Nucleic acid binding drugs--XIV. The crystal structure of 1-methyl amsacrine hydrochloride; relationships to DNA-binding ability and anti-tumour activity.

Journal Article

The crystal structure of the 1-methyl derivative of the anticancer drug amsacrine [4'-(acridin-9-ylamino)-3'-methoxy-methanesulphonanilide+ ++] as its hydrochloride salt has been determined. The compound crystallizes in the monoclinic space group P21/n with cell dimensions a = 15.302(3), b = 8.035(2), c = 18.258(4) A and beta = 102.68(2) degrees, and has been refined to a final R of 0.055. The acridine chromophore is significantly non-planar, with a butterfly conformation about the C(9)-N(11) bond. The bonding geometry about the C(9) atom has been significantly altered compared to non-distorted amsacrine structures, as a result of this non-planarity. Energy calculations have been used to examine the flexibility of the molecule with respect to rotations about the C(9)-N(11) and N(11)-C(12) bonds, and with respect to intercalation into a dinucleoside duplex model for DNA. The latter calculations have been compared with solution DNA-binding and in vitro activity data for 1-methyl-amsacrine hydrochloride. The molecular modelling studies find that the energy of interaction between 1-methyl-amsacrine and a DNA intercalation fragment is significantly higher than for amsacrine itself, in accord with the biological data.

Full Text

Duke Authors

Cited Authors

  • Neidle, S; Webster, GD; Baguley, BC; Denny, WA

Published Date

  • November 15, 1986

Published In

Volume / Issue

  • 35 / 22

Start / End Page

  • 3915 - 3921

PubMed ID

  • 3778515

International Standard Serial Number (ISSN)

  • 0006-2952

Language

  • eng

Conference Location

  • England