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.
Three stable mononuclear hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) complexes of Pt(III), namely cis-[ Pt(III)(NH(3))(2)(Hp(-3H))(H(2)O)(2)].H(2)O 1, [Pt(III)(Hp(-3H))(H(2)O)(2)].H(2)O 2 and [Pt(III)((O,O)Hp(-2H))Cl(H(2)O)(3)] 3 with distorted octahedral structure and (d(z)2)(1) ground state have been tested in vitro for antineoplastic activity in a panel of tumor cell lines. The novel platinum(III) complexes showed cytotoxic activity in a concentration-dependent manner with IC(50) values comparable to those of referent cytotoxic agent cisplatin together with lower cytotoxicity against renal cells. Further detailed evaluation of the active analogue 2 and the less active complex 3 showed that their potency greatly correlates with the ability to induce apoptosis and to bind DNA. Despite the structural dissimilarities between complex 2 and cisplatin, their DNA-adducts were equally effectively recognized and repaired by the nucleotide excision repair system. Complex 2 showed quite superior ability to accumulate in K-562 cells relative to cisplatin.
The antineoplastic potential of a stable monomeric Au(II) complex with hematoporphyrin IX (Hp), namely [Au(II)Hp−2H.(H2O)2], was investigated in a panel of tumor cell lines. The complex exhibits strong cytotoxicity, whereby the leukaemia- and lymphoma-derived cell lines are more sensitive, with IC50 values comparable to those of the reference anticancer drug cisplatin. In contrast, the solid tumor models are more sensitive to the platinum drug. A comparative assessment of both agents against the human kidney cell line 293T has shown that [Au(II)Hp−2H.(H2O)2] is less cytotoxic. The gold complex induces oligonucleosomal DNA fragmentation in tumour cells following 24-hour treatment and hence its cytotoxic effect is at least partly mediated by induction of apoptotic cell death. A prominent intracellular gold accumulation was detected after treating tumor cells with [Au(II)Hp−2H.(H2O)2] which shows that its putative pharmacological targets are readily accessible after a short incubation period.
Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2O, Pd2 have been synthesized reproducibly and isolated as neutral compounds at different reaction conditions. Their structure and solution stability have been assayed by UV/Vis and EPR spectroscopy. The compounds researched have shown in vitro cell growth inhibitory effects at micromolar concentration against a panel of human tumor cell lines. A DNA fragmentation test in the HL-60 cell line has indicated that Pd1 causes comparable proapoptotic effects with regard to cisplatin but at substantially higher concentrations. Pd1 and cisplatin form intra-strand guanine bis-adducts as the palladium complex is less capable of forming DNA adducts. This demonstrates its cisplatin-dissimilar pharmacological profile. The test for efficient removal of DNA-adducts by the NER synthesis after modification of pBS plasmids with either cisplatin or Pd1 has manifested that the lesions induced by cisplatin are far better recognized and repaired compared those of Pd1. The study on the recognition and binding of the HMGB-1 protein to cisplatin or Pd1 modified DNA probes have shown that HMG proteins are less involved in the palladium agent cytotoxicity.
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