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Ficellomycin: An Investigation into Its Synthesis and Biological Activity Kaylib Robinson, and Amanda Wolfe Department of Chemistry, University of North Carolina Asheville, Asheville, NC 28804. Abstract.

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Ficellomycin: An Investigation into Its

Synthesis and Biological Activity

Kaylib Robinson, and Amanda Wolfe

Department of Chemistry, University of North Carolina Asheville, Asheville, NC 28804

Abstract

  • In Scheme 1, the first 4 steps have been carried out, resulting in the synthesis of Structure 4.
  • So far, high percent yields suggest that Scheme 1 may be an efficient route to synthesize ficellomycin.
  • Future work includes completing the synthesis of ficellomycin’s coreand performing assays to
  • determine the compound’s biological activity.
  • Scheme 1. Potential scheme for the synthesis of ficellomycin’score.

Results and Discussion

Ficellomycin. is a compound produced by the Streptomyces ficellus bacterium that has been found to inhibit the growth of a number of bacteria, including some antibiotic-resistant strains.1 There has not been a significant amount of research done on ficellomycin, because the compound is unstable due to a constituent azabicycle ring (Fig. 1). However, previous research suggests that ficellomycin may inhibit bacterial replication by a different mechanism than many other antibacterial compounds currently on the market, making it a potentially significant antibiotic in an increasingly antibiotic-resistant environment. The objective of this research is to determine the most efficient way to synthesize ficellomycin, find a more stable structure for the compound, and test its biological activity using biological assays. Specifically, research will involve starting from the chiral amino acid serine and using [3+2]-azide alkene cycloaddition to synthesize the core of ficellomycin.

  • Two initial syntheses of Structure 3 resulted in high percent yields of the methyl-ester hydrochloride:
  • Synthesis 1: 85.15% yield
  • Synthesis 2: 87.95% yield
  • These high percent yields are a promising start for using Scheme 1 in the synthesis of ficellomycin’s core. If similar high percent yields continue to be encountered in each of the remaining steps, then the proposed scheme may be an excellent scheme to use for the synthesis of the core of ficellomycin.

Introduction

Conclusions and Future Work

  • Ficellomycin is structurally similar to azinomycin A and B, which are known anticancer compounds.2 All three compounds contain a 3-membered azabicycle ring, which has been show to endown the azinomycin’s with their anticancer properties.(Fig 1).
  • It is hypothesized that the azabicycle gives ficellomycin its antibacterial properties.
  • However, the azabicycle makes ficellomycin highly unstable and difficult to synthesize.
  • The objective of this research is to determine a way to synthesize ficellomycin and stabililize its azabicycle core.

Figure 1. Structural comparison of ficellomycin and azinomycin A and B

Experimental Methods

  • The synthesis of the core of ficellomycin will be attempted starting from the chiral amino acid L-serine and using a late [3+2]-azide alkene cycloaddition (Scheme 1).
  • Scheme 1 has been carried through the synthesis of Structure 4.
  • C-1 of L-serine was methylated using methyl hydroxide and acetyl chloride (AcCl).
  • This product was then treated with di-tert-butyl dicarbonate (Boc2O), tetrahydrofuran (THF), and tri-ethyl amine (Et3N) to protect the amine group on C-2.
  • In the third step, a Swern Oxidation reaction was carried out, effectively reducing the alcohol on C-3 to an aldehyde, using oxalyl chloride ((COCl)2), dimthylsulfoxide (DMSO), and Et3N.
  • The results from the latter two steps were verified using Thin Layer Chromatography (TLC) and NMR.

References

1. Argoudelis, A.D; Reusser, F.; Mizsak, S.A.; Bacynskyj, L.; Antibiotics Produced by Streptomyces ficellus. Journal of Antibiotics,1976, 29(10), 1001-1014.

2. Reusser, F.; Ficellomycin and Feldamycin; Inhibitors of Bacterial Semiconservative DNA Replication. Biochemistry, 1977, 16, 3406-3412.

Acknowledgements

Special thanks to Dr. Amanda Wolfe for her guidance and support in the lab.