
24. Routine feeding experiments on S. argillaceus using [1-¹³C]- and [2-¹³C]-acetate resulted in an incorporation pattern in mithramycin identical to that found earlier in chromomycin A₃(ref. 10).