The Skaggs Institute
for Chemical Biology

Scientific Report 2006

Synthetic, Medicinal, and Bioorganic Chemistry

D.L. Boger, S.B. Boga, K. Bunker, R. Clark, D. Colby, J. Cottell, B. Crowley, J. DeMartino, G. Elliott, C. Ezzili, J. Fuchs, J. Garfunkle, A. Hamasaki, N. Haq, S. Hong, I. Hwang, H. Ishikawa, W. Jin, D. Kato, M. Kelso, F.S. Kimball, B. Lawhorn, S. Lee, C. Liu, K. MacMillan, J. Nam, P. Patel, A. Romero, M. Schnermann, A. Shaginian, C. Slown, J. Stover, L. Takaoka, H. Tao, M. Tichenor, J. Trzupek, L. Whitby, Y. Zhang

The research interests of our group include the total synthesis of biologically active natural products, the development of new synthetic methods, heterocyclic chemistry, bioorganic and medicinal chemistry, combinatorial chemistry, the study of DNA-agent interactions, and the chemistry of antitumor antibiotics. We place a special emphasis on investigations to define the structure-function relationships of natural or designed agents in efforts to understand the origin of the biological properties.

DNA-Binding Agents

Our continuing examination of naturally occurring antitumor agents that derive their biological properties through sequence-selective DNA binding resulted in a detailed exploration of yatakemycin. In the course of these studies, we defined the exceptional potency of the natural material; characterized its DNA alkylation properties, consisting of an adenine N3 alkylation central to a 5-bp adenine-thymine–rich site; and conducted a total synthesis of the natural product in efforts that provided both the natural and the unnatural enantiomers. The unnatural enantiomer was just as effective and as potent as the natural product itself. These efforts not only provided a sufficient amount of the scarce natural product for more detailed studies of its properties but also allowed the assignment of its previously unknown absolute configuration. Unexpectedly, these efforts also led to a reassignment of the structure of the natural product and revealed a new group (thiomethyl ester) in the molecule that contributes to the properties of the product (Fig. 1).

Fig. 1. Structure reassignment of yatakemycin based on total synthesis.

Vancomycin and Related Glycopeptide Antibiotics

Vancomycin and its family of related naturally occurring glycopeptides, which include teicoplanin and ristocetin, are used to treat infections caused by microorganisms resistant to other antibiotics. Antibiotics in the vancomycin family inhibit the synthesis of bacterial cell walls by binding to the terminal D-Ala-D-Ala of the precursor of the cell wall peptidogycan, thereby inhibiting the action of transpeptidases and transglycosylases required to complete the cell wall synthesis.

As part of a program to define the structural features that contribute to the properties of members of the vancomycin family and to explore approaches to improvements in their biological properties, we developed an efficient de novo synthesis of the aglycons of these antibiotics. The emergence of vancomycin resistance is associated with an alteration of the precursor in the bacterial cell wall to D-Ala-D-Lac, resulting in a 1000-fold loss in vancomycin-binding affinity and antimicrobial activity. We showed experimentally that this loss in binding affinity is due principally to destabilizing lone-pair interactions (100-fold) rather than to the simple loss of a single hydrogen bond (10-fold) in the bound complex. In turn, this finding has consequences in the reengineering of vancomycin to bind D-Ala-D-Lac so that activity against vancomycin-resistant bacteria can be restored. We recently completed the total synthesis of the [ψ[CH₂NH]Tpg⁴]vancomycin aglycon in which the residue 4 carbonyl and its destabilizing lone pairs have been removed from the vancomycin structure (Fig. 2). Examination of this aglycon revealed that such a reengineering of vancomycin provides antibiotics active against vancomycin-sensitive or vancomycin-resistant bacteria.

Fig. 2. Structure of [ψ[CH2NH]Tpg4]vancomycin aglycon.

