Monofunctional Platinum Research Articles

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism.

Mitochondria are potential therapeutic targets for anticancer drugs. A series of mitochondrion-targeted monofunctional platinum complexes, [Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2 (OPT), [Pt(meta-PPh3CH2Py)(NH3)2Cl](NO3)2 (MPT), and [Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2 (PPT) (PPh3 = triphenylphosphonium, Py = pyridine), are studied in this article. The antitumor activity and mechanism of action have been investigated in vitro and in vivo as well as on molecular levels. OPT exhibits higher efficacy than cisplatin against A549 lung cancer cells; furthermore, it shows a strong inhibition towards the growth of non-small-cell lung cancer in nude mice. The DNA binding ability of these complexes follows an order of PPT > OPT > MPT. Cellular uptake and distribution studies show that OPT accumulates mainly in mitochondria, while MPT and PPT accumulate more preferentially in nuclei than in mitochondria. As a result, OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin. The release of cytochrome c from mitochondria is more evident for cells treated with OPT than with cisplatin, though the apoptosis of A549 cells induced by OPT is similar to that induced by cisplatin. Disruption to mitochondrial oxidative phosphorylation and glycolysis is involved in the antitumor mechanism of these compounds. The results indicate that in addition to DNA binding, bioenergetic pathways also play crucial roles in the antitumor activity of mitochondrion-targeted monofunctional platinum complexes.

New Platinum(II) agent induces bimodal death of apoptosis and autophagy against A549 cancer cell

Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands. In comparison to cisplatin, n-Mon-Pt-1 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that n-Mon-Pt-1 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition, ROS release and an ER stress response, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, n-Mon-Pt-1 exhibits lower acute toxicity and better anticancer activity in a murine tumor model.

New monofunctional platinum(II) and palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interaction, and cytotoxic activity

Four new complexes [Pd(H2LtBu)Cl]Cl (Pd1), [Pt(H2LtBu)Cl]Cl (Pt1), [Pd(Me2LtBu)Cl]Cl (Pd2) and [Pt(Me2LtBu)Cl]Cl (Pt2) (where H2LtBu = 2,6-bis(5-(tert-butyl)-1H-pyrazol-3-yl)pyridine and Me2LtBu = 2,6-bis(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), l-methionine (l-Met), l-cysteine (l-Cys) and guanosine-5′-monophosphate (5′-GMP) was investigated. The obtained order was established as follows: Tu > l-Cys > l-Met > 5′-GMP. Complexes Pd1 and Pt1, that contain H2LtBu as chelator, showed higher reactivity towards biomolecules than those with Me2LtBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV–Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (Kb = 104 M−1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H2LtBu/Me2LtBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest.

Using Theory To Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters.

The monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only one guanine base. However, there is still insufficient experimental data to improve its cytotoxicity and all previously proposed chemical modifications of the parent structure have resulted in a loss of activity. We use theoretical tools to illustrate the key steps in the biological mechanisms of phenPt; that is, its activation in water and the subsequent attack on DNA. Our simulations suggest that the measured kinetic parameters, which are based on free nucleobases in solution, need to be reinterpreted because the self-assembled stacked reactive adduct formed in the reaction is inaccessible in real DNA. The constants reported here will help guide future work in the synthesis of anticancer platinum drugs.

Platinum Complexes Can Bind to Telomeres by Coordination.

It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.

Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells

Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1Cl]Cl [L1 = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2Cl]Cl [L2 = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2). In comparison to cisplatin, Mon-Pt-2 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that Mon-Pt-2 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition ROS release and an ER stress response, mediated by mitochondrial dysfunction, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, Mon-Pt-2 exhibits lower acute toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Mon-Pt-2 is the first mono-functional platinum complex inducing pro-death autophagy and apoptosis of cancer cells.

Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand.

