Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: 1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; 2) the biological effect was influenced by the nature of the central azole ring of the ligands—1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; 3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin’s lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

Comparative assessment of clinical trials, indications, pharmacokinetic parameters and side effects of approved platinum drugs

Platinum complexes are among the most commonly applied anticancer agents. The aim of current work is collection, analysing and comparative estimation of clinical trials and pharmacological indications of currently approved for application platinum detivatives: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin (Japan), Lobaplatin (China), Heptaplatin (North Korea), and Satraplatin. The other aim of the study includes the summarizing of the hystoric data for the stages of the developlement of these drugs, and the comparison of pharmacokimetic parameters, side effecs and the dose-liniting factors of the drugs. The observational study on pharmacokinetic parameters shows that protein binding decreases in order: 95% (Cisplatn); 90% (Oxaliplatin); 50% (Nedaplatin); low (Carboplatin). For every of Cisplatin, Carboplatin, Oxaliplatin have been reported more than 1000 clinical trials; for Lobaplatin, Nedaplatin, Satraplatin - about 10 trials. The differenses in dose-limiting effects are: neuro-, nephro-, ototoxicity (Cisplatin); neurotoxicity (Oxaliplatin); nephrotoxicity (Heptaplatin); myelosuppression: thrombocytopenia, neutropenia, leukopenia (Carboplatin, Nedaplatin, Satraplatin).

Platinum Complexes of Bicyclopropylidene and Related Ligands

<p>The coordination chemistry of the cyclopropyl-substituted alkenes, bicyclopropylidene (BCP) and methylenecyclopropane (MCP), with platinum was explored. A range of complexes with ŋ²-alkene ligands were synthesised by the displacement of a ligand, typically ethene, from a precursor complex. These complexes are [Pt(L)(P—P)] (L = BCP, MCP; P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂, ᵗBu₂PCH₂(o-C₆H₄)₂PᵗBu₂), [Pt(L)(P—S)] (L = BCP, MCP; P—S = ᵗBu₂PCH₂(o-₆H4)CH₂SᵗBu), [Pt(C₂H4)(L)(PR₃)] (L = BCP, MCP; PR₃ = PPh₃, PCy₃), [Pt(MCP)₂(PR₃)] (PR₃ = PPh₃, PCy₃) and [PtCl₂(L)(L′)] (L = BCP, MCP; L′ = Py, DMSO). These were the first examples of platinum complexes with ŋ²-BCP ligands, and the first bis-MCP Pt complexes. BCP underwent ring-opening reactions with both Pt(0) and Pt(II) complexes to form the 1,3-diene allylidenecyclopropane (ACP). The first transition metal complexes of ACP [Pt(ACP)(P—P)] (P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂) were synthesised. Some of these complexes rearranged to form ŋ²:σ²-metallacyclopentene complexes, the first instances of the formation of ŋ²:σ²-metallacyclopentene complexes from ŋ²:π-diene complexes. With MCP, the ring-opening reaction only occurred with [₂(COD)], as a result of the anti-Markovnikov addition of Pt–H, generated by the β-hydride elimination of an Et group, across the double-bond. The major products of this reaction were the 1-methylcyclopropyl complexes [Pt(C(CH₂)₂CH₃)Et(COD)] and [Pt(C(CH₂)₂CH₃)₂(COD)], the first examples of such complexes. Protonation of [Pt(L)(P—P)] resulted in a ring-opening reaction to form both the 2-substituted and 1-methyl allyl complexes, [Pt(ŋ³-CH₂CRCH₂)(P—P)]⁺ (R = ᶜPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBu₂PCH₂(o-C₆H₄)CH₂PᵗBu₂) and [Pt(ŋ³-CR₂CHCHMe)(P—P)]⁺ (R = cPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBuPCH₂(o-C₆H₄)CH₂PᵗBu₂). The analogous 1-methyl complexes were also formed from [Pt(L)(P—S)], wherein the alkene reacted with a hydride formed by the ortho-metallation of the P—S ligand. Computational models were used to investigate the formation of the allyl structures and it was found that the activation energy had a more significant effect than complex stability on product distributions. Complexes with β-chloroalkyl ligands [Pt(C(CH₂)₂CR₂Cl)Cl(L)₂] (R = CH₂, H, L = SEt₂, NCᵗBu, Py) were formed by the addition of Pt–Cl across the alkene double bond. Phosphine complexes were formed by the displacement of a ligand from cis–[Pt(C(CH₂)₂CR₂Cl)Cl(Py)₂] (R = CH₂, H). These are the first examples of stable Pt(II) β-haloalkyl complexes. It was found using computational models that the presence of cyclopropyl rings had a stabilising effect on these complexes.</p>