Ramoplanin, a naturally occurring complex of 3 components, is emerging as a new and potent agent effective against antibiotic-resistant bacteria, including vancomycin-resistant strains. As a complement to our studies on the reengineering of vancomycin, we are examining this new class of antibiotics. To date, this research has resulted in the total synthesis of the ramoplanin A2 aglycon (major component of the complex), the total synthesis and structural reassignment of both the ramoplanin A1 and A3 aglycons, and the preparation of a series of key analogs. One analog, [Dap²]ramoplanin A2 aglycon in which the labile depsipeptide ester is replaced by a stable amide, is slightly more potent and much more stable than the natural product and provides a stable template for detailed structure-function studies (Fig. 3).

Fig. 3. Structure of ramoplanins.

Publications

Boger, D.L., Miyauchi, H., Du, W., Hardouin, C., Fecik, R.A., Cheng, H., Hwang, I., Hedrick, M.P., Leung, D., Acevedo, O., Guimarães, C.R.W., Jorgensen, W.L., Cravatt, B.F. Discovery of a potent, selective, and efficacious class of reversible
α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics.
J. Med. Chem. 48:1849, 2005.

Capps, K.J., Humiston, J., Dominique, R., Hwang, I., Boger, D.L. Discovery of a new class of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization. Bioorg. Med. Chem. Lett. 15:2840, 2005.

Cheng, H., Chong, Y., Hwang, I., Tavassoli, A., Zhang, Y., Wilson, I.A., Benkovic, S.J., Boger, D.L. Design, synthesis, and evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorg. Med. Chem. 13:3577, 2005.

Cheng, H., Hwang, I., Chong, Y., Tavassoli, A., Webb, M.E., Zhang, Y., Wilson, I.A., Benkovic, S.J., Boger, D.L. Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorg. Med. Chem. 13:3593, 2005.

Choi, Y., Ishikawa, H., Velcicky, J., Elliott, G.I., Miller, M.M., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindoline. Org. Lett. 7:4539, 2005.

Chong, Y., Hwang, I., Tavassoli, A., Zhang, Y., Wilson, I.A., Benkovic, S.J., Boger, D.L. Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF₃CO-DDACTHF. Bioorg. Med. Chem. 13:3587, 2005.

Chou, T.-C., Guan, Y., Soenen, D.R., Danishefsky, S.J., Boger, D.L. Potent reversal of multidrug resistance by ningalin and its use in drug combinations against human colon carcinoma xenografts in nude mice. Cancer Chemother. Pharmacol. 56:379, 2005.

Du, W., Hardouin, C., Cheng, H., Hwang, I., Boger, D.L. Heterocyclic sulfoxide and sulfone inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 15:103, 2005.

Guimarães, C.R.W., Boger, D.L., Jorgensen, W.L. Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations. J. Am. Chem. Soc. 127:17377, 2005.

Hamasaki, A., Zimpleman, J.M., Hwang, I., Boger, D.L. Total synthesis of ningalin D. J. Am. Chem. Soc. 127:10767, 2005.

Leung, D., Du, W., Hardouin, C., Cheng, H., Hwang, I., Cravatt, B.F., Boger, D.L. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. Bioorg. Med. Chem. Lett. 15:1423, 2005.

Schnermann, M.J., Boger, D.L. Total synthesis of piercidin A1 and B1. J. Am. Chem. Soc. 127:15704, 2005.

Tse, W.C., Boger, D.L. A fluorescent intercalator displacement (FID) assay for establishing DNA binding selectivity and affinity. In: Current Protocols in Nucleic Acid Chemistry. Beaucage, S.L., et al. (Eds.). Wiley & Sons, New York, in press.

Walker, S., Chen, L., Hu, Y., Rew, Y., Shin, D., Boger, D.L. Chemistry and biology of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. Chem. Rev. 105:449, 2005.

Yuan, Z., Ishikawa, H., Boger, D.L. Total synthesis of natural (+)- and ent-(–)-4-desacetoxy-6,7-dihydrovindorosine [corrected] and natural and ent-minovine: oxadiazole tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reaction [published correction appears in Org. Lett. 7:2079, 2005]. Org. Lett. 7:741, 2005.