Cyclization, Decyclization, and Metallacyclization of Pyridine-Substituted Homopropargylic Alcohols on Ruthenium(II) and Osmium(II) Centers.

Systematic investigations on the reactions between cis-[M(dppm)2 Cl2 ] (M=Ru/Os; dppm=1,1-bis(diphenylphosphino)methane) and pyridine/quinoline substituted homopropargylic alcohols uncovered the diverse Ru(II)/Os(II)-induced alkyne activation pathways. The alkynes underwent cyclization on M via a "non-vinylidene" pathway at lower temperatures, resulting in alkenyl intermediates which might further metallacyclize to give metallapyrroloindolizines. Conversely, reactions at higher temperatures induced alkyne cyclization on M via a "vinylidene" pathway, affording cyclic oxacarbene complexes. Additionally, a rare decyclization mechanism was observed during the transformation of a metallacyclization-resistant alkenyl complex into a cyclic oxacarbene complex. DFT calculations were employed to validate the experimental findings. Overall, these results not only provide insights into controlling alkyne activation pathways, but also offer new strategies for preparing metalated heterocyclic and metallacyclic complexes.

Multitargeted Platinum(IV) Anticancer Complexes Bearing Pyridinyl Ligands as Axial Leaving Groups.

Although multitargeted PtIV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. Herein, we report the synthesis of PtIV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted PtIV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumor in vivo. This research adds to the array of synthetic methods for accessing PtIV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a PtIV center.

Intramolecular Cyclization: A Convenient Strategy to Realize Efficient BT.2020 Blue Multi-Resonance Emitter for Organic Light-Emitting Diodes.

Rationally tuning the emission position and narrowing the full width at half-maximum (FWHM) of an emitter is of great importance for many applications. By synergistically improving rigidity, strengthening the resonant strength, inhibiting molecular bending and rocking, and destabilizing the HOMO energy level, a deep-blue emitter (CZ2CO) with a peak wavelength of 440 nm and an ultranarrow spectral FWHM of 16 nm (0.10 eV) was developed via intramolecular cyclization in a carbonyl/N resonant core (QAO). The dominant υ0-0 transition character of CZ2CO gives a Commission Internationale de I'Éclairage coordinates (CIE) of (0.144, 0.042), nicely complying with the BT.2020 standard. Moreover, a hyper-fluorescent device based on CZ2CO shows a high maximum external quantum efficiency (EQEmax ) of 25.6 % and maintains an EQE of 22.4 % at a practical brightness of 1000 cd m-2 .

Ruthenafuran Complexes Supported by the Bipyridine-Bis(diphenylphosphino)methane Ligand Set: Synthesis and Cytotoxicity Studies.

Mononuclear and dinuclear Ru(II) complexes cis-[Ru(κ2-dppm)(bpy)Cl2] (1), cis-[Ru(κ2-dppe)(bpy)Cl2] (2) and [Ru2(bpy)2(µ-dpam)2(µ-Cl)2](Cl)2 ([3](Cl)2) were prepared from the reactions between cis(Cl), cis(S)-[Ru(bpy)(dmso-S)2Cl2] and diphosphine/diarsine ligands (bpy = 2,2'-bipyridine; dppm = 1,1-bis(diphenylphosphino)methane; dppe = 1,2-bis(diphenylphosphino)ethane; dpam = 1,1-bis(diphenylarsino)methane). While methoxy-substituted ruthenafuran [Ru(bpy)(κ2-dppe)(C^O)]+ ([7]+; C^O = anionic bidentate [C(OMe)CHC(Ph)O]- chelate) was obtained as the only product in the reaction between 2 and phenyl ynone HC≡C(C=O)Ph in MeOH, replacing 2 with 1 led to the formation of both methoxy-substituted ruthenafuran [Ru(bpy)(κ2-dppm)(C^O)]+ ([4]+) and phosphonium-ring-fused bicyclic ruthenafuran [Ru(bpy)(P^C^O)Cl]+ ([5]+; P^C^O = neutral tridentate [(Ph)2PCH2P(Ph)2CCHC(Ph)O] chelate). All of these aforementioned metallafuran complexes were derived from Ru(II)-vinylidene intermediates. The potential applications of these metallafuran complexes as anticancer agents were evaluated by in vitro cytotoxicity studies against cervical carcinoma (HeLa) cancer cell line. All the ruthenafuran complexes were found to be one order of magnitude more cytotoxic than cisplatin, which is one of the metal-based anticancer agents being widely used currently.

Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues.

Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.

BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity.

Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.

Visible light photocatalytic cross-coupling and addition reactions of arylalkynes with perfluoroalkyl iodides.

Visible light photocatalytic cross-coupling and addition reactions of arylalkynes with perfluoroalkyl iodides have been developed. Through slight modifications of the reaction conditions, reactions that are selective for the preparation of the C-C coupling product (perfluoroalkyl alkynes) and the addition products (iodo-perfluoroalkyl substituted alkenes) can be achieved. These reactions work well with different types of alkynes and perfluoroalkyl iodides. As the iodide generated from the reaction can serve as a reductant to regenerate the photocatalyst from its oxidized form, no sacrificial electron donor is required.

Talaromyces marneffei Mp1 Protein, a Novel Virulence Factor, Carries Two Arachidonic Acid-Binding Domains To Suppress Inflammatory Responses in Hosts.

Talaromyces marneffei infection causes talaromycosis (previously known as penicilliosis), a very important opportunistic systematic mycosis in immunocompromised patients. Different virulence mechanisms in T. marneffei have been proposed and investigated. In the sera of patients with talaromycosis, Mp1 protein (Mp1p), a secretory galactomannoprotein antigen with two tandem ligand-binding domains (Mp1p-LBD1 and Mp1p-LBD2), was found to be abundant. Mp1p-LBD2 was reported to possess a hydrophobic cavity to bind copurified palmitic acid (PLM). It was hypothesized that capturing of lipids from human hosts by expressing a large quantity of Mp1p is a virulence mechanism of T. marneffei It was shown that expression of Mp1p enhanced the intracellular survival of T. marneffei by suppressing proinflammatory responses. Mechanistic study of Mp1p-LBD2 suggested that arachidonic acid (AA), a precursor of paracrine signaling molecules for regulation of inflammatory responses, is the major physiological target of Mp1p-LBD2. In this study, we use crystallographic and biochemical techniques to further demonstrate that Mp1p-LBD1, the previously unsolved first lipid binding domain of Mp1p, is also a strong AA-binding domain in Mp1p. These studies on Mp1p-LBD1 support the idea that the highly expressed Mp1p is an effective AA-capturing protein. Each Mp1p can bind up to 4 AA molecules. The crystal structure of Mp1p-LBD1-LBD2 has also been solved, showing that both LBDs are likely to function independently with a flexible linker between them. T. marneffei and potentially other pathogens highly expressing and secreting proteins similar to Mp1p can severely disturb host signaling cascades during proinflammatory responses by reducing the availabilities of important paracrine signaling molecules.

Phosphonium-Ring-Fused Bicyclic Metallafuran Complexes of Ruthenium and Osmium.

Metallafuran complexes with a fused five-membered phosphonium ring were synthesized from reactions between terminal ynones HC≡C(C=O)R and cis-[Ru/Os(dppm)2 Cl2 ] (dppm=1,1-bis(diphenylphosphino)methane). A metal-vinylidene-involving pathway was found to be an energetically feasible formation mechanism for these complexes. These phosphonium-containing metallafurans, like many phosphonium-functionalized drugs, have the ability to induce mitochondrial dysfunction. They also exhibit stronger cytotoxicity against several human cancer cell lines in comparison with their metal precursors and the classic anticancer drug cisplatin. Overall, this work provides structural and mechanistic insights for the rational design of functional metallacycles via activation of alkynes by RuII and OsII centers.

Synthesis, Cytotoxicity, and Mechanistic Investigation of Platinum(IV) Anticancer Complexes Conjugated with Poly(ADP-ribose) Polymerase Inhibitors.

Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPi) have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. Herein, we obtained seven potential PARPi with structural diversity and then conjugated them with cisplatin-based platinum(IV) complexes. Both the synthesized PARPi ligands and PARPi-Pt conjugates [PARPi-Pt(IV)] show inhibitory effects against PARP-1's catalytic activity. The PARPi-Pt(IV) conjugates are cytotoxic in a panel of human cancer cell lines, and the leading ones display the ability to overcome cisplatin resistance. A mechanistic investigation reveals that the representative PARPi-Pt(IV) conjugates efficiently enter cells, bind to genomic DNA, disturb cell cycle distribution, and induce apoptotic cell death in both cisplatin-sensitive and -resistant cells. Our study provides a strategy to improve the cytotoxicity of platinum(IV)-based anticancer complexes and overcome cisplatin resistance by using a small-molecule anticancer complex that simultaneously damages DNA and inhibits PARP.

Synthesis and Cytotoxic Study of a Platinum(IV) Anticancer Prodrug with Selectivity toward Luteinizing Hormone-Releasing Hormone (LHRH) Receptor-Positive Cancer Cells.

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.

A Cancer Cell-Selective and Low-Toxic Bifunctional Heterodinuclear Pt(IV)-Ru(II) Anticancer Prodrug.

Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC50 values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin.

Synthesis, Structure, and Cytotoxicity of Oxaliplatin-Based Platinum(IV) Anticancer Prodrugs Bearing One Axial Fluoride.

Fluorine plays more and more important roles in drug design and development. In recent years, fluorine-containing organic drugs have already been applied in a broad range of therapeutic areas. Herein, we report our attempt to introduce an axial fluorine ligand to Pt(IV) complexes by oxidizing oxaliplatin with electrophilic fluorinating reagents in different protic solvents. The crystal structure of one representative complex is presented. The fluorinated Pt(IV) complexes are further expanded by functionalization with different anhydrides, and their analogues bearing one different axial ligand (OAc or OH group) are also synthesized. Further investigations show that the axial fluorine atom has dramatic effects on the chemical properties of these prodrugs. These new fluorinated Pt(IV) complexes are proved to be stable in physiological conditions. For most of the fluorinated Pt(IV) complexes, a higher reduction potential indicates its greater tendency to be reduced by ascorbate. Introducing an axial fluorine ligand in Pt(IV) complexes does not lead to the increase of their lipophilicity. Moreover, these new fluorinated Pt(IV) complexes show better cytotoxicity than nonfluorinated analogues which may derive from their higher cellular accumulation in cancer cells. Therefore, the good stability and high cytotoxicity of these fluorinated Pt(IV) prodrugs indicate their great potential as a building block for further functionalization.

Reduction of RuVI≡N to RuIII-NH3 by Cysteine in Aqueous Solution.

The reduction of metal nitride to ammonia is a key step in biological and chemical nitrogen fixation. We report herein the facile reduction of a ruthenium(VI) nitrido complex [(L)RuVI(N)(OH2)]+ (1, L = N, N'-bis(salicylidene)- o-cyclohexyldiamine dianion) to [(L)RuIII(NH3)(OH2)]+ by l-cysteine (Cys), an ubiquitous biological reductant, in aqueous solution. At pH 1.0-5.3, the reaction has the following stoichiometry: [(L)RuVI(N)(OH2)]+ + 3HSCH2CH(NH3)CO2 → [(L)RuIII(NH3)(OH2)]+ + 1.5(SCH2CH(NH3)CO2)2. Kinetic studies show that at pH 1 the reaction consists of two phases, while at pH 5 there are three distinct phases. For all phases the rate law is rate = k2[1][Cys]. Studies on the effects of acidity indicate that both HSCH2CH(NH3+)CO2- and -SCH2CH(NH3+)CO2- are kinetically active species. At pH 1, the reaction is proposed to go through [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a), [(L)RuIII(NH2SCH2CHNH3CO2H)(OH2)]2+ (3), and [(L)RuIV(NH2)(OH2)]+ (4) intermediates. On the other hand, at pH around 5, the proposed intermediates are [(L)RuIV(NHSCH2CHNH3CO2)(OH2)]+ (2b) and [(L)RuIV(NH2)(OH2)]+ (4). The intermediate ruthenium(IV) sulfilamido species, [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a) and the final ruthenium(III) ammine species, [(L)RuIII(NH3)(MeOH)]+ (5) (where H2O was replaced by MeOH) have been isolated and characterized by various spectroscopic methods.