Unlike cisplatin, which forms bifunctional DNA adducts, monofunctional platinum(II) complexes bind only one strand of DNA and might target cancer without causing auditory side-effects associated with cisplatin treatment. We synthesized the monofunctional triamine-ligated platinum(II) complexes, Pt(diethylenetriamine)Cl, [Pt(dien)Cl]+, and Pt(N,N-diethyldiethylenetriamine)Cl, [Pt(Et2dien)Cl]+, and the monofunctional heterocyclic-ligated platinum(II) complexes, pyriplatin and phenanthriplatin, and compared their 5’-GMP binding rates, cellular compartmental distribution and cellular viability effects. A zebrafish inner ear model was used to determine if the monofunctional complexes and cisplatin caused hearing threshold shifts and reduced auditory hair cell density. The four monofunctional complexes had varied relative GMP binding rates, but similar cytosolic and nuclear compartmental uptake in three cancer cell lines (A549, Caco2, HTB16) and a control cell line (IMR90). Phenanthriplatin had the strongest effect against cellular viability, comparable to cisplatin, followed by [Pt(Et2dien)Cl]+, pyriplatin and [Pt(dien)Cl]+. Phenanthriplatin also produced the highest hearing threshold shifts followed by [Pt(dien)Cl]+, [Pt(Et2dien)Cl]+, cisplatin and pyriplatin. Hair cell counts taken from four regions of the zebrafish saccule showed that cisplatin significantly reduced hair cell density in three regions and phenanthriplatin in only one region, with the other complexes having no significant effect. Utricular hair cell density was not reduced by any of the compounds. Our results suggest that placing greater steric hindrance cis to one side of the platinum coordinating center in monofunctional complexes promotes efficient targeting of the nuclear compartment and guanosine residues, and may be responsible for reducing cancer cell viability. Also, the monofunctional compounds caused hearing threshold shifts with minimal effect on hair cell density, which suggests that they may affect different pathways than cisplatin.

Monofunctional BODIPY-Appended Imidazoplatin for Cellular Imaging and Mitochondria-Targeted Photocytotoxicity.

Monofunctional platinum(II) complexes of formulation cis-[Pt(NH3)2(L)Cl](NO3), where L is an imidazole base conjugated to 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) with emissive (L1 in 1) and nonemissive (L2 in 2) moieties were prepared and characterized, and their singlet oxygen-mediated photoinduced cytotoxicity was studied. The 1-methylimidazole (1-MeIm) complex 3 was prepared as a control and for structural characterization by X-ray crystallography. Complexes 1 and 2 showed strong visible absorption bands at 500 nm (ε = 2.7 × 104 M-1 cm-1) and 540 nm (1.4 × 104 M-1 cm-1). Complex 1 is emissive with a band at 510 nm (ΦF = 0.09) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH 7.2). Singlet oxygen generation upon photoirradiation with visible light (400-700 nm) was evidenced from 1,3-diphenylisobenzofuran titration experiments showing significant photosensitizing ability of the BODIPY complexes. Both 1 and 2 were remarkably photocytotoxic in visible light (400-700 nm, 10 J cm-2) in skin keratinocyte HaCaT and breast cancer MCF-7 cells giving IC50 values in nanomolar concentration. The complexes were, however, essentially nontoxic to the cells in the dark (IC50 > 80 μM). Complex 2 having a diiodo-BODIPY unit is nonemissive but an efficient photosensitizer with high singlet oxygen generation ability in visible light (400-700 nm). Confocal microscopy using the emissive complex 1 showed significant mitochondrial localization of the complex. Cell death via apoptotic pathway was observed from the Annexin-V-FITC/PI assay. The formation of Pt-DNA adducts was evidenced from the binding experiments of the complexes 1 and 2 with 9-ethylguanine as a model nucleobase from 1H NMR and mass spectral studies.

Tuning the Optical Properties of Phenanthriplatin: Towards New Photoactivatable Analogues

AbstractThe activity of traditional bifunctional platinum‐based drugs is based on a double binding attack of DNA strands that eventually damages the genetic code. Unfortunately, such therapy comes with severe side effects, which drastically limit its efficiency and more importantly, its large‐scale applicability. One emerging alternative is the use of monofunctional platinum complexes based on phenanthriplatin, a new molecule that develops a potent toxicity in tumorous cells by reacting with one DNA base only. Herein, we use theoretical tools to assess the optical properties of phenanthriplatin as well as a series of analogues in an effort to pave the way to their use in photoactivated chemotherapy. In a first step, the absorption signatures of both isolated and DNA‐embedded drugs are predicted through ab initio calculations. Two nitro derivatives are shown to activate a charge transfer from the DNA to the drug and might consequently initiate a cascade of photodamage events. In a second step, we performed molecular dynamics simulations that reveal that such structural change is enough to perturb the DNA‐binding mode. The biological implications of these results in the framework of the design of novel photoactivatable drugs are discussed.

