An original approach intended to facilitate the intratumoral activation of Pt(IV)
diamines by illumination with visible light to form photolysis products that irreversibly bind to
DNA and are cytotoxic to human
cancer cells is reported. The novel Pt(IV) complex trans,cis-[Pt(OAc)2I2-(en)] was prepared by the acetylation of trans,cis-[Pt(
OH)2I2(en)] with
acetic anhydride in CH2-Cl2; trans,cis-[Pt(
OH)2I2(en)] was synthesized by oxidation of [PtI2(en)] with 30% aqueous H2O2. trans,cis-[Pt(OAc)2I2(en)] crystallized from
methanol as deep-red needles with a = 9.029(4) A, b = 11.443(2) A, c = 12.822(2) A, beta = 95.48(3) degrees, monoclinic space group Cc, and Z = 4. The conformation of the acetato groups around the O-Pt-O axis deviated significantly from the conformation of the acetato groups in the X-ray crystal structure reported for the cis-dichloro analog, which may explain the very different aqueous solubilities of the two compounds. trans,-cis-[Pt(OAc)2I2(en)] and trans,cis-[Pt(
OH)2I2(en)] displayed broad
ligand-to-
metal charge-transfer bands centered at lambda = 389 and 384 nm, respectively (epsilon = 1372 and 1425 M-1 cm-1, respectively), with tailing out to ca. 550 nm. When trans,cis-[Pt(OAc)2I2(en)] was incubated with
calf thymus DNA in the absence of light, no covalent binding of Pt to
DNA was measurable after 6 h; however, irradiation with light of wavelengths > 375 nm resulted in 63 +/- 13% of the
platinum being covalently bound to
DNA after 6 h, suggesting that a photoreduction to Pt(II) species took place. Although trans,cis-[Pt(
OH)2I2(en)] was also labile to visible light, only 10 +/- 2%
DNA platination was observed after 6 h of illumination; however, covalent binding of Pt to
DNA took place quantitatively when a
reducing agent such as
glutathione was added to the photolyzed incubations. These results provide evidence that the photolysis of the trans-dihydroxo analog resulted predominately in the substitution of the
iodide ligands for water rather than a reduction of Pt(IV) to Pt(II). When protected from light, trans,cis-[Pt(OAc)2I2-(en)] and trans,cis-[Pt(
OH)2I2(en)], both at a concentration of 10 microM, had half-lives of 6.6 +/- 0.5 and 46.8 +/- 8.8 h, respectively, at 37 degrees C in Eagle's minimum essential medium (EMEM) containing 5%
fetal calf serum. When irradiated with light lambda(
irr) > 375 nm, the half-lives were decreased by 24- and 53-fold for the diacetato- and dihydroxoplatinum(IV) complexes, respectively. Compared to the "dark" control, the in vitro treatment of TCCSUP human
bladder cancer cells with trans,cis-[Pt(OAc)2I2(en)] resulted in 35% greater growth inhibitory activity when during the first 1.5 h of
drug exposure the cells were irradiated with light lambda
irr > 375 nm. The photolysis of trans,cis-[Pt(
OH)2I2(en)] with visible light resulted in a 22% enhancement of antiproliferative activity.