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A novel series of (diamine)platinum(IV) complexes of mixed carboxylates have been synthesized by electrophilic substitution of the tetrahydroxoplatinum(IV) complex (dach)Pt(OH)4 (dach = trans-(+/-)-1,2-diaminocyclohexane) with three different carboxylic anhydrides, pivalic, acetic, and trifluoroacetic anhydrides. Consecutive two-step acylations with two different carboxylic anhydrides in acetone or dichloromethane gave the mixed carboxylate complexes (dach)Pt(O2CR)x(O2CR')4 - x (R = C(CH3)3 or CF3, R' = CH3, x = 1-4) including all the possible stereoisomers, which could be separated and identified by means of HPLC, column chromatography, 1H NMR, and X-ray crystallography. From analysis of the reaction products we have found that the positions of electrophilic substitution of (dach)Pt(OH)4 were influenced by the kinds of carboxylic anhydrides exhibiting different electrophilicity or steric effects. The initial substitution by the first reactant occurs more favorably on axial OH, but in the case of pivalic anhydride, equatorial substitution is favored probably because of the bulkiness of the pivalate group. Such a result seems to be related to their stereochemical factors rather than to differences in electrophilicity. The lipophilicity of the title complexes was affected not only by the carbon numbers of substituents but also by the conformation of the resulting compound.

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A novel class of tetrakis(carboxylato)platinum(IV) complexes, [Pt(O(2)CR)(4)(dach)] (dach = trans-(+/-)-1,2-diaminocyclohexane; R = C(n)H(2n+1), n = 1 approximately 5), was synthesized and studied for physicochemical properties and oral antitumor activity. Lipophilicity and aqueous solubility of the title complexes were greatly dependent on the alkyl chain length of the carboxylate ligand, and their partition coefficient and solubility changed by 4 or 5 orders of magnitude from acetate to hexanoate complexes. On the other hand, the range of their cathodic reduction potential (-546 approximately -403 mV) depending on the chain length of the carboxylate ligand was relatively small. Among the title complexes, the tetrakis(propionato)platinum(IV) complex, [Pt(O(2)CC(2)H(5))(4)(dach)], with appropriate lipophilicity (log P = 0.18) and aqueous solubility (14.6 mg/mL) was found to exhibit better oral antitumor activity than JM216 against the human ovarian tumor xenograft SKOV3 in nude mice.