Boger, Dale - The Scripps Research Institute

研究领域

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. Synthetic Methodology 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. Bioorganic Chemistry 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.

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C. J. Dreyton, E. D. Anderson, V. Subramanian, D. L. Boger, P. R. Thompson, Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation, Bioorg. Med. Chem. Lett. 2014, 22, 1362–1369. K. Lee, D. L. Boger, Total Syntheses of (?)-Kopsifoline D and (?)-Deoxoapodine: Divergent Total Synthesis via Late-Stage Key Strategic Bond Formation, J. Am. Chem. Soc. 2014, 136, 3312–3317. K. Otrubova, B. F. Cravatt, D. L. Boger, Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase, J. Med. Chem. 2014, 57, 1079–1089. A. S. Duerfeldt, D. L. Boger, Total Syntheses of (?)-Pyrimidoblamic Acid and P-3A, J. Am. Chem. Soc. 2014, 136, 2119–2125. E. L. Campbell, C. K. Skepper, K. Sankar, K. K. Duncan, D. L. Boger, Transannular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Total Synthesis of a Unique Set of Vinblastine Analogues, Org. Lett. 2013, 15, 5306–5309. T. J. Barker, K. K. Duncan, K. Otrubova, D. L. Boger, Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line, ACS Med. Chem. Lett. 2013, 4, 985–988. A. L. Wolfe, K. K. Duncan, J. P. Lajiness, K. Zhu, A. S. Duerfeldt, and D. L. Boger, A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin SA class of DNA alkylating antitumor drugs: hydrophobic binding-driven bonding, J. Med. Chem. 2013, 56, 6845–6857. M. Gochin, L. R. Whitby, A. H. Phillips, and D. L. Boger, NMR-assisted computational studies of peptidometric inhibitors bound in the hydrophobic pocket of HIV-1 glycoprotein 41, J. Compt. Aids Med. Des. 2013, 27, 569–582. S. Connelly, J. K. DeMartino, D. L. Boger, and I. A. Wilson, Biological and structural evaluation of 10R- and 10S-methylthio-DDACTHF reveals a new role for sulfur in inhibition of glycinamide ribonucleotide transformylase, Biochemistry 2013, 52, 5133–5144. J. R. Pinchman and D. L. Boger, Investigation into the functional impact of the vancomycin C-ring aryl chloride, Bioorg. Med. Chem. Lett. 2013, 23, 4817–4819. J. R. Pinchman and D. L. Boger, Probing the role of the vancomycin E-ring chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues, J. Med. Chem. 2013, 56, 4116–4124. A. L. Wolfe, K. K. Duncan, N. K. Parelkar, D. Brown, G. A. Vielhauer, and Dale. L. Boger, Efficacious cyclic N-acyl O-amino phenol duocarmycin prodrugs, J. Med. Chem. 2013, 56, 4109–4115. G. A. Vielhauer, M. Swink, N. K. Parelkar, J. P. Lajiness, A. L. Wolfe, and D. L. Boger, Evaluation of a Redcutively Activated Duocarmycin Prodrug Against Murine and Human Solid Cancers, Cancer Biol. Ther. 2013, 14, 527–536. K. Otrubova, M. Brown, M. S. McCormick, G. W. Han, S. T. O'Neal, B. F. Cravatt, R. C. Stevens, A. H. Lichtman, and D. L. Boger, Rational Design of Fatty Acid Amide Hydrolase Inhibitors That Act by Covalently Bonding to Two Active Site Residues, J. Am. Chem. Soc. 2013, 135, 6289–6299. T. C. Turner, K. Shibayama, and D. L. Boger, Hypervalent iodine(III)-promoted intermolecular C-C coupling of vindoline with β-ketoesters and related substrates, Org. Lett. 2013, 15, 1100–1103. J. Xie, A. L. Wolfe, and D. L. Boger, Total synthesis of kopsinine, Org. Lett. 2013, 15, 868–870. S. P. Breazzano, Y. B. Poudel, and D. L. Boger, A Pd(0)-mediated indole (macro)cyclization reaction, J. Am. Chem. Soc. 2013, 135, 1600–1606. E. K. Leggans, K. K. Duncan, T. J. Barker, K. D. Schleicher, and D. L. Boger, A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20’ urea derivatives, J. Med. Chem. 2013, 56, 628–639. K. D. Schleicher, Y. Sasaki, A. Tam, D. Kato, K. K. Duncan, and D. L. Boger, Total synthesis and evaluation of vinblastine analogues containing systematic deep-seated modifications in the vindoline subunit ring system: core redesign, J. Med. Chem. 2013, 56, 483–495. T. J. Barker and D. L. Boger, Fe(III)/NaBH4-mediated free radical hydrofluorination of unactivated alkenes, J. Am. Chem. Soc. 2012, 134, 13588–13591.