Ionic titanocene complexes: a new type of antitumor agent

Abstract

Five ionic cyclopentadienyltitanium (IV) derivatives were investigated for their activity against fluid Ehrlich ascites tumor. Four compounds were built up by the intact bis(cyclopentadienyl)titanium(IV) ("titanocene") unit, forming the cationic moiety together with two covalently bound ligands, with certain anions being bonded via electrostatic forces: the acetonitrile complex [(C5H5)2TiCl(NCCH3)]+[FeC14]- (I), the 2'2'-bipyridyl derivative [(C5H5)2Ti(bipy)]2+[CF3SO3]2 (II), the o-phenanthroline complex [(C5H5)2Ti(phen)]2+[CF3SO3]2 (III), and the N-methyl-o-aminothiophenolate derivative [(C5H5)2Ti[o-S(NACH3)C6H4]]+I- (IV). Another ionic cyclopentadienyltitanium derivative investigated was the five-coordinate bis(dithiolene) chelate (C5H5)Ti(1,2,4-S2C6H3CH3)2]-N(C2H5)4)+ (V), the cyclopentadienyltitanium moiety representing the anionic part of the complex salt. All complexes were ionic, salt-like compounds, distinguished by good water solubility. Whereas complexes I, III, and V, given at optimal dose levels, effected maximal cure rates of only 70%-80%, all animals were cured after receiving complexes II and IV at dose ranges of 200-220 and 240-300 mg/kg, respectively. The antitumor activity of complex I was confirmed against solid experimental tumor systems B16 melanoma, colon 38 carcinoma, and Lewis lung carcinosarcoma. Because of their improved solubility in water and pronounced antitumor activity (especially that of II and IV against fluid Ehrlich ascites tumor), ionic cyclopentadienyl titanium complexes are considered to be an interesting new type of antitumor agent.