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Nucleic Acid Binding drugs--XIV. The Crystal Structure of 1-methyl Amsacrine Hydrochloride; Relationships to DNA-binding Ability and Anti-Tumour Activity

Nucleic Acid Binding drugs--XIV. The Crystal Structure of 1-methyl Amsacrine Hydrochloride; Relationships to DNA-binding Ability and Anti-Tumour Activity

S Neidle, G D Webster, B C Baguley, W A Denny

Biochem Pharmacol. 1986 Nov 15;35(22):3915-21.

PMID: 3778515

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54301154	Amsacrine hydrochloride		54301-15-4	Price

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