Part I: Synthesis of nucleobase lactams: Putative anti-HIV drugs. Part II. Synthesis of potential soluble epoxide hydrolase (sEH) inhibitors

Date of Completion

January 2005

Keywords

Chemistry, Biochemistry|Chemistry, Organic

Degree

Ph.D.

Abstract

Part I. New class of nucleoside analogs have been synthesized in comparable yields. The lactam based nucleoside analogs have been synthesized from D- and L-Glutamic acids in 7 and 8 steps. The biological activities of these nucleoside analogs have never been explored before. The synthesis involved the construction of the key intermediate alcohols, 6-Hydroxy-3-phenyl-tetrahydro-pyrrolo[1,2-O] oxazol-5-one (shown below, 1--4). Antipodes of the key intermediate alcohol (1--4) were synthesized from enantiomerically pure D- and L- glutamic acid.* ^ Both antipodes of 3-adeninyl-5-hydroxymethyl-2-pyrrolidinon and carbovir analogue partially protected 3-guaninyl-5-hydroxymethyl-2-pyrrolidinone (23) were synthesized. Adenine and guanine heterocycles were successfully attached to the lactam ring through coupling of antipode 2 with adenine, and 4 with adenine and properly protected guanine under Mitsunobu conditions (DIAD, PPh3). Stereochemical integrity was maintained throughout the synthetic steps. The biological activity (particularly the anti HIV-1 activity) of the synthesized lactam based nucleoside analogs will be evaluated. ^ Part II. Soluble epoxide hydrolase catalyzes a hydrolytic epoxide ring opening reaction to yield vicinal diols and at the same time its N-terminal domain was recently implicated to have a distinctive phosphatase function. The biological impacts of the recently discovered phosphatase function of the N-terminal domain is still under investigation, thus developing inhibitors to selectively block this function will be invaluable to shed some light on detailed aspects of this function. Along the same lines, potent phosphatase inhibitors might provide an explanation for the existence of these two distinct and chemically irrelevant functions at the same enzyme. ^ Interestingly, a phosphatase (and/or pyrophosphatase) that is structurally similar to the N-terminal domain of sEH, is believed to contribute to the biosynthesis of insect juvenile hormone (JH). JH is required to ensure growth and maturation of larva and for the production of eggs in female insects in addition to the vital developmental and physiological functions. Subsequently, potent phosphates and/or pyrophosphatase inhibitors might provide powerful means to control insect development. ^ Careful analysis of the sEH N-terminal domain architectural and structural features combined with preliminary results obtained by Grant and coworkers on farnesol derivative inhibitors, allowed us to design potential inhibitors for the catalytic function of this part of the enzyme. For this purpose several alcohols were targeted for synthesis and designed to have a long hydrophobic chain that will fit into a 25 Å long cleft, situated along the active site lined with extensive hydrophobic surface that can interact with hydrophobic substrates. ^ *Please refer to dissertation for diagrams.^

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