College of Science & Engineering

Synthesis and Characterisation of Bottromycin Precursor -Amino Acids

Supervisor: Dr Sudha Shankar

School: Chemistry

Description:

At this time when we are going through an unprecedented global pandemic, it is an unarguable fact that new and advanced drugs are of paramount importance. A pressing issue is the development of new medicines that treat microbial infections to prevent the growing health threat posed by resistant pathogenic microorganisms. Many drug-resistant pathogenic strains have been identified to correspond to each of these traditional antimicrobial drugs. As a result, developing a new antimicrobials is becoming more and more difficult. Today, peptide natural products are highly represented in antimicrobial therapeutics and in clinical use. Studies reveals that naturally occurring peptide i.e Bottromycin having non-proteinogenic amino acid and distinct stereochemical challenges, are one of the best targets for development of new class of antimicrobial drug. Also, bottromycin has been observed with no cross-resistance to the tetracycline-resistant strains S. aureus because of different mechanism of action and binding sites1 .

Our research group proposed new synthetic strategy for synthesis of Bottromycin that involves modern solid phase peptide chemistry techniques which will be used to improve the current solution-phase synthesis. 2 . The power of a solid phase peptide synthesis in the total synthesis of complex cyclic peptides could be demonstrated by its single round synthetic protocol in a very short time. The concise synthetic routes provides a practical and economical approach for further structure-activity-relationship study of their analogues. Currently we are working to develop concise synthetic route for Bottromycin and their analogues using solid phase strategy which requires synthesis and incorporation of non-proteinogenic amino acid i.e Fmoc-Thia--Ala. So, in this proposed work, we will develop one-pot synthetic route for the synthesis of Thia--Ala amino acids and characterize using various analytical techniques. Further, the N-terminus of Thia- -Ala amino acid is protected by Fmoc group for its further use in synthesis of bottromycin. Also, the racemic mixture of synthesized -amino acid will be separated using enzymatic method. The planned protocol will be more efficient and environment friendly as the one-pot synthetic strategy circumvents tedious intermediate isolation and purification procedures with simple filtrations.

Objectives:

1.Synthesis of non-protein Thia--Ala amino acid (2).

2.Fmoc-protection and enzymatic resolution of synthesized amino acid (3-5).

3.Purification of synthesized amino acids and derivative using column chromatography and highperformance liquid chromatography (HPLC).Further, characterization will be done LC-MS, high- resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), melting point instrument, polarimeter and Fourier-transform infrared spectroscopy (FT-IR).

References: (1) Franz, L., Kazmaier, U., Truman, A. W., & Koehnke, J. (2021). Bottromycins-biosynthesis, synthesis and activity. Natural Product Reports.; (2) Yamada, T., Yagita, M., Kobayashi, Y., Sennari, G., Shimamura, H., Matsui, H., ... & Sunazuka, T. (2018). Synthesis and evaluation of antibacterial activity of bottromycins. The Journal of Organic Chemistry, 83(13), 7135-7149.