Synthesis and X-ray Crystal Structure of trans,cis-[Pt(OAc)₂I₂(en)]:  A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro

Abstract

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.

Effects of light-activated diazido-PtIVcomplexes on cancer cellsin vitro

“…This approach was initially tried with diiodido-Pt IV diamines, which were activated by visible light to cytotoxic species that platinated DNA, but the dark stability of the complexes in the presence of biological reducing agents such as GSH was poor and the complexes showed relatively high dark activity [11,12]. The first light-activated Pt IV complexes that were sufficiently stable in the presence of biological reducing agents were the diazido-Pt IV 2 ] developed by Sadler and co-workers [13].…”

“…As in the case of the other two complexes, no reactions between either 4 or 6 and 5 -GMP took place in the dark. atomic absorption spectroscopy (AAS) [11,12] [24]. While all-trans-complexes 2 and 4 showed similar rates of photolysis (see §2c), photolysed 2 bound much more rapidly to ct-DNA than did the photolysed pyridine analogue 4, evidence that the pyridine ring has a substantial influence on the rate of reaction with ct-DNA [19].…”

Metals in Medicine

“…[134] The toxicity of trans,cis-[Pt(en)(OAc) 2 I 2 ] towards human bladder cancer cells is enhanced (by 35 %) when the treated cells are irradiated with light of l b 375 nm. It has been shown that visible light can induce the aquation of this complex followed by photoreductive platination of guanosine monophosphate, in contrast to the dihydroxo analogue.…”

Photoactivated Biological Activity of Transition‐Metal Complexes

“…[81] Cytotoxicity studies on TCCSUP human bladder cancer cells showed a small but statistically significant reduction in the IC 50 values and thus establish this complex as a light-sensitive prodrug. [82] The axial and equatorial anionic ligands allow some modulation of the general lead structure, and for trans,cis-[Pt-(N 3 ) 2 (OH) 2 (en)], it was found that their rate of photolysis closely parallels that of DNA platination, indicating that the photolysis products interact directly and rapidly with DNA. The response of the cell to photoactivation, however, was different to that induced by cisplatin, and although the formation of platinum(II) species is thought to follow photoactivation, this indicates a mechanism of action different from that of cisplatin.…”