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Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Stohner, Jürgen

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IMPACT FACTOR 2017: 5.294

CiteScore 2017: 3.42

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1365-3075
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Volume 83, Issue 3

Issues

2-Substituted agelasine analogs: Synthesis and biological activity, and structure and reactivity of synthetic intermediates

Heidi Roggen
  • Corresponding author
  • Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway
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/ Lars Bohlin
  • Corresponding author
  • Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
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/ Robert Burman
  • Corresponding author
  • Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
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/ Colin Charnock
  • Corresponding author
  • Faculty of Health Sciences, Oslo University College, P.O. Box 4 St. Olavs Plass, N-0130 Oslo, Norway
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/ Jenny Felth
  • Corresponding author
  • Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
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/ Carl Henrik Görbitz
  • Corresponding author
  • Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway
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/ Rolf Larsson
  • Corresponding author
  • Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
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/ Toomas Tamm
  • Corresponding author
  • Tallinn University of Technology, Ehitajate tee 5, EE-19086 Tallinn, Estonia
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/ Lise-Lotte Gundersen
  • Corresponding author
  • Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway
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Published Online: 2011-01-25 | DOI: https://doi.org/10.1351/PAC-CON-10-09-25

2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl-9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1H NMR. The tautomers were identified by 1D and 2D 1H, 13C, and 15N NMR techniques, and showed significant variation both in 13C and 15N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6-amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.

Keywords: agelasine; biological activity; density functional theory; purine; tautomerism; X-ray crystallography

Conference

International Conference on Organic Synthesis (ICOS-18), International Conference on Organic Synthesis, ICOS, Organic Synthesis, 18th, Bergen, Norway, 2010-08-01–2010-08-06

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About the article

Published Online: 2011-01-25

Published in Print: 2011-01-25


Citation Information: Pure and Applied Chemistry, Volume 83, Issue 3, Pages 645–653, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1351/PAC-CON-10-09-25.

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