Bisphosphines related to
bis(diphenylphosphino)ethane (
dppe) and their
gold complexes are described that are active in a spectrum of transplantable
tumor models. When administered ip on days 1-5 at its maximally tolerated dose (MTD) of 40 mumol/kg,
dppe reproducibly gives 100% increase in life span (ILS) in mice bearing ip
P388 leukemia. Coordination of chlorogold(I) to each
phosphine in
dppe gave a complex that had similar activity but at a much lower dose level than
dppe; the MTD for the
gold(I) complex was 7 mumol/kg. Among other
metal complexes of
dppe, the Au(III) complex was active (greater than 50% ILS) whereas Ag(I), Ni(II), Pt(II), Pd(II), and Rh(I) complexes were inactive. Among
dppe analogues, replacement of phenyl groups with ethyl or benzyl groups resulted in inactivity for both
ligands and the corresponding
gold complexes whereas substitution with cyclohexyl or heterocyclic ring systems yielded
ligands and/or
gold complexes with antitumor activity. Among substituted-phenyl
dppe and
dppe(AuCl)2 analogues, 3-fluoro, 4-fluoro, perdeuterio, 4-methylthio, and 2-methylthio analogues were active; 4-methyl, 3-methyl, 4-methoxy, 4-dimethylamino, and 4-trifluoromethyl analogues were marginal or inactive. Analogues in which the
ethane bridge of
dppe or
dppe(AuCl)2 was varied between one and six carbons, unsaturated or substituted, revealed that activity was maximal with
ethane or cis-
ethylene. Compounds with good P388 activity were also active in other animal
tumor models.