Structure of 2-amino-6-dimethylamino-4-(tricyclo[3.3.1.13,7]dec-1-yl)-1,3,5-triazine

Abstract

Abstract. C15H23Ns, Mr = 273.4, triclinic, P1, a = 6.907(6), b=10.260(5), c=10.619 (2) ~, a= 104.64 (4), fl = 91.61 (7), y = 104.88 (5) °, V = 700.2 (14) A 3, Z = 2, Dm = 1.295, Dx = 1.296 Mg m -3, A(Cu Ka) = 1.54184 ,~, /.1, = 0.648 mm-~, F(000) = 296, T= 293 K, final R = 0.059 for 1510 observed reflections. In pyrimidine analogs of this class of antifolate agents, a lipophilic substituent at position 5 disrupts the ring planarity [Cody (1986). J. Mol. Graphics, 4(1), 69-73]. Here, the adamantyl substituent at position 4 does not have a similar effect. The adamantyl assumes one of the two observed possible conformations relative to the triazine ring. Introduction. Dihydrofolate reductase [5,6,7,8-tetra- hydrofolate:NADP + oxidoreductase (E.C. 1.5.1.3)], an enzyme which reduces dihydrofolic to tetrahydro- folic acid, is a protein of prime importance in bio- chemistry and medicinal chemistry (Blakley, 1969). It is used as a target for several antibacterial and antineoplasmic (antitumor) drugs. The activity of 0108-2701/92/020347-04503.00 these drugs is due to selective inhibition of the enzyme from species to species (Baccarani, Daluge & King, 1982; Hitchings & Smith, 1980). Unfortu- nately, the exact molecular mechanism of selective inhibition is not yet known, despite extensive efforts. The discovery that diamino-s-triazines interfere with folic acid metabolism triggered research on the antifolate activity of this class of compounds and has shown promise in cancer chemotherapy (Modest, Foley, Pechet & Farber, 1952). A conclusion drawn from these studies is that for several antifolates the extent of their uptake and their growth inhibitory potency on tumor cells, as well as their affinity to dihydrofolate reductase (DHFR), correlate well with lipophilicity (Greco & Hakala, 1980). In the course of our investigations on compounds containing adamantane rings (Antoniadou-Vyza & Foscolos, 1986; Garoufalias, Vyza, Fytas, Foscolos & Chytiroglou, 1988) we considered it likely that attachment of this group to a triazine ring would allow it to make effective use of the enzyme hydro- phobic cavity. In addition, the absence of any © 1992 International Union of Crystallography