Platinum Complexes of Bicyclopropylidene and Related Ligands

<p>The coordination chemistry of the cyclopropyl-substituted alkenes, bicyclopropylidene (BCP) and methylenecyclopropane (MCP), with platinum was explored. A range of complexes with ŋ²-alkene ligands were synthesised by the displacement of a ligand, typically ethene, from a precursor complex. These complexes are [Pt(L)(P—P)] (L = BCP, MCP; P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂, ᵗBu₂PCH₂(o-C₆H₄)₂PᵗBu₂), [Pt(L)(P—S)] (L = BCP, MCP; P—S = ᵗBu₂PCH₂(o-₆H4)CH₂SᵗBu), [Pt(C₂H4)(L)(PR₃)] (L = BCP, MCP; PR₃ = PPh₃, PCy₃), [Pt(MCP)₂(PR₃)] (PR₃ = PPh₃, PCy₃) and [PtCl₂(L)(L′)] (L = BCP, MCP; L′ = Py, DMSO). These were the first examples of platinum complexes with ŋ²-BCP ligands, and the first bis-MCP Pt complexes. BCP underwent ring-opening reactions with both Pt(0) and Pt(II) complexes to form the 1,3-diene allylidenecyclopropane (ACP). The first transition metal complexes of ACP [Pt(ACP)(P—P)] (P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂) were synthesised. Some of these complexes rearranged to form ŋ²:σ²-metallacyclopentene complexes, the first instances of the formation of ŋ²:σ²-metallacyclopentene complexes from ŋ²:π-diene complexes. With MCP, the ring-opening reaction only occurred with [₂(COD)], as a result of the anti-Markovnikov addition of Pt–H, generated by the β-hydride elimination of an Et group, across the double-bond. The major products of this reaction were the 1-methylcyclopropyl complexes [Pt(C(CH₂)₂CH₃)Et(COD)] and [Pt(C(CH₂)₂CH₃)₂(COD)], the first examples of such complexes. Protonation of [Pt(L)(P—P)] resulted in a ring-opening reaction to form both the 2-substituted and 1-methyl allyl complexes, [Pt(ŋ³-CH₂CRCH₂)(P—P)]⁺ (R = ᶜPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBu₂PCH₂(o-C₆H₄)CH₂PᵗBu₂) and [Pt(ŋ³-CR₂CHCHMe)(P—P)]⁺ (R = cPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBuPCH₂(o-C₆H₄)CH₂PᵗBu₂). The analogous 1-methyl complexes were also formed from [Pt(L)(P—S)], wherein the alkene reacted with a hydride formed by the ortho-metallation of the P—S ligand. Computational models were used to investigate the formation of the allyl structures and it was found that the activation energy had a more significant effect than complex stability on product distributions. Complexes with β-chloroalkyl ligands [Pt(C(CH₂)₂CR₂Cl)Cl(L)₂] (R = CH₂, H, L = SEt₂, NCᵗBu, Py) were formed by the addition of Pt–Cl across the alkene double bond. Phosphine complexes were formed by the displacement of a ligand from cis–[Pt(C(CH₂)₂CR₂Cl)Cl(Py)₂] (R = CH₂, H). These are the first examples of stable Pt(II) β-haloalkyl complexes. It was found using computational models that the presence of cyclopropyl rings had a stabilising effect on these complexes.</p>