This grant application is divided into three major sections to study the total synthesis and biosynthesis of three unrelated families of natural products: (1) taxol;(2) the paraherquamides, stephacidins, norgeamides, notoamides, malbrancheamides, asperparalines and congeners;and (3) the okaramines. I. Stephacidins, Paraherquamides, norgeamides, notoamides, malbrancheamides &Asperparalines. The goals of this program are to utilize the tools of total synthesis to fully elucidate the biosynthetic pathway from the primary amino acids (isoleucine, proline, and tryptophan) and mevalonate-derived isoprene moieties to the polycyclic indole alkaloids comprising the paraherquamides, stephacidins, avrainvillamide, notoamides, norgeamides, malbrancheamides and asperparalines. Provocative evidence has been elucidated in our laboratory indicating that this class of alkaloids, are constructed by a rare biosynthetic intramolecular [4+2] cycloaddition reaction. Through the use of total chemical synthesis of isotopically labeled intermediate metabolites, key features of the biosynthetic pathways to these complex secondary metabolites will be experimentally elucidated. In collaboration with Prof. David Sherman's laboratory (University of Michigan), we are actively engaged in the identification, isolation, cloning and functional expression of the biosynthetic gene clusters responsible for the biosynthesis of these agents. Stephacidins A, B and the norgeamides A-D represent new structural and mechanistic classes of anticancer agents. Their mechanism of action is unique which holds promise to develop more selective and less toxic chemotherapeutic agents for treating cancer. The recently discovered malbrancheamides display calmodulin inhibitory activity which is an entirely new biological activity for this family of natural products. Our broad synthetic platform has allowed the synthesis of numerous unnatural, structural analogs of these natural products and are continuously being evaluated for cytotoxic activity and calmodulin inhibitory acitivity. II. Taxol. The biosynthesis of taxol from the cyclization of geranylgeranyl pyrophosphate (ggPP) via taxa- 4(5),11(12)-diene, will be studied in collaboration with Prof. Rod Croteau's laboratory at Washington State University. The sequence of hydroxylation reactions from this simple diterpenoid comprising the core A/B/C ring system of taxol shall be elucidated. Taxol is the number one selling anti-cancer drug in the world. Determination of the biosynthetic pathway to taxol holds significant promise in assisting the expected growing demand for this drug because of limitations on its isolation and production which comes from the Yew tree. III. Okaramines. As a natural out-growth of our work on the paraherquamide family of prenylated indole alkaloids, we propose to initiate a new project to study the total synthesis and biosynthesis of the okaramines, which are complex, polycyclic prenylated indole alkaloids that possess insecticidal activity.
The purpose of this application is to utilize the tools of chemical synthesis to study the molecular details of how Nature biosynthesizes anti-cancer drugs. In one sub-project, involving the study of taxol biosynthesis, the goal is to improve the cell-culture yields of production of the drug, which is currently obtained from the Yew tree, the harvest of which, has created a severe supply-demand problem and important environmental consequences. In addition, the chemical technologies being developed, will be applied to the design and synthesis of new anti-cancer drugs.
|Newmister, Sean A; Romminger, Stelamar; Schmidt, Jennifer J et al. (2018) Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway. Org Biomol Chem 16:6450-6459|
|Newmister, Sean A; Li, Shasha; Garcia-Borràs, Marc et al. (2018) Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis. Nat Chem Biol 14:345-351|
|Klas, Kimberly R; Kato, Hikaru; Frisvad, Jens C et al. (2018) Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi. Nat Prod Rep 35:532-558|
|Fraley, Amy E; Garcia-Borràs, Marc; Tripathi, Ashootosh et al. (2017) Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids. J Am Chem Soc 139:12060-12068|
|Sugimoto, Kayo; Sadahiro, Yusaku; Kagiyama, Ippei et al. (2017) Isolation of amoenamide A and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600. Tetrahedron Lett 58:2797-2800|
|Kato, Hikaru; Kai, Aika; Kawabata, Tetsuro et al. (2017) Enantioselective inhibitory abilities of enantiomers of notoamides against RANKL-induced formation of multinuclear osteoclasts. Bioorg Med Chem Lett 27:4975-4978|
|Li, Shasha; Lowell, Andrew N; Newmister, Sean A et al. (2017) Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids. Nat Chem Biol 13:467-469|
|Kagiyama, Ippei; Kato, Hikaru; Nehira, Tatsuo et al. (2016) Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404). Angew Chem Int Ed Engl 55:1128-32|
|Newmister, Sean A; Gober, Claire M; Romminger, Stelamar et al. (2016) OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30. J Am Chem Soc 138:11176-84|
|Le, V H; Inai, M; Williams, R M et al. (2015) Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. Nat Prod Rep 32:328-47|
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