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Diversity oriented syntheses of fused pyrimidines designed as potential antifolates

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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 journalArticle

Harvard

Gibson, CL, Huggan, JK, Kennedy, A, Kiefer, L, Lee, JH, Suckling, CJ, Clements, C, Harvey, AL, Hunter, WN & Tulloch, LB 2009, 'Diversity oriented syntheses of fused pyrimidines designed as potential antifolates' Organic and Biomolecular Chemistry, vol 7, no. 9, pp. 1829-1842., 10.1039/b818339b

APA

Gibson, C. L., Huggan, J. K., Kennedy, A., Kiefer, L., Lee, J. H., Suckling, C. J., ... Tulloch, L. B. (2009). Diversity oriented syntheses of fused pyrimidines designed as potential antifolates. Organic and Biomolecular Chemistry, 7(9), 1829-1842. 10.1039/b818339b

Vancouver

Gibson CL, Huggan JK, Kennedy A, Kiefer L, Lee JH, Suckling CJ et al. Diversity oriented syntheses of fused pyrimidines designed as potential antifolates. Organic and Biomolecular Chemistry. 2009;7(9):1829-1842. Available from: 10.1039/b818339b

Author

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. / Diversity oriented syntheses of fused pyrimidines designed as potential antifolates.

In: Organic and Biomolecular Chemistry, Vol. 7, No. 9, 2009, p. 1829-1842.

Research output: Contribution to journalArticle

Bibtex - Download

@article{9c5ab67dc20747c6aac5a00034506cac,
title = "Diversity oriented syntheses of fused pyrimidines designed as potential antifolates",
keywords = "DIHYDROFOLATE-REDUCTASE INHIBITORS, CROSS-COUPLING REACTIONS, TYROSINE KINASE INHIBITORS, SOLID-PHASE SYNTHESIS, BIOLOGICAL EVALUATION, THYMIDYLATE SYNTHASE, RECEPTOR ANTAGONISTS, SELECTIVE INHIBITORS, CONVENIENT SYNTHESIS, ANTITUMOR AGENTS",
author = "Gibson, {Colin L.} and Huggan, {Judith K.} and Alan Kennedy and Lionel Kiefer and Lee, {Jeong Hwan} and Suckling, {Colin J.} and Carol Clements and Harvey, {Alan L.} and Hunter, {William N.} and Tulloch, {Lindsay B.}",
year = "2009",
doi = "10.1039/b818339b",
volume = "7",
number = "9",
pages = "1829--1842",
journal = "Organic and Biomolecular Chemistry",
issn = "1477-0520",

}

RIS (suitable for import to EndNote) - Download

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 -

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