Synthetic and Mechanistic Studies of Myrocin Antitumor Agents

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Project Summary This proposal outlines a synthetic route to the antitumor natural product (−)-myrocin B (1, Figure 1).1 1 has never before been synthesized, though the related metabolite (+)-myrocin C (2, Figure 1)2,3 has been prepared.4,5 1 and 2 possess antibiotic properties and anticancer activity in vivo1–3,6 and 1 has been shown to be more active than 2.1 However, a comprehensive evaluation of the biological activity of either 1 or 2 has not been undertaken. In vitro model studies7 conducted on synthetic 2 suggest that these natural products may cross-link of DNA, but no experimental evidence using isolated oligonucleotides in vitro or seeking markers of DNA alkylation in culture have been disclosed. DNA-reactive agents comprise a considerable portion of the modern chemotherapeutic arsenal.8–11 Moreover, the purported mechanism of action of 1 and 2 closely resembles that of the illudin family of natural products12–17, a derivative of which (irofulven, 3, Figure 1)18,19 advanced to Phase II and III clinical trials as a chemotherapeutic for the treatment of breast, gastric, and pancreatic cancers, among others.12,20 The development of 3 exemplifies the underexplored potential of DNA cross- linking natural products as a viable source of chemotherapeutic agents. Total synthesis of 1 represents an essential first step in translational development toward a potential novel chemotherapeutic. Ready access to 1 could also provide a chemical tool for biological studies involving DNA cross-linking, which may ultimately result in further insight into important biological processes such as DNA repair. With biological evaluation and translational development of 1 as the ultimate goal, the synthetic route toward 1 is designed to be scalable and concise. The overall strategy centers on joining two complex cyclohexyl fragments through a robust acetylide addition, with a subsequent Heck-type cyclization envisioned to construct the final carbocyclic ring of the target. Specific aims entail: 1) development of syntheses of the two cyclohexyl precursor fragments of 1, 2) synthesis of the model system and analogue 4, and 3) completion of the synthesis of 1 using conditions developed for synthesis of 4. As projected, the total synthesis of 1 should be achieved in 15 steps. The long-term goals of this project include intensive mechanism of action studies of 1, design and synthesis of analogues for structure–function studies, elucidation of the activity and cell line selectivities of 1, and validation of 1 as a lead for translational development. Figure 1. The myrocins (1, 2), irofulven (3), and the analogue 4     CH3 H X CH OH O CH3 3 H CH3 OHCH3 HO OH O CH3 H CH3 O O OH O CH H 3 O OH O O X = O, (−)-myrocin B (1) X = H,H, (+)-myrocin C (2) irofulven (3) (−)-myrocin B analogue (4)