Relation of conformation to antitumor activity of platinum(II) complexes of 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine isomers against leukemia P388.

Abstract

The antitumor activity of various platinum(II) complexes of 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine isomers against leukemia P388 was evaluated by means of the platinum analogue study protocol recommended by the National Cancer Institute. For the former complexes, trans isomers are more efficacious than the corresponding cis isomers. For the latter complexes, cis isomers seem to be somewhat more active than trans isomers. 2-(Aminomethyl)cyclohexylamine platinum complexes exhibited higher activity than 1,2-cyclohexanediamine complexes in this tumor system. These findings encouraged us to determine the structural differences between 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine complexes. Their structures of platinum complexes were elucidated from circular dichroism and 13C NMR spectral analyses, and it has been concluded that the cyclohexane ring of cis-1,2-cyclohexanediamine is nearly perpendicular to the chelate ring, while both rings of trans-1,2-cyclohexanediamine and trans-2-(aminomethyl)cyclohexylamine complexes lie in a common plane. The structure of cis-2-(aminomethyl)cyclohexylamine complexes is flexible, and the cyclohexane ring is not perpendicular to the chelate ring. The coplanarity of trans isomers and the flexibility of cis-2-(aminomethyl)cyclohexylamine complexes allow them easy approach to the target DNA. However, the perpendicular ring of cis-1,2-cyclohexanediamine complexes would prevent their interactions with dna molecules due to the steric hindrance.