Our continuing examination of naturally occurring antitumor agents that derive their biological properties through sequence-selective DNA binding resulted in a detailed study of yatakemycin. 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 first- and second-generation syntheses of the natural product in efforts that provided both the natural and the unnatural enantiomers. The unnatural enantiomer was just as effective and potent as the natural product itself.
These efforts not only provided a sufficient amount of the scarce natural product for detailed studies of its properties but also enabled the assignment of its 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 yatakemycin. With the systematic preparation of more than 70 analogs, we have defined key structural features responsible for the biological properties of this antitumor agent.
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 cell wall peptidoglycan, 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 activity of members of the vancomycin family and to explore approaches to improvements in the drugs' 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 in the bacterial cell wall precursor 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 primarily to destabilizing lone-pair interactions
(100-fold) rather than to the simple loss of a single hydrogen bond (10-fold) in
the bound complex (Fig. 2).
This finding has consequences in the reengineering of vancomycin to bind D-Ala-D-Lac so that antimicrobial 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. Examination of this aglycon revealed that such a reengineering of vancomycin provides antibiotics active against vancomycin-sensitive and vancomycin-resistant bacteria.
Ramoplanin, a naturally occurring complex of 3 components, represents a new and potent antibiotic 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 the ramoplanin A1 and A3 aglycons (minor components), 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, was slightly more potent and much more stable than the natural product and provided a stable template for detailed structure-function studies.
Clark, R.C., Pfeiffer, S.S., Boger, D.L. Diastereoselective Diels-Alder reactions of N-sulfonyl-1-aza-1,3-butadienes with optically active enol ethers: an asymmetric variant of the 1-azadiene Diels-Alder reaction. J. Am. Chem. Soc. 128:2587, 2006.
Crowley, B.M., Boger, D.L. Total synthesis and evaluation of [ψ[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J. Am. Chem. Soc. 128:2885, 2006.
DeMartino, J.K., Hwang, I., Xu, L., Wilson, I.A., Boger, D.L. Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase. J. Med. Chem. 49:2998, 2006.
Elliott, G.I., Fuchs, J.R., Blagg, B.S.J., Ishikawa, H., Tao, H., Yuan, Z.-Q., Boger, D.L. Intramolecular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. J. Am. Chem. Soc. 128:10589, 2006.
Elliott, G.I., Velcicky, J., Ishikawa, H., Li, Y., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindorosine: tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition of 1,3,4-oxadiazoles. Angew. Chem. Int. Ed. 45:620, 2006.
Fang, X., Tiyanont, K., Zhang, Y., Wanner, J., Boger, D., Walker, S. The mechanism of action of ramoplanin and enduracidin, Mol. Biosyst. 2:69, 2006.
Hamasaki, A., Ducray, R., Boger, D.L. Two novel 1,2,4,5-tetrazines that participate in inverse electron demand Diels-Alder reactions with an unexpected regioselectivity. J. Org. Chem. 71:185, 2006.
Ishikawa, H., Elliott, G.I., Velcicky, J., Choi, Y., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindoline and related alkaloids. J. Am. Chem. Soc. 128:10596, 2006.
Lawhorn, B.G., Boga, S.B., Wolkenberg, S.E., Boger, D.L. Total synthesis of cytostatin. Heterocycles 70:65, 2006.
Lawhorn, B.G., Boga, S.B., Wolkenberg, S.E., Colby, D.A., Gauss, C.-M., Swingle, M.R., Amable, L., Honkanen, R.E., Boger, D.L. Total synthesis of cytostatin, its C10-C11 diastereomers and additional key analogues: impact on PP2A inhibition. J. Am. Chem. Soc. 128:16720, 2006.
Romero, F.A., Hwang, I., Boger, D.L. Delineation of a fundamental α-ketoheterocycle substituent effect for use in the design of enzyme inhibitors. J. Am. Chem. Soc. 128:14004, 2006.
Schnermann, M.J., Romero, F.A., Hwang, I., Nakamaru-Ogiso, E., Yagi, T., Boger, D.L. Total synthesis of piericidin A1 and B1 and key analogues. J. Am. Chem. Soc. 128:11799, 2006.
Tichenor, M.S., Trzupek, J.D., Kastrinsky, D.B., Shiga, F., Hwang, I., Boger, D.L. Asymmetric total synthesis of (+)- and ent-(–)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer. J. Am. Chem. Soc. 128:15683, 2006.
Trzupek, J.D., Gottesfeld, J.M., Boger, D.L. Alkylation of duplex DNA in nucleosome core particles by duocarmycin SA and yatakemycin. Nat. Chem. Biol. 2:79, 2006.