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 Pt(II) complexes of 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine isomers against leukemia P388 [mouse] was evaluated by means of the Pt analog 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 Pt complexes exhibited higher activity than 1,2-cyclohexanediamine complexes in this tumor system. The structural differences were determined between 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine complexes. Their structures of Pt 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 the steric hindrance.