The Chemistry and Biological Activity of Platensimycin. Kaitlyn Gray Chem March 2008
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1 The Chemistry and Biological Activity of Platensimycin Kaitlyn Gray Chem March 2008
2 Multidrug-Resistant Bacteria thicillin resistant Stapholoccus areus (MRSA) N2 C 2 Cl Vancomycin resistant enterococci (VRE) N N 2 C Cl N N vancomycin N N N N 2 Klein, E.; Smith, D.L.; Laxminarayan, R. Emerg. Infect. Dis. 2007, 13, 1840.
3 A Novel Antibiotic Discovery and Biological Activity Total Synthesis Structure/Function Studies
4 Fatty Acid Synthesis (FAS) Type I (associated) FAS Found in mammals ighly integrated multienzyme Single protein carries out all steps of FAS Type II (dissociated) FAS Found in bacteria and plants Class of discrete enzymes Each enzyme carries out a single step of FAS Lomakin, I.B.; Xiong, Y.; Steitz, T.A. Cell 2007, 129, 319. uang, W. et al. Embo J. 1998, 17, äbich, D.; von Nussbaum, F. ChemdChem 2006, 1, 951.
5 An Ideal Antibacterial Target äbich, D.; von Nussbaum, F. ChemdChem 2006, 1, 951.
6 Discovery of Platensimycin Sensitized FabF for inhibition by decreasing its expression Screened 250,000 microbial extracts Extract from South African soil sample was active Platensimycin isolated from Streptomyces platensis Wang, J. et al. Nature 2006, 441, 358. Singh, S. B. et al. J. Am. Chem. Soc. 2006, 128,
7 N Biological Activity platensimycin rganism and genotype Platensimycin Linezolid Antibacterial activity (MIC, μg ml -1 ) S. aureus (MRSA) S. aureus (MRSA, macrolide R ) S. aureus (MRSA, linezolid R ) 1 32 S. aureus (VISA, vancomycin I ) Enterococcus faecium (VRE) E. coli (wild-type) >64 >64 E. coli (tolc) Toxicity (IC 50, μg ml -1 ) ela MTT >1,000 >100 Wang, J. et al. Nature 2006, 441, 358.
8 Studies on chanism Direct Binding Assay Used a radioactive label on DPMN Binding of DMPN to FabF produces a detectable increase in signal Binding in the Presence and Absence of an Acyl Donor Wang, J. et al. Nature 2006, 441, 358.
9 Wang, J. et al. Nature 2006, 441, 358. lsen, J.G.; Kadziola, A.; von Wettstein-Knowles, P.; Siggaard-Andersen, M.; Larsen, S. Structure (Camb) 2001, 9, 233. Conformational Changes of FabF Apo FabF (blue) and FabF (C163S) acylenzyme intermediate (yellow) FabF(C163S) acyl enzyme intermediate (yellow) and platensimycin bound FabF(C163Q) (cyan)
10 Crystal Structure 2.6 Å structure of platensimycin bound to FabF(C163Q) Aromatic amine lies in the active site Tetracyclic enone blocks the entrance to the active site Wang, J. et al. Nature 2006, 441, 358.
11 ydrogen Bonding Interactions Aromatic amine hydrogen bonding interactions Amide and tetracyclic enone hydrogen bonding interactions Wang, J. et al. Nature 2006, 441, 358.
12 Mode of Action äbich, D.; von Nussbaum, F. ChemdChem 2006, 1, 951.
13 A Novel Antibiotic Discovery and Biological Activity Total Synthesis Structure/Function Studies
14 Retrosynthetic Analysis cycloisomerization TBS Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
15 Synthesis of the Aromatic Amine Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
16 Racemic Synthesis of Tetracycle Precursor Et 1. LDA; Br 2. LDA; Br TBS,92%,97% TBS Et 1. DIBAL-; Cl 2. TBSCl, 84% over 2steps TBS [CpRu(CN) 3 ]PF 6, 92% TBS Ru TBS Ru 1. LiMDS, TMSCl 2. Pd(Ac) 2 68% over 2 steps aq. Cl 85% TBS d.r. 1:1 TBS Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, Trost, B.M.; Muller, T.J.J.; Martinez, J. J. Am. Chem. Soc. 1995, 117, 1888.
