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Isolation, structure elucidation, antitumor activity and total synthesis of two novel spirotetronate natural products, spirohexenolides A and B

Brian Jones

Appointment Period: 2007-2009, Grant Years: [23,24]

Brian JonesSpirohexenolides A and B were isolated in our laboratory and shown to be cytotoxic to several tumor cell lines in the NCI 60 cell line screen, with increased activity in leukemia (GI50 value of 254 nM in RPMI-8226 cells), lung cancer (GI50 value of 191 nM in HOP-92 cells) and colon cancer (GI50 value of 565 nM in SW-620 cells).

These spirohexenolides were originally isolated from cultures of the soil microbes Streptomyces Platensis MER-11107. We sought to find media and growth conditions optimal for producing the spirohexenolides in higher, more reproducible yields. At the same type, access to the natural products was thought to be possible by chemical synthesis, since methodology has been developed by others for synthesizing these types of molecules. I worked on the development of this route during culturing downtimes (a typical fermentation experiment in liquid media takes 1 week for these microbes, and an extra day to complete purification of the natural products). After about 18 months of these culturing experiments, it was discovered that the media used for the fermentation of Micromonospora Chalcea, also soil microbes that produce spirotetronate natural products (the tetrocarcins), when used with our microbes, facilitated in the production of the spirohexenolides in reproducible yields of about 20 mg/L. Additionally, when polystyrene resins were added to the culturing media during fermentation, the optimized production conditions could yield more than 300 mg/L of spirohexenolide A. These increased production levels enabled the NCI to evaluate spirohexenolide A in their hollow-fiber assay with nude mice. In terms of development of the synthesis, the second generation route has constructed the entire carbon skeleton and all of the stereocenters of spirohexenolide B. The route to the most advanced intermediate is robust with the lowest yield in the linear sequence being 54%. I expect to complete the molecule in the next few months.

We are using the method I developed for making analogs of spirohexenolide A to improve its in vitro and in vivo antitumor activity via semisynthesis. Additionally, the synthetic methods developed could enable the synthesis of more active spirotetronates in the future.

Mandel AL, Jones BD, La Clair JJ, Burkart MD. A synthetic entry to pladienolide B and FD-895. Bioorg Med Chem Lett. (2007) 17:5159-64. PMID: 17681759; PMCID: PMC2652656.

Kang M, Jones BD, Mandel AL, Hammons JC, DiPasquale AG, Rheingold AL, La Clair JJ, Burkart MD. Isolation, structure elucidation, and antitumor activity of spirohexenolides A and B. J Org Chem. (2009) 74:9054-61. PMID: 19883063.

Jones BD, La Clair JJ, Moore CE, Rheingold AL, Burkart MD. Convergent route to the spirohexenolide macrocycle. Org Lett. (2010) 12:4516-9. PMID: 20849075; PMCID: PMC2956428.

Kang MJ, Jones BD, Mandel AL, Hammons JC, Pasquale AG, Rheingold AL, La Clair JJ, Burkart MD, Isolation, Structure Elucidation, and Antitumor Activity of Spirohexenolide A and B, submitted.

Jones BD, La Clair JJ, Burkart MD. Total Synthesis of (±)-Spirohexenolide B, in preparation.