New water-soluble platinum(ii) phenanthroline complexes tested as cisplatin analogues: first-time comparison of cytotoxic activity between analogous four- and five-coordinate species

Abstract

Four- and five-coordinate platinum(II) complexes, cis-[PtCl2(A2)] (1) and [PtCl2(A2)(eta2-ethylene)] (2) {A2 = 4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BPS (mixture of isomers) (a); 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BCS (mixture of isomers) (b)} have been synthesized and characterized by 1H, 13C, and 195Pt NMR spectroscopy. The stability and high water solubility of complexes 1a, 1b and 2b, due to the presence of the polar SO3- groups on the ligands skeleton, allowed to test their in vitro cytotoxicity on HeLa tumour cells in a wide range of drug concentration. At low and medium incubation doses (<200 microM) 1a, 1b and 2b all showed similar in vitro cytotoxicity, negligible or much lower with respect to cisplatin. At doses higher than 200 microM their activity increased and 1b, the most active among the new complexes, exhibited a cytotoxicity comparable, although still lower, with respect to cisplatin. GFAAS Platinum analytical data showed that the tested compounds 1a, 1b and 2b, although carrying sulfonate charged groups, may undergo cellular uptake, which, in the case of 1b and 2b, is even higher with respect to cisplatin. Furthermore, in the case of 1b and 2b it has been possible to compare, for the first time, the cytotoxic activity for square-planar four-coordinate and trigonal-bipyramidal five-coordinate platinum(II) complexes having the same carrier ligand. The tendency of the five-coordinate species 2b to give at longer incubation time similar cytotoxicity with respect to the square-planar compound 1b suggests a possible use of the trigonal-bipyramidal five-coordinate complexes as prodrugs.

Structure-cytotoxicity relationship for different types of mononuclear platinum(II) complexes with 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine

“…Additionally, the induced drug resistance to cells and its low aqueous solubility has restricted the application of this drug. These clinical inconveniences in cisplatin chemotherapy prompted the design and synthesis of more effective and less toxic platinum-based anticancer drugs [5][6][7][8]. Consequently, new platinum drugs with equal or greater antitumor activity but lower toxicity have been developed by replacing the labile chloride and stable amine ligands with other leaving groups such as cyclic and acyclic amines.…”

NMR study on iridium(III) complexes for identifying disulfonate substituted bathophenanthroline regio‐isomers

“…As three DSBP 2-regio-isomers are theoretically possible and have been actually identified in the work of De Pascali et al, [16] the reasons why only two fractions of the iridium(III) complexes have been isolated from the resulting products are tentatively proposed as follows: Reasons (2) and (3) are unlikely. The last reason (4) has not been founded by the NMR data of this work.…”

“…As a diimine (N^N) ligand, bathophenanthroline disulfonic acid disodium salt (DSBPNa 2 , see the molecular structure in Scheme 1) is frequently used as a ligand that extends water solubility to the resulting metal complexes, which have been widely utilized as chromogenic, [1][2][3] fluorogenic, [4][5][6][7][8][9] chemiluminescent, [10][11][12] electrochemiluminescent [13][14][15] reagents and cancer drugs. [16] Unfortunately, the commercially available grades of this compound are often marked as isomeric forms. Because of the difficulty in isolating these isomers, their chemical natures and the isomerism of the resulting metal complexes made of this isomeric mixture have received little attention until very recently.…”

Synthesis, Crystal Structure, and Biological Study of PtII Complexes with 4‐Acyl‐5‐pyrazolones

“…[6,7] Our aim is to obtain new Pt II -based drugs as alternatives to cisplatin. Cisplatin is one of the most potent chemotherapy drugs, and it is widely used for cancer treatment.…”