Synthesis, Structural Characterization, and Cytotoxic Activity of Novel Paramagnetic Platinum Hematoporphyrin IX Complexes: Potent Antitumor Agents

Abstract

Three novel stable Pt(III) complexes with distorted octahedral structure and (dz2)1 ground state have been obtained in the course of Pt(II)-hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) interaction in alkaline aqueous medium and aerobic conditions. A redox interaction also takes place together with the complexation process leading to the formation of Pt(III) species and organic radicals. The processes in the reaction system and the structure of the complexes formed cis-[Pt(III)false(NH3false)2(Hp−3H)false(H2Ofalse)2]⋅H2O 1, [Pt(III)(Hp−3H)false(H2Ofalse)2]⋅H2O 2, and [Pt((O,O)Hp−2H)Clfalse(H2Ofalse)3] 3, were studied by UV-Vis, IR, EPR and XPS spectra, thermal (TGS, DSC), potentiometric and magnetic methods. The newly synthesized complexes show promising cytotoxic activity comparable with that of cis-platin in in vitro tests against a panel of human leukemia cell lines. The observed cytotoxicity of the complex 2 against SKW-3 cells (KE-37 derivative) is due to induction of cell death through apoptosis.

In vitro pharmacological study of monomeric platinum(III) hematoporphyrin IX complexes

“…In the Brunner's works [26][27][28], the significant cytotoxicity of Pt II -porphyrin conjugates as well as their ability to accumulate in tumor cells has been already demonstrated. The novel Pt III -Hp complexes showed cytotoxicity within a preliminary bioactivity program, employing three human leukemic cell lines [25]. In the present study we report their detailed pharmacological and biochemical evaluation in terms of cytotoxicity, induction of apoptosis, DNA-binding and repair and cellular accumulation.…”

“…The tested complexes cis-[Pt(NH 3 ) 2 (Hp −3H ). ) were synthesized, characterized and purified as previously described [25].…”

“…At the studied reaction conditions, where the hematoporphyrinligand interacts as twofold deprotonated at carboxylic groups, anion (Hp −2H ), the coordination reactions were complicated with a parallel redox-process [25] and the obtaining of different Pt III -species was proved by potentiometry and EPR [25]. Water solutions of cis-diammine (diaqua)platinum(II)hydroxide (obtained from cisplatin after precipitation of Cl − ) and K 2 PtCl 4 were used as starting Pt(II)-compounds.…”

“…The axial positions of the three structures are occupied by water molecules. The solid-state structure of the complexes and the coordination mode of the Hp-ligand were elucidated in detail using magnetic measurements, EPR, IR, X-ray photoemission spectra, thermogravimetric and calorimetric measurements, and elemental analysis [25].…”

“…Thus, three stable mononuclear hematoporphyrin IX -containing Pt III complexes with distorted octahedral structure were obtained ( Fig. 1) [25]. The porphyrins are considered as promising carrier ligands, because of their well-established propensity to accumulate preferentially in tumor cells.…”