Multisubstrate analogs of the glycinamide ribonucleotide formyltransferase reaction

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Title Multisubstrate analogs of the glycinamide ribonucleotide formyltransferase reaction
Publication Type dissertation
School or College College of Pharmacy
Department Medicinal Chemistry
Author Licato, Nicholas J.
Date 1986-06
Description A prototype multisubstrate analog of the glycinamide ribonucleo- tide formyltransferase (GAR Tfase) reaction would permit a more detailed study of the mechanism of formyl group transfer and allow for further determination of the parameters of enzyme binding and inhibition. The important structural features which could be modified in approaching a viable synthesis are discussed. The rationale for the types of structural modifications suggested, which include biological studies and their inferences are reviewed. The synthesis of diethyl N-2-isobutoxycarbonyl-5,8-dideaza folic acid, incorporating a novel carbamoyl blocking group has proven useful in the synthesis of a ureide-bridged intermediate towards a multisubstrate analog. The success of the N-2-isobutoxycarbonyl blocking group was limited to the dideazafolate class. Only the analog missing the pteridine portion of the analog, diethyl (N(2'3' -O-isopropylidene-(beta)-D-ribofuranos-1-yl)carbamoyl)methylureido - benzoylglutamate, was additionally approachable. Formation of an active acylation intermediate of the dideazafolate and phosgene allowed for the synthesis of the nucleoside, diethyl 2-isobutoxycarbonyl-5,8-dideaza-10-N((N(2'3'-O-isopropylidene-(beta)- D-ribofuranos-1-yl)carbamoyl)methyl)carbamoyl folic acid. Phospho- rylation of this nucleoside with a commercially available phosphoro- chloridate gave the pentultimate 5,8-dideaza multisubstrate analog. The characterization by proton NMR of the deblocked intermediates was successful through the tetraacid intermediate, 5,8-dideaza-10-N((N(2'3'-O-isopropylidene-(beta)-D-ribofuranos-1-yl) carbamoyl)methyl)carbamoyl folic acid-5'-phosphate. The difficul- ties toward this intermediate, as well as the results of application of several methods toward the fully deblocked intermediate are discussed.
Type Text
Publisher University of Utah
Subject Organic Chemistry; Pharmacy
Subject MESH Transferases; Purines
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Multisubstrate analog inhibitors of thymidylate synthetase." Spencer S. Eccles Health Sciences Library. Print version of "Multisubstrate analog inhibitors of thymidylate synthetase." available at J. Willard Marriott Library Special Collection. QP 6.5 1986 L53.
Rights Management © Nicholas J. Licato.
Format application/pdf
Format Medium application/pdf
Format Extent 1,525,718 bytes
Identifier undthes,5492
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 1,525,740 bytes
ARK ark:/87278/s6rj4m6h
Setname ir_etd
ID 190631
Reference URL https://collections.lib.utah.edu/ark:/87278/s6rj4m6h
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