17 Ketyl Radical Cyclization/Etherification TFA, 87% TFA no reaction 9 steps, 11% yield Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371.
18 Completion of (±)-Platensimycin sn Ns KMDS, I, 88% KMDS, I,79% Cl Cl PinB Ru Ph PCy 3,85% PinB 6:1 E:Z 3 N, 95% NaCl 2,95% 1. 2 C MM N 2 MM ATU, Et 3 N, 85% 2. Li; aq. Cl, 90% N (±)-platensimycin 16 steps (LLS) 4.5% yield Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
19 Making the Route Enantioselective N (-)- platensimycin amide bond formation 2 C MM N 2 MM + double alkylation ketyl radical cyclization/ etherification enantioselective cycloisomerization Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.
20 Enantioselective Cycloisomerization TMS 1. TMSTf, Et 3 N 2. nbuli, C()CN IBX, MP 67% over 3 steps aq Cl, 91% TBS TBS C 2 TBS C 2 C 2 [{Rh(cod)Cl} 2 ], AgSbF 6, (S)-BINAP, 91% Rh C 2 Rh * P P * * P C 2 P * >95% ee C 2 Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, Lei, A.; Waldkirch, J.P.; e, M.; Zhang, X. Angew. Chem. Int. Ed. 2002, 41, 4526.
21 Completing the Tetracyclic Enone 16 steps, 5.6% yield Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
22 Another Approach to the Tetracyclic Enone N (-)- platensimycin Tiefenbacher, K.; Mulzer, J. Angew. Chem. Int. Ed. 2008, 47, Li, P.; Payette, J. N.; Yamamoto,. J. Am. Chem. Soc. 2007, 129, 9534.
23 Enantioselective Diels-Alder Li, P.; Payette, J. N.; Yamamoto,. J. Am. Chem. Soc. 2007, 129, Payette, J.N.; Yamamoto,. J. Am. Chem. Soc. 2007, 129, 9536.
24 Completion of the Tetracyclic Enone L-proline; Na, 95%, dr = 5:1 N C 2 11 steps, ~9% yield Li, P.; Payette, J. N.; Yamamoto,. J. Am. Chem. Soc. 2007, 129, Clemente, F.R.; ouk, K.N. Angew. Chem. Int. Ed. 2004, 43, 5766.
25 A Novel Antibiotic Discovery and Biological Activity Total Synthesis Structure/Function Studies
26 Examining Derivatives at the Tetracycle Can different tetracyclic frameworks still have potent biological activity? N (-)-adamantaplatensimycin N (-)-carbaplatensimycin Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2007, 46, Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem. Soc. 2007, 129,
27 Synthesis of (±)-Adamantaplatensimycin 13 steps (LLS), 12% yield Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2007, 46, 4712.
28 Antibacterial Activity rganism and genotype (-)-PMN (±)-PMN (+)-APMN (-)-APMN (±)-APMN Antibacterial activity (MIC, μg ml -1 ) MRSA > VRE > Escherichia coli >88 >88 >88 >88 >88 Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds, D. J. Angew. Chem. Int. Ed. 2007, 46, 4712.
29 Synthesis of Carbaplatensimycin Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem. Soc. 2007, 129,
30 Antibacterial Activity N (-)-platensimycin ((-)-PMN) rganism and genotype (-)-PMN (-)-APMN (-)-CPMN Antibacterial activity (MIC, μg ml -1 ) MRSA VRE Staphylococcus aureus Staphylococcus epidermidis < Bacillus cereus Lysteria monocytogenes < Escherichia coli >88 >88 >88 Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem. Soc. 2007, 129,
31 Conclusions Biological Activity Platensimycin targets the active site of FabF No cross resistance observed Pharmacological profile still limited Total Synthesis Tetracyclic enone is the key synthetic target Efficient and enantioselective routes have been developed Structure/Function Studies ydrogen bonding to the ether oxygen is important Derivatives of the tetracycle are still biologically active
32 Future Directions Focus structure/function studies on the aromatic amine Find derivatives with better plasma stability Look for other natural products in the same class Wang, J. et al Proc. Nat. Acad. Sci. 2007, 104, 7612.
33 Acknowledgements Professor Burke Burke Group Professor Baranger Chem 535
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