Platinum Anticancer Drugs

Abstract

Carboplatin, [Pt(cbdca-O,O 0 )(NH 3 ) 2 ] (Figure 4.1), where cbdca is cyclobutane-1,1-dicarboxylate and O and O 0 are the ligand donor atoms, is a so-called second-generation platinum anticancer drug that is much less otoand nephrotoxic than cisplatin [1]. The drug, which was reported by Cleare and Hoeschele in 1973 [2,3] and later patented [4], gained approval by the US Food and Drug Administration (FDA) under the brand name Paraplatin in 1989. The key difference between the structures of carboplatin and cisplatin is that the former possesses a six-membered dicarboxylate ring, which, because of the chelate effect, makes it much less chemically reactive than cisplatin. Carboplatin by itself or in combination with other drugs is in worldwide clinical use for the treatment of a variety of different cancers, including head and neck cancer, and ovarian, breast, small lung cell, testicular, bladder and brain tumors [1]. Although carboplatin is much less oto-and nephrotoxic than cisplatin, it is myelosuppressive, which leads to a reduction in the white cell count in the blood, thus exposing the patient to infection by various organisms. Synthesis and properties of carboplatinAs shown in Figure 4.2, carboplatin can be synthesized by reacting potassium tetrachloroplatinate with excess KI in water, which produces the bright-orange complex anion [PtI 4 ] 2À [5]. This complex precipitates from solution as its sparingly-soluble dipotassium salt, K 2 [PtI 4 ]. Reaction of the tetraiodo complex with two equivalents of ammonia produces yellow cis-[PtI 2 (NH 3 ) 2 ]. Due to the strong trans-directing ability of I À , only the cis isomer is formed. Suspension of this complex in water containing one equivalent of Ag 2 SO 4 in the dark with constant stirring results in the formation of insoluble silver iodide, AgI, and the formation of the very water-soluble cis diaquao complex, cis-[Pt(NH 3 ) 2 (H 2 O) 2 ]SO 4 . Since sulfate anion (a hard base) is low in the spectrochemical series and Pt þ2 is a soft acid, water (and not sulfate ion) binds to the platinum ion. The final step in the syntheses requires the addition of a solution containing one equivalent of Ba(cbdca), previously prepared by the reaction of Ba(OH) 2 with H 2 -cbdca, to the solution containing the diaqua complex cis-[Pt-(NH 3 ) 2 (H 2 O) 2 ]SO 4 . Since BaSO 4 is very insoluble in water it can be removed by filtration and carboplatin can be recovered from the filtrate by reduction of the volume of the solution. Carboplatin is a pale-white solid with a high aqueous solubility at ambient temperature of $18 mg ml À1 or $48 mM [6]. Metals in MedicineJames C. DabrowiakThe UV-visible absorption spectrum of carboplatin in water is shown in Figure 4.3 [7]. The drug has a complicated absorption envelope, having at least two strong absorptions at 203 (e ¼ 4600 M À1 cm À1 ) and 229 nm (e ¼ 2300 M À1 cm À1 ), and a weaker band at 330 nm (e ¼ 40 M À1 cm À1 ). Since the two strong bands at high energy have intensities consistent with a Laporte-allowed transition, Dl 6 ¼ 0, these...