The Skaggs Institute for Chemical Biology
Faculty, Graduate Program
Synthetic Organic And Bioorganic Chemistry
Our research interests include the total synthesis of natural products, development of new synthetic methodology, heterocyclic chemistry, bioorganic and medicinal chemistry, the study of DNA-agent interactions, and the chemistry of antitumor antibiotics. We place special emphasis on investigations to define the structure-function relationships of natural or designed agents.
Our ongoing investigations emphasize the development and application of hetero Diels-Alder reactions, the thermal reactions of cyclopropenone ketals, inter- and intramolecular acyl radical-alkene addition reactions, medium and large ring cyclization procedures, and combinatorial chemistry. In each instance, the methodology development represents the investigation of chemistry projected as a key step in the total synthesis of a natural or nonnatural product.
Natural Products Total Synthesis
Problems recently or currently being addressed include vinblastine, vincristine, (+)-CC-1065 and functional analogs (antitumor antibiotic processing sequence selective DNA alkylation properties), duocarmycins (antitumor antibiotics possessing sequence selective DNA alkylation properties), yatakemycin, tropoloalkaloids, deoxybouvardin/bouvardin, K-13, OF4949-1 - OF4949-IV (immunopotentiating agents with confirmed antitumor activity), piperazinomycin, luzopeptins, sandramycin quinoxapeptins, thiocoraline and BE 22179, (DNA binding peptides with antitumor and antiviral properties), vancomycin, teicoplanin, ristocetin, chloropeptins, RP-66453, ramoplanin, bleomycin A2 (clinically employed antitumor agent), quinolinequinone antitumor antibiotics including streptonigrone, streptonigrin, and lavendamycin, isochrysohermidin, fredericamycin A (antitumor agents with topoisomerase I and II inhibitory activity), rhizoxin (antitumor antibiotic and potent mitotic inhibitor), fostriecin, cytostatin, phostriecin, combretastatins, and trikentrin A.
The orgin of interest in the specific agents detailed above rests with their properties and in many instances represents the selection of agents related by a projected property (e.g., (+)-CC-1065 and duocarmycin). Representatives of such efforts, studies on (+)-CC-1065 have been employed to identify agent structural features contributing to its sequence-selective DNA alkylation properties and the source of catalysis of the DNA alkylation reaction. Efforts are under way to develop DNA cross-linking agents of a predefined cross-link, to further understand the nature of the covalent and noncovalent agent-DNA interactions, and to apply this understanding to the de novo design of DNA-binding agents.
Collaborative efforts in securing biological data, 1H NMR of DNA-agent complexes, molecular modeling studies of large molecule-small molecule interactions, and experimental studies of DNA-agent interactions constitute an integral part of the program.
B.S., Chemistry, The University of Kansas, 1975
Ph.D., Chemistry, Harvard University, 1980
Searle Scholar Award, 1981-84; NIH Research Career Development Award, 1983-88; Alfred P. Sloan Fellow, 1985-89; ACS Arthur C. Cope Scholar Award, 1988; American Cyanamid Academic Award, 1988; ISHC Katritzky Award, 1997; ACS Award for Creativity in Organic Synthesis, 1999; Yamanouchi U.S.A. Faculty Award, 2000; Paul Janssen Prize for Creativity in Organic Synthesis, 2002; RSC Adrien Albert Medal, 2003; Fellow, American Association for the Advancement of Science, 2003; Member, Medicinal Chemistry Study Section, National Institutes of Health, 1999-2003; Member, American Academy of Arts and Sciences, 2006; ACS Guenther Award in Natural Products, 2007; Fellow, Royal Society of Chemistry, 2009; Fellow, American Chemical Society, 2010; Editor-in-Chief of Bioorganic and Medicinal Chemistry Letters, and Executive Board Member of Tetrahedron Publications; Editorial Boards, Tetrahedron Publications, Organic Reactions, Chemtracts, Drug Discovery Today, Progress in Heterocyclic Chemistry, Current Opinion in Drug Discovery and Development, Journal of Heterocyclic Chemistry, Current Drugs.
C. P. Burke, N. Haq, and D. L. Boger, Total synthesis, assignment of relative and absolute stereochemistry, and structural reassignment of phostriecin (aka sultriecin), J. Am. Chem. Soc. 2010, 132, 2157–2159.
H. Shimamura, S. P. Breazzano, J. Garfunkle, F. S. Kimball, J. D. Trzupek, and D. L. Boger, Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization, J. Am. Chem. Soc. 2010, 132, 7776–7783.
Y. Sasaki, D. Kato, and D. L. Boger, Asymmetric total synthesis of vindorosine, vindoline, and key vinblastine analogues, J. Am. Chem. Soc. 2010, 132, 13533–13544.
J. Xie, J. G. Pierce, R. C. James, A. Okano, and D. L. Boger, A redesigned vancomycin engineered for dual D-Ala-D-Ala and D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria, J. Am. Chem. Soc. 2011, 133, 13946–13949.
A. Okano, A. Nakayama, K. Wu, E. A. Lindsey, A. W. Schammel, Y. Feng, K. C. Collins, and D. L. Boger, Total synthesis and initial examination of [Ψ[C(=S)NH]Tpg4]vancomycin, [Ψ[C(=NH)NH]Tpg4]vancomycin, [Ψ[CH2NH]Tpg4]vancomycin and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics, J. Am. Chem. Soc. 2015, 137, 3693–3704
D. W. Carney, J. C. Lukesh III, D. M. Brody, M. M. Brutsch, and D. L. Boger, Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface, Proc. Natl. Acad. Sci. USA 2016, 113, 9691–9698.