Structural studies on DNA-binding drugs: crystal structure and molecular dynamics studies of triazoloacridinones

Structural and conformational studies on two 8-substituted triazoloacridinone antitumor agents, C1295 and C1303, have been carried out to compare the conformation of the (aminoalkyl)amino side chain and the effect of C-8 substitution. Crystal data for 5-[2-(diethylamino)ethylamino]-8-methyl-6H-[1,2,3]-triazolo[4,5,1- de]acridin-6-one (C1295), C20H23N5O, M(r) = 349.4, triclinic, P1, a = 12.200 (1), b = 14.890 (1), c = 5.185 (1) A, alpha = 93.54 (1), beta = 102.21 (1), gamma = 80.61 (1)degree, V = 907.9 (1) A3, Z = 2, Dx = 1.278 g cm-3, lambda(Cu K alpha) = 1.54178 A, mu = 6.2 cm-1, F(000) = 372, T = 293 K, R = 0.061 for 1631 observed reflections; for 5-[2-(diethylamino)ethylamino]-8- hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one (C1303), C17H17N5O2, M(r) = 323.4, monoclinic, P2(1)/n, a = 15.823 (2), b = 5.790 (1), c = 16.856 (2) A, beta = 98.59 (1)degree, V = 1526.9 (2) A3, Z = 4, Dx = 1.404 g cm-3, lambda(Cu K alpha) = 1.54178 A, mu = 7.5 cm-1, F(000) = 680, T = 293 K, R = 0.054 for 1303 observed reflections. There is a difference in the orientation of the (aminoalkyl)amino side chain in the two compounds in the solid state, but molecular dynamics simulations indicate that in the gas phase the orientation is very similar. This difference could result from the different crystal packing in the case of C1303, due to the presence of an intermolecular hydrogen bond.(ABSTRACT TRUNCATED AT 250 WORDS)