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Selective chemical modifications of polymyxin B
J Weinstein1, A Afonso, E Moss
1Schering-Plough Research Institute, Department of Chemistry, Kenilworth, New Jersey 07033-0539, USA.
Bioorganic & Medicinal Chemistry Letters
|January 5, 1999
Summary
Researchers developed a method to protect and modify Polymyxin B, creating new derivatives. These novel Polymyxin B derivatives were synthesized and tested for antibacterial activity, offering potential new therapeutic options.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Microbiology
Background:
- Polymyxin B is a critical antibiotic for treating multidrug-resistant Gram-negative bacterial infections.
- Selective functionalization of Polymyxin B is challenging due to its complex structure.
- Development of new derivatives is crucial to overcome emerging resistance mechanisms.
Purpose of the Study:
- To develop a robust method for the selective protection and functionalization of Polymyxin B.
- To synthesize novel Polymyxin B derivatives with modifications at specific positions.
- To evaluate the antibacterial activity of the newly synthesized derivatives.
Main Methods:
- Polymyxin B monohydrochloride was protected using di-tert-butyl dicarbonate to yield tetra-BOC derivatives.
- A degradative sequence was employed to establish the structures of protected intermediates.
- A novel deprotection method using a strongly basic ion-exchange resin was developed for 2,4-dinitrophenylamines.
- Selective functionalization was achieved at the DAB1 and DAB9-gamma-amine positions of the protected derivatives.
- Antibacterial activity assays were performed on the synthesized Polymyxin B derivatives.
Main Results:
- Successfully synthesized tetra-BOC protected derivatives of Polymyxin B (1b and 1c).
- Established the structures of key intermediates (3 and 5) through a degradative process.
- Developed and validated an efficient deprotection strategy for 2,4-dinitrophenylamines.
- Generated a library of 22 novel Polymyxin B derivatives (6-27) via selective functionalization.
- Reported the antibacterial activity profiles of the synthesized derivatives.
Conclusions:
- A versatile synthetic route for selective modification of Polymyxin B has been established.
- The developed protection and deprotection methods facilitate the synthesis of diverse Polymyxin B analogs.
- The synthesized derivatives represent potential candidates for new antibacterial agents.
- This work expands the chemical space of Polymyxin B, aiding in the search for improved antibiotics.