Synthesis of pyrrolo[2,3-d]pyrimidines and pyrazino[2,3-d]pyrimidines and their biological activities

Pyrrolo[2,3-d]pyrimidines and pyrazino[2,3-d]pyrimidines were synthesised to investigate their biological activities to eventually produce potential new antifolates. Funtionalised nitroalkenes were successfully added to the C5 of 2-thioalkyl-6-amino-4-oxopyrimidines via a Michael reaction. Subsequent cyclisation was accomplished by a Nef reaction using a titanium(III) chloride mediated system. Displacement of the thioalkyl moiety at C2 was also successful via a modified oxidation-substitution methodology, obtaining crude sulfone by oxidation followed by reaction in neat amine. 6,7-Functionalised pteridines were prepared by the Isay cyclocondensation. The thiobenzyl group at C4 of prepared pteridines was effectively displaced by five different amines without an oxidation step. Microwave assisted reaction reduced the reaction times and produced a library of 25 compounds in moderate to good yields. Cytotoxic, antibacterial and antiparasitic activities were screened for thirty pteridines and eight 7-deazapurines. In many cases, pteridines having 2-chlorophenyl groups at C6 and C7 exhibited cell growth inhibition for cancer/normal cells and bacterial cells. The majority of compounds had antiparasitic activity for T. b. brucei and four pyrrolo[2,3-d]pyrimidines had encouraging IC₅₀s (12.5 ~ 50 μM) depending on the functional group at the C2 position. Through a modeling study, a deazaguanine was selected as an ideal framework to design potential inhibitors for trypanosomatid parasites' pteridine reductase 1 (PTR1). Two major hydrophobic pockets were found at the C5 and C6 positions of a deazaguanine scaffold. To occupy hydrophobic pockets in the active sites of trypanosomal PTR1, phenethyl and phenyl groups were introduced at the C5 and C6, respectively. Six 4-thiobenzyl pyrimidines were also synthesised to investigate for their inhibitory activities for PTR1. Two deazaguanines and six pyrimidines were examined for inhibitory activity for L. major and T. brucei PTR1. Two deazaguanines exhibited 70% inhibition at 10 μM for T. brucei but only less than 30% inhibitory activities for L. major were found. Six pyrimidines showed better inhibitory activities (45 ~ 61%) for L. major PTR1 than the two deazaguanines but lower activities (2 ~ 38%) were found for T. brucei PTR1.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2010

Author dc:creator

• Lee, Jeong-Hwan

DOI

10.48730/6n7q-rd79

Identifier

T12671

OAI identifier oai:identifier

oai:strathclyde:sq87bt61f