The influence of the ethane-1,2-diamine ligand on the activity of a monofunctional platinum complex

The continued use of platinum-based chemotherapeutic drugs in the clinic mandates the need for further investigation of the biological activity of structural analogues of the clinically approved complexes. Of interest are monofunctional platinum(II) complexes, which bear only one labile ligand, for which it is believed that each complex binds to DNA only once. Pyriplatin ([PtCl(NH3)2(py)]+) and enpyriplatin ([PtCl(en)(py)]+) are both monofunctional platinum(II) complexes that bear a pyridine ligand and a labile chlorido ligand, differing in their cis‑ammine and ethane-1,2-diamine (en) ligands respectively. Despite their similar structure, the complexes exhibit dramatically different cytotoxicities. In this study, we synthesized and characterized both complexes in terms of their cytotoxicity, lipophilicity, DNA binding and cellular accumulation. There was no significant difference between the lipophilicities of the complexes and both complexes exhibited monofunctional type binding, but it was the temporal accumulation profiles of the two complexes which differed greatly. The complexes were further analyzed with size exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS) to determine the platination state of the proteins. Consistent with the accumulation studies, pyriplatin bound to proteins in far greater amounts than enpyriplatin, and this study also revealed some different protein targets between the bifunctional cisplatin and monofunctional pyriplatin. This study highlights the need for more sophisticated techniques, such as SEC-ICP-MS, to determine not only how much of a platinum complex accumulates in cells, but also the speciation and metabolites of platinum anticancer drugs.

Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption.

Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt-MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition.

A Very Rare Example of a Structurally Characterized 3'-GMP Metal Complex. NMR and Synthetic Assessment of Adducts Formed by Guanine Derivatives with [Pt(Ltri)Cl]Cl Complexes with an N,N',N″ Tridentate Ligand (Ltri) Terminated by Imidazole Rings.

[Pt(N(R)-1,1'-Me2dma)Cl]Cl complexes with tridentate ligands (bis(1-methyl-2-methylimidazolyl)amine, R = H; N-(methyl)bis(1-methyl-2-methylimidazolyl)amine, R = Me) were prepared in order to investigate Pt(N(R)-1,1'-Me2dma)G adducts (G = monodentate N9-substituted guanine or hypoxanthine derivative). Solution NMR spectroscopy is the primary tool for studying metal complexes of nucleosides and nucleotides because such adducts rarely crystallize. However, [Pt(N(H)-1,1'-Me2dma)(3'-GMPH)]NO3·5H2O (5) was crystallized, allowing, to our knowledge, the first crystallographic molecular structure determination for a 3'-GMP platinum complex. The structure is one of only a very few structures of a 3'-GMP complex with any metal. Complex 5 has the syn rotamer conformation, with 3'-GMP bound by N7. All Pt(N(R)-1,1'-Me2dma)G adducts exhibit two new downfield-shifted G H8 signals, consistent with G bound to platinum by N7 and a syn/anti rotamer mixture. Anticancer-active monofunctional platinum(II) complexes have bulky carrier ligands that cause DNA adducts to be distorted. Hence, understanding carrier-ligand steric effects is key in designing new platinum drugs. Ligand bulk can be correlated with the degree of impeded rotation of the G nucleobase about the Pt-N7 bond, as assessed by the observation of rotamers. The signals of syn and anti rotamers are connected by EXSY cross-peaks in 2D ROESY spectra of Pt(N(H)-1,1'-Me2dma)G adducts but not in spectra of Pt(N(H)dpa)G adducts (N(H)dpa = bis(2-picolyl)amine), indicating that rotamer interchange is more facile and carrier-ligand bulk is lower in Pt(N(H)-1,1'-Me2dma)G than in Pt(N(H)dpa)G adducts. The lower steric hindrance is a direct consequence of the greater distance of the G nucleobase from the H4/4' protons in the N(R)-1,1'-Me2dma carrier ligand in comparison to that from the H6/6' protons in the N(H)dpa carrier ligand. Although in 5 the nucleotide is 3'-GMP (not the usual 5'-GMP) and the N(H)-1,1'-Me2dma carrier ligand is very different from those typically present in structurally characterized Pt(II) G complexes, the rocking and canting angles in 5 adhere to long-recognized trends.

A New Approach to Sensitize Antitumor Monofunctional Platinum(II) Complexes via Short Time Photo-Irradiation.

Sensitizing the antitumor activity of monofunctional PtII complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional PtII complexes, in this study, the photosensitizing monofunctional PtII complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the PtII center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional PtII complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional PtII complex and renders the possibility of monofunctional PtII prodrugs for precise chemotherapy via only short time photoactivation.

Anticancer Effects of a New Aminosugar-conjugated Platinum Complex Agent Against Cisplatin-resistant Gastric Cancer.

Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer.

Phenanthriplatin Acts As a Covalent Poison of Topoisomerase II Cleavage Complexes.

