Document Type
Dissertation
Degree
Doctor of Philosophy
Major
Chemistry, Organic
Date of Defense
4-5-2023
Graduate Advisor
Christopher D. Spilling, PhD
Committee
Eike Bauer, PhD
Janet Braddock-Wilking, PhD
Alexei V. Demchenko, PhD
Abstract
Cyclophostin and cyclipostins are naturally occurring organophosphates with common structural core units and different phosphate ester substituents. Cyclophostin is a cyclic phosphate triester with a chiral center at phosphorous and C-3a carbon atom while the cyclipostins have characteristic alkyl substituents with varying chain lengths at the phosphate center. Long-chain substituted monocyclic phosphate (2b) and phosphonate (2a) analogs of cyclophostin and cyclipostin are promising inhibitors against serine hydrolases acetylcholinesterase with an IC50 in the nanomolar range.
Biologically active β-lactones and lactams owe their activity, in part, to ring strain. The ring opening of β-lactones and lactams is much faster than that of larger ring-sized lactones. In phosphonate and phosphate chemistry, ring strain is observed in five-membered rings. We believe that altering the ring size of monocyclic enol phosphonates will cause variations in ring strain which will in turn affect their biological activities. New monocyclic phosphonate analogs of cyclophostin and cyclipostin have been synthesized and their biological activity against Mycobacterium abscessus has been evaluated.
Sepsis is a whole-body inflammation resulting from severe infection and potentially leads to septic shock and death. The prime cause of sepsis is the release of the bacterial endotoxin called lipopolysaccharide (LPS) into the blood system. LPS consists of three structural regions: a nonrepeating core oligosaccharide, a distal polysaccharide (O antigen), and a hydrophobic domain Lipid A. Lipid A is a poly acylated glucosamine disaccharide and is primarily responsible for the toxic activity. A structure-activity relationship study on LPS suggests that structurally modified Lipid A analogs have the potential to be developed as lead compounds for the treatment of sepsis. With the aim to investigate the impact of the side chain length and lipophilicity of the molecule on the activity and cytotoxicity, we synthesized a series of carbohydrate lactone analogs with varying chain lengths and evaluated their LPS antagonizing activity.
Recommended Citation
Kafle, Saroj, "Synthesis and Evaluation of Biologically Active Phosphorous Heterocycles and Lipid A Antagonist Compounds" (2023). Dissertations. 1299.
https://irl.umsl.edu/dissertation/1299