Diversity oriented syntheses of fused pyrimidines designed as potential antifolates. / Gibson, Colin L.; Huggan, Judith K.; Kennedy, Alan; Kiefer, Lionel; Lee, Jeong Hwan; Suckling, Colin J.; Clements, Carol; Harvey, Alan L.; Hunter, William N.; Tulloch, Lindsay B.
In: Organic and Biomolecular Chemistry, Vol. 7, No. 9, 2009, p. 1829-1842.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Diversity oriented syntheses of fused pyrimidines designed as potential antifolates
A1 - Gibson,Colin L.
A1 - Huggan,Judith K.
A1 - Kennedy,Alan
A1 - Kiefer,Lionel
A1 - Lee,Jeong Hwan
A1 - Suckling,Colin J.
A1 - Clements,Carol
A1 - Harvey,Alan L.
A1 - Hunter,William N.
A1 - Tulloch,Lindsay B.
AU - Gibson,Colin L.
AU - Huggan,Judith K.
AU - Kennedy,Alan
AU - Kiefer,Lionel
AU - Lee,Jeong Hwan
AU - Suckling,Colin J.
AU - Clements,Carol
AU - Harvey,Alan L.
AU - Hunter,William N.
AU - Tulloch,Lindsay B.
PY - 2009
Y1 - 2009
N2 - <p>Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d] pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.</p>
AB - <p>Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d] pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.</p>
KW - DIHYDROFOLATE-REDUCTASE INHIBITORS
KW - CROSS-COUPLING REACTIONS
KW - TYROSINE KINASE INHIBITORS
KW - SOLID-PHASE SYNTHESIS
KW - BIOLOGICAL EVALUATION
KW - THYMIDYLATE SYNTHASE
KW - RECEPTOR ANTAGONISTS
KW - SELECTIVE INHIBITORS
KW - CONVENIENT SYNTHESIS
KW - ANTITUMOR AGENTS
U2 - 10.1039/b818339b
DO - 10.1039/b818339b
M1 - Article
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
SN - 1477-0520
IS - 9
VL - 7
SP - 1829
EP - 1842
ER -