Drugs capable of trapping topoisomerase II (Top2), an essential enzyme that cleaves DNA to remove naturally occurring knots and tangles, can serve as potent anticancer agents. The monofunctional platinum agent phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl](NO3), is shown here to trap Top2 in addition to its known modes of inhibition of DNA and RNA polymerases. Its potency therefore combines diverse modes of action by which phenanthriplatin kills cancer cells. The observation that phenanthriplatin can act as a Top2 poison highlights opportunities to design nonclassical platinum anticancer agents with this novel mechanism of action. Such complexes have the potential to overcome current limitations with chemotherapy, such as resistance, and to provide treatment options for cancers that do not respond well to classical agents. Covalent DNA-platinum lesions implicated in Top2 poisoning are distinctive from those generated by known therapeutic topoisomerase poisons, which typically exert their action by reversible binding at the interface of Top2-DNA cleavage complexes.

Monofunctional Platinum (PtII) Compounds - Shifting the Paradigm in Designing New Pt-based Anticancer Agents.

Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key components in combination chemotherapy. However, their effective use is hindered by toxicity and emergence of drug resistance. They bind to DNA and mainly form the Pt-GG diadduct, subsequently leading to apoptosis to mediate cell death. On the other hand, the Pt drug -proteins and -metabolites interactions, which involve the reaction between Pt and sulfur sites located in protein side chains and important bionucleophiles (e.g., glutathione), are responsible for the toxicity and drug resistance problem. Therefore, carefully designed coordinating ligands may provide the means of fine tuning the electronic environment around the core Pt atom and allow the resulting Pt compounds to bind with the DNA in a different manner. This may produce alternative cell death mechanisms in cancer cells, thereby circumventing Pt resistance. This article reviewed the recent development in monofunctional Pt complexes and their prospects in becoming a new generation of anticancer drugs.

Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin.

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N(1) or N(7) position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N(7) -bound species. Both of the 9-methyladenine linkage isomers (N(1) and N(7) ) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N(1) -bound platinum complex and the N(7) -linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.

Platinum-based drugs: past, present and future.

Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of human neoplasms. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Much effort has been put into the development of new platinum anticancer complexes, but none of them has reached worldwide clinical application so far. Nedaplatin, lobaplatin and heptaplatin received only regional approval. Some new platinum complexes and platinum drug formulations are undergoing clinical trials. Here, we review the main classes of new platinum drug candidates, such as sterically hindered complexes, monofunctional platinum drugs, complexes with biologically active ligands, trans-configured and polynuclear platinum complexes, platinum(IV) prodrugs and platinum-based drug delivery systems. For each class of compounds, a detailed overview of the mechanism of action is given, the cytotoxicity is compared to that of the clinically used platinum drugs, and the clinical perspectives are discussed. A critical analysis of lessons to be learned is presented. Finally, a general outlook regarding future directions in the field of new platinum drugs is given.

A monofunctional platinum complex coordinated to a rhodium metalloinsertor selectively binds mismatched DNA in the minor groove.

We report the synthesis and characterization of a bimetallic complex derived from a new family of potent and selective metalloinsertors containing an unusual Rh-O axial coordination. This complex incorporates a monofunctional platinum center containing only one labile site for coordination to DNA, rather than two, and coordinates DNA nonclassically through adduct formation in the minor groove. This conjugate displays bifunctional, interdependent binding of mismatched DNA via metalloinsertion at a mismatch as well as covalent platinum binding. DNA sequencing experiments revealed that the preferred site of platinum coordination is not the traditional N7-guanine site in the major groove, but rather N3-adenine in the minor groove. The complex also displays enhanced cytotoxicity in mismatch repair-deficient and mismatch repair-proficient human colorectal carcinoma cell lines compared to the chemotherapeutic cisplatin, and it triggers cell death via an apoptotic pathway, rather than the necrotic pathway induced by rhodium metalloinsertors.

Design and development progress of platinum-based anticancer drugs

Abstract: Platinum-based anticancer drugs which are widely used in clinic have nearly 40 years history of research and application. In this review, we make a brief introduction of platinum-based anticancer drugs which have been used in clinic or still during the clinical trails, and summarized the drugs which were failed in clinical trails. We introduce the design and development methods of new generation platinum-based anticancer drugs consisting of platinum(II) complexes such as modified and improved trans -platinum(II) complexes, platinum(IV) complexes, and mono-functional platinum complexes. Coordination-saturation platinum complexes and multinuclear platinum complexes are discussed emphatically. This review has put forward some design methods of platinum-based anticancer drugs through listing some of the latest research results, and let readers understand the development of platinum-based anticancer drugs and the future direction of development.