The primary focus of this application is to study the total synthesis and biosynthesis of complex, biomedically significant natural products constituted of tetrahydroisoquinolines. The synthetic chemistry that will be developed shall be utilized to prepare analogues of the natural substances as biological, biosynthetic and mechanistic probes. This proposal is primarily hypothesis-driven, and extensively employs new synthetic methodologies developed in this laboratory for the construction of such agents.
The specific aims of this program are to study the interaction of the natural antitumor antibiotics and mechanistically inspired synthetic analogs, including ecteinascidin 743 (Et-743), saframycin, jorumycin, tetrazomine, lemonomycin and the bioxalomycins with cellular nucleic acids. The DNA-alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and proteins that bind to cellular nucleic acids. We have recently discovered that bioxalomycin 12 specifically cross-links duplex DNA at 54dCpG34 steps. We propose to elucidate the exact molecular structure of the covalent adduct. This finding has inspired new design concepts for simpler analogs based on the tetrahydroisoquinoline core that may be capable of alkylating and cross-linking DNA as well as potentially cross-linking DNA to DNA-binding proteins. The antiproliferative activity of this family of alkaloids is intimately associated with the capacity of these agents to bind to and covalently modify DNA. This is particularly evident in the case of Et-743. Plans are presented to mechanistically separate the DNA alkylation and cross-linking chemistry of these agents from their capacity to inflict oxidative damage on cells. The investigation of the biosynthesis of Et-743 with a particular focus on the late-stage assembly of the macrocyclic sulfide-bridged spiro-tetrahydroisoquinoline ring system will be pursued. We plan to apply high throughput genome sequencing methods using 454 technology to identify the Et-743 biosynthetic gene cluster from Ecteinascidia turbinata. The ultimate goals of the biosynthesis studies are to genetically engineer a fermentable microorganism to produce Et-743 for clinical use.

Public Health Relevance

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 particular, this program will deploy new technologies to produce the clinically relevant anticancer drug ecteinascidin 743 (Et-743) on industrially practical scale through genetic engineering of a microbial host. In addition, the chemical technologies being developed will be applied to the design and synthesis of new anti-cancer drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Lees, Robert G
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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Jiménez-Somarribas, Alberto; Williams, Robert M (2013) Synthetic studies on lemonomycin: construction of the tetracyclic core. Tetrahedron 69:7505-7512
Williams, Robert M (2011) Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism. J Org Chem 76:4221-59
Williams, Robert M; Stille, J; Echavarren, A et al. (2011) Discussion Addendum for: 4-Methoxy-4'-nitrophenyl. Recent Advances in the Stille Biaryl Coupling Reaction and Applications in Complex Natural Products Synthesis. Organic Synth 88:197-201
Fishlock, Dan; Williams, Robert M (2008) Synthetic studies on Et-743. Assembly of the pentacyclic core and a formal total synthesis. J Org Chem 73:9594-600
Vincent, Guillaume; Lane, Jonathan W; Williams, Robert M (2007) Regioselectivity of Pictet-Spengler Cyclization Reactions to Construct the Pentacyclic Frameworks of the Ecteinascidin-Saframycin Class of Tetrahydroisoquinoline Antitumor Antibiotics. Tetrahedron Lett 48:3719-3722
Vincent, Guillaume; Williams, Robert M (2007) Asymmetric total synthesis of (-)-cribrostatin 4 (renieramycin H). Angew Chem Int Ed Engl 46:1517-20
Fishlock, Dan; Williams, Robert M (2006) Synthetic studies on Et-743. Asymmetric, stereocontrolled construction of the tetrahydroisoquinoline core via radical cyclization on a glyoxalimine. Org Lett 8:3299-301
Lane, Jonathan W; Estevez, Alberto; Mortara, Kyle et al. (2006) Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G. Bioorg Med Chem Lett 16:3180-3
Lane, Jonathan W; Chen, Yuyin; Williams, Robert M (2005) Asymmetric total syntheses of (-)-jorumycin, (-)-renieramycin G, 3-epi-jorumycin, and 3-epi-renieramycin G. J Am Chem Soc 127:12684-90
Jin, Wei; Metobo, Sammy; Williams, Robert M (2003) Synthetic studies on ecteinascidin-743: constructing a versatile pentacyclic intermediate for the synthesis of ecteinascidins and saframycins. Org Lett 5:2095-8

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