The development of novel pterin chemistry leading to potential dihydrofolate reductase inhibitors with potential antimalarial activity
Date
2012-01-31
Authors
Nxumalo, Winston
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
This thesis describes the application pteridine chemistry in various aspects of methodology
development and natural product synthesis. The introductory chapter sets the scene by describing
naturally occurring pteridines, their applications in biological systems, and recent synthetic
strategies.
Firstly, Sonogashira coupling reactions employing benzenesulfonyloxy-O-pteridine (27) and
terminal alkynes to give various 6-substituted pteridines are described. This methodology
allowed for the total synthesis of a natural occurring pteridine, Sepiapterin-C (46).
Negishi coupling reactions involving benzenesulfonyloxy-O-pteridine (27) and various Znreagents
are also reported. This methodology, representing the first Negishi coupling on a
pteridine nucleus, allowed for the introduction of both aryl- and heteroaryl- substituents at the 6-
position of the pteridine ring. The use of methanesulfonyloxy-O-pteridine (26) as a coupling
partner is also described.
Selective deprotection and hydrolysis of the formamidine protecting groups to give either the 6-
substituted 2,4-diaminopterine or 2-amino-4-oxo-pteridine (pterin), is described.
The synthesized structures are supported by NMR and mass spectral data and melting points
where applicable. Novel compounds are verified by NMR spectroscopy, infrared and mass
spectrometry.
Description
Ph.D., Faculty of Science, University of the Witwatersrand, 2011
Keywords
Enzyme inhibitors, Pyrimidines, Pteridines, Chemistry, Organic