Date of Completion

6-25-2018

Embargo Period

7-5-2019

Keywords

UL12, Enolase, Ras, aminocarbonylation, cross-coupling, NOESY

Major Advisor

Dr. Dennis Wright

Associate Advisor

Dr. Amy Howell

Associate Advisor

Dr. Nicholas Leadbeater

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Metalloenzymes have gained interest in drug development. In this study, small molecules with metal binding groups were synthesized to target two metalloenzymes: alkaline nuclease (UL12) that causes a viral infection resulted in the simplex herpes 1 disease. The other enzyme was E. colienolase which is essential for the survival of several pathogens. Three general motifs were modified in this study inspired from natural products. Tropolone was diversified through aminocarbonylation and cross coupling reaction with diethyl phosphite to provide a series of tropolone derivatives. Pyridone series which has two sites for diversifications was also prepared. The last series was based on 8-hydroxyquinoline-7-carboxylic acid motif. In addition to these three motifs, the natural product SF-2312 and its analogs were prepared to target E. colienolase.

Results showed that the SF-2312 was potent against enolase with IC50of 33 nM. The other three motifs had moderate activity against enolase with IC50between 8 and 20 mM. The crystal structures of enolase co-crystallized with SF-2312 and the substrate 2-PGA were determined. These structures were used in molecular docking and the results of this experiment indicated that interactions with Lys392 is essential for potency against enolase.

Screening of the synthesized compounds against the alkaline nuclease enzyme resulted in one lead motif. The 8-hydroxyquinoline-7-carboxamide derivatives with hydrophobic residues were active against this enzyme with IC50between 6 and 10 mM. Molecular modeling was conducted on the crystal structure of the protein homolog of UL12 (KSHV-SOX). The results of this experiment showed that interactions of ligands with Tyr373 led to a significant activity against UL12.

The APT1 enzyme was targeted using analogs of palmostatin M. The initial results indicated that the polarity of the chain at C4 is essential in the activity of this motif. The presence of an alkene residue at C3 diminished the activity of the probes. Reduction of the a-alkylidene-b-lactone series and screening the corresponding analogs revealed that trans-analogs with a sulfoxide group in the chain at C4 were active. Analogs where the chain at C3 of the b-lactone contains sulfonamide are in the process of screening.

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