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Pure Appl. Chem., 2011, Vol. 83, No. 3, pp. 645-653

Published online 2011-01-25

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

Heidi Roggen1*, Lars Bohlin2, Robert Burman2, Colin Charnock3, Jenny Felth2, Carl Henrik Görbitz1, Rolf Larsson2, Toomas Tamm4 and Lise-Lotte Gundersen1

1 Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway
2 Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
3 Faculty of Health Sciences, Oslo University College, P.O. Box 4 St. Olavs Plass, N-0130 Oslo, Norway
4 Tallinn University of Technology, Ehitajate tee 5, EE-19086 Tallinn, Estonia

Abstract: 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.