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

Heidi Roggen 1 , Lars Bohlin 2 , Robert Burman 2 , Colin Charnock 3 , Jenny Felth 2 , Carl Henrik Görbitz 1 , Rolf Larsson 2 , Toomas Tamm 4  and Lise-Lotte Gundersen 1
  • 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

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.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1

    , M. Gordaliza. Mar. Drugs 7, 833 (2009) and refs. therein.

  • 2

    , L. Calcul, K. Tenney, J. Ratnam, J. H. McKerrow, P. Crews. Aust. J. Chem. 63, 915 (2010).

    • Crossref
    • Export Citation
  • 3

    I. C. Pina, P. Crews, K. Tenney. Abstr. Pap. 232nd ACS Natl. Meet., San Fransisco, Sept. 10–14, 2006, MEDI-544 (2006).

  • 4

    , A. Vik, E. Hedner, C. Charnock, O. Samuelsen, R. Larsson, L.-L. Gundersen, L. Bohlin. J. Nat. Prod. 69, 381 (2006) and refs. therein.

    • Crossref
    • Export Citation
  • 5

    , A. K. Bakkestuen, L.-L. Gundersen, D. Petersen, B. T. Utenova, A. Vik. Org. Biomol. Chem. 3, 1025 (2005).

    • Crossref
    • Export Citation
  • 6

    , A. Proszenyak, C. Charnock, E. Hedner, R. Larsson, L. Bohlin, L.-L. Gundersen. Arch. Pharm. (Weinheim, Ger.) 340, 625 (2007) and refs. therein.

    • Crossref
    • Export Citation
  • 7

    , H. Roggen, L.-L. Gundersen. Eur. J. Org. Chem. 5099 (2008).

  • 8

    , H. Roggen, C. Charnock, R. Burman, J. Felth, R. Larsson, L. Bohlin, L.-L. Gundersen. Arch. Pharm. 344, 50 (2011).

    • Crossref
    • Export Citation
  • 9

    , L.-L. Gundersen, C. H. Gørbitz, L. Neier, H. Roggen, T. Tamm. Theor. Chem. Acc. In press

    • Crossref
    • Export Citation
  • 10

    , A. Vik, E. Hedner, C. Charnock, L. W. Tangen, O. Samuelsen, R. Larsson, L. Bohlin, L.-L. Gundersen. Bioorg. Med. Chem. 15, 4016 (2007) and refs. therein.

    • Crossref
    • Export Citation
  • 11

    , T. Krüger, C. Wagner, C. Bruhn, T. Lis, D. Steinborn. J. Mol. Struct. 891, 110 (2008).

    • Crossref
    • Export Citation
  • 12

    , T. Fujii, K. Ogawa, T. Saito, K. Kobayashi, T. Itaya. Heterocycles 38, 477 (1994).

    • Crossref
    • Export Citation
  • 13

    , I. S. Marcos, N. Garcia, M. J. Sexmero, P. Basabe, D. Diez, J. G. Urones. Tetrahedron 61, 11672 (2005), and refs. therein.

    • Crossref
    • Export Citation
  • 14

    , A. Proszenyak, M. Brændvang, C. Charnock, L.-L. Gundersen. Tetrahedron 65, 194 (2009) and refs. therein.

    • Crossref
    • Export Citation
  • 15

    , M. Brændvang, L.-L. Gundersen. Bioorg. Med. Chem. 15, 7144 (2007) and refs. therein.

    • Crossref
    • Export Citation
  • 16

    , C. Hansch, A. Leo, R. W. Taft. Chem. Rev. 91, 165 (1991).

  • 17

    , A. E. Reed, R. B. Weinstock, F. Weinhold. J. Chem. Phys. 83, 735 (1985).

    • Crossref
    • Export Citation
  • 18

    T. Fujii, T. Saito, T. Itaya, K. Kizu, Y. Kumazawa, S. Nakajima. Chem. Pharm. Bull. 35, 4482 (1987).

  • 19

    , M. T. Geballe, A. G. Skillman, A. Nicholls, J. P. Guthrie, P. J. Taylor. J. Comput.-Aided Mol. Des. 24, 259 (2010).

    • Crossref
    • Export Citation
  • 20

    A. L. McClellan. Tables of Experimental Dipole Moment, Vol. 2, Rahara Enterprises, El Cerrito, CA (1974).

  • 21

    , F. Hill, D. M. Williams, D. Loakes, D. M. Brown. Nucleic Acids Res. 26, 1144 (1998).

    • Crossref
    • Export Citation
FREE ACCESS

Journal + Issues

Pure and Applied Chemistry is the official monthly Journal of the International Union of Pure and Applied Chemistry (IUPAC), with responsibility for publishing works arising from those international scientific events and projects that are sponsored and undertaken by the Union.

Search