DISCOVERY OF NOVEL MACROLIDE ANTIBIOTICS AND METHODOLOGY DEVELOPMENT OF N-SULFINYL METALLODIENAMINES

My Ph.D. research consists of two components: discovery of novel macrolide antibiotics and methodology development of N-sulfinyl metallodienamines. To tackle bacterial resistance, new antibiotics are desperately needed. My research objective is to address this need by designing, synthesizing, and evaluating novel macrolide antibiotics based on the best-in-class drug candidate, solithromycin. The drug discovery including following three projects: 1) Synthesis of solithromycin analogs wherein the desosamine sugar has been replaced with an acyclic amino alcohol surrogate; 2) In cellulo Click chemistry wherein the bacterial cell serves as the reaction vessel and the ribosome catalyzes the formation of triazole cycloadducts by testing different combinations of azide and alkyne fragments. One of the mechanisms of resistance to macrolide antibiotics is exemplified by methylation of A2058 by the methyltransferase encoded in erm genes. Methylation or dimethylation of A2058 leads to a steric clash with the macrolides and reduces the affinity of the macrolide for the ribosome. Thus, the bacterial resistant can be relieved via disrupting steric clashes between desosamine and A2058 residues. In 2017, I started a new project looking at the scope of the acyclic domino Michael/Mannich reaction to prepare chiral cyclohexenes developed by a previous group member, Dr. Vijay Chatare. This reaction is highly regioselective and stereoselective. Recent research showed that this reaction could be utilized on acroleins, acrylates and unsaturated ketones. Thus, we applied this useful methodology towards the concise total synthesis of (+)-ibogamine.

Grantor dc:publisher

Temple University. Libraries

Year dc:date.issued

2019

Author dc:creator

• Jin, Xiao

Advisor dc:contributor.advisor

• Andrade, Rodrigo B.

Committee members dc:contributor.committeemember

• Sieburth, Scott McNeill
• Davis, Franklin A.
• Cannon, Kevin C.

• Chemistry
• Domino Michael Mannich
• Ibogamine
• In cellulo click
• In situ click
• Macrolide antibiotics
• N-sulfinyl metallodienamine

Statement dc:rights

• IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/20.500.12613/615

OAI identifier oai:identifier

oai:scholarshare.temple.edu:20.500.12613/615