Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

7-25-2016

Graduate Advisor

Cynthia Dupureur

Committee

Dupureur, Cynthia

Dr. Chung Wong

Dr. Mike Nichols

Abstract

Polyamides are a class of DNA minor groove binders that were developed from the natural product Distamycin A. PA25 (20-ring PA) showed better activity (3-fold) in the elimination of HPV16 episomes than PA1 (14-ring PA). Binding studies of PA1 and PA25 were performed in the long control region of HPV16 (7348-122 bp). PA1 showed similar binding affinity to perfect match and single mismatch binding sites. PA1 bound to double, triple, and quadruple mismatch sites with lower affinity. PA25 bound with similar binding affinity to perfect through triple mismatch binding sites. PA25 bound quadruple mismatch sites and nonspecifically. Therefore, it was concluded that PA25 is better at accommodating mismatches in its binding sites. The serine hydrolase family has a catalytic triad that consists of Serine, Histidine, and Glutamic/Aspartic Acid. Acetylcholinesterase (AChE) belongs to the serine hydrolase family. AChE hydrolyzes acetylcholine to stop signal transmission between neurons and thus is a drug target for Alzheimer’s disease. The previously extracted natural product cyclophostin showed a low nM inhibitory effect against AChE; its phosphonate derivative irreversibly modified the AChE active site. The cyclophostin phosphate or phosphonate, bicyclic or monocyclic derivatives showed low μM potency against human AChE. Fluorination of the monocyclic phosphonate cyclophostin showed no inhibitory effect against AChE up to 100 μM. Hormone sensitive lipase (HSL) is also a serine hydrolase. It hydrolyzes diacylglycerol to monoacylglycerol and is a drug target for type II diabetes. The previously extracted natural product cyclipostin, showed low nM potency against HSL. Cyclipostin has a similar structure to cyclophostin; the only difference is that cyclipostin has a long alkyl chain off the phosphate moiety. SAR studies on the cyclipostin derivatives showed that absence of the long alkyl chain and the phosphate to phosphonate substitution in the bicyclic framework decreased the inhibitory effect against HSL while lactone ring opening did not affect inhibition. SAR studies in the monocyclic phosphonate framework showed that compounds with the alkyl chain on the phosphate moiety have a better inhibitory effect than compounds with the alkyl chain on the 5th carbon in the seven-membered ring.

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Chemistry Commons

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