Part I. design and synthesis of prototypes as leads on a compound library aimed at plasmepsin ii inhibition. Part II. synthesis and evaluation of modified nucleotides for dna aptamer selection

by 1978- DiDonato, Dana A

DIDONATO, DANA A. Part I. Design and Synthesis of Prototypes as Leads on a Compound Library Aimed at Plasmepsin II Inhibition. Part II. Synthesis and Evaluation of Modified Nucleotides for DNA Aptamer Selection. (Under the direction of Dr. Bruce E. Eaton.) Malaria infects approximately 300 million people worldwide each year and of those infected, between 1 and 1.5 million people die from the disease. The increasing number of individuals both infected with and dying from this disease is due, in part, to the rise in the number of parasites that are resistant to conventional drug therapies. 1-6 My research focuses on the synthesis of prototypes to be expanded into leads on a compound library, which, exhibit selective inhibition towards the malarial protease plasmepsin II (Plm II). The attributes of the prototypes include the following: (1) A simple core which can be rapidly elaborated upon in a small number of synthetic steps; (2) A compact, low molecular weight substrate, which is bioavailable as well as biodistributable; and (3) Allows for reverse binding with the enzyme active site. A short series of synthetic transformations were performed to arrive at the key intermediate, enol 5. With this compound in hand, the prototypes were generated and their log P and C log P values determined using ChemDraw Ultra. The log P and C log P values ranged from 1 – 5. DNA, deoxyribonucleic acid, has become an attractive material for functional molecules due to its chemical stability and its ability to be directly amplified using the polymerase chain reaction (PCR). A limitation to the use of DNA as a functional molecule is its lowered activity, i.e. antibodies versus aptamers and enzymes versus ribozymes.1 In an effort to overcome this limitation, the research to be discussed focuses on enhancing the chemical diversity of DNA via the synthesis of modified deoxyuridines (*dUTPs) and deoxycytidines (*dCTPs). The functionality is introduced at the 5 – position through a carboxyamidation reaction. Because any primary amine can be used for this transformation, it is possible to examine a wide range of structural motifs. The aforementioned modified deoxynucleotides will be incorporated into in vitro selection to aid in the isolation of novel protein aptamers.