Monochalcoplatin: An Actively Transported, Quickly Reducible, and Highly Potent PtIV Anticancer Prodrug.

Recently, PtIV prodrugs have attracted much attention as the next generation of platinum-based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated PtIV prodrug that is among the most cytotoxic PtIV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC50 values in the nanomolar range in both cisplatin-sensitive and -resistant cells; these IC50 values are up to 422-fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter-mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective PtIV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.

Push-Pull Heptamethines Near the Cyanine Limit Exhibiting Large Quadratic Electro-Optic Effect.

Harnessing the quadratic electro-optic (QEO) of near-infrared polymethine chromophores over broad telecom wavelength bands is a subject of immense potential but remains largely under-investigated. Herein a series of push-pull heptamethines containing the tricyanofuran (TCF) acceptors and indoline or benzo[e]indoline donors are reported. These dipolar chromophores can attain a highly delocalized "cyanine-like" electronic ground state in solvents spanning a wide range of polarities, in some cases even closer to the ideal polymethine state than symmetrical cyanines. A transmission-mode electromodulation spectroscopy is used to study the electric-field-induced changes in optical absorption and refraction of polymer films doped with heptamethine chromophores, and large and thermally stable QEO effect with high efficiency-loss figure-of-merits that compare favorably to those from dipolar polyenes in poled or unpoled polymers and III-V semiconductors is obtained. The study opens a path for developing organic materials based on cyanine-like merocyanines for complementary metal oxide semiconductor -compatible, fast, efficient, and low-loss electro-optic modulation.

An ultrasound-activatable platinum prodrug for sono-sensitized chemotherapy.

Despite the great success achieved by photoactivated chemotherapy, eradicating deep tumors using external sources with high tissue penetration depth remains a challenge. Here, we present cyaninplatin, a paradigm of Pt(IV) anticancer prodrug that can be activated by ultrasound in a precise and spatiotemporally controllable manner. Upon sono-activation, mitochondria-accumulated cyaninplatin exhibits strengthened mitochondrial DNA damage and cell killing efficiency, and the prodrug overcomes drug resistance as a consequence of combined effects from released Pt(II) chemotherapeutics, the depletion of intracellular reductants, and the burst of reactive oxygen species, which gives rise to a therapeutic approach, namely sono-sensitized chemotherapy (SSCT). Guided by high-resolution ultrasound, optical, and photoacoustic imaging modalities, cyaninplatin realizes the overall theranostics of tumors in vivo with superior efficacy and biosafety. This work highlights the practical utility of ultrasound to precisely activate Pt(IV) anticancer prodrugs for the eradication of deep tumor lesions and broadens the biomedical uses of Pt coordination complexes.

Direct Synthesis of Ammonia from Nitrate on Amorphous Graphene with Near 100% Efficiency.

Ammonia is an indispensable commodity in the agricultural and pharmaceutical industries. Direct nitrate-to-ammonia electroreduction is a decentralized route yet challenged by competing side reactions. Most catalysts are metal-based, and metal-free catalysts with high nitrate-to-ammonia conversion activity are rarely reported. Herein, it is shown that amorphous graphene synthesized by laser induction and comprising strained and disordered pentagons, hexagons, and heptagons can electrocatalyze the eight-electron reduction of NO3 - to NH3 with a Faradaic efficiency of ≈100% and an ammonia production rate of 2859 µg cm-2 h-1 at -0.93 V versus reversible hydrogen electrode. X-ray pair-distribution function analysis and electron microscopy reveal the unique molecular features of amorphous graphene that facilitate NO3 - reduction. In situ Fourier transform infrared spectroscopy and theoretical calculations establish the critical role of these features in stabilizing the reaction intermediates via structural relaxation. The enhanced catalytic activity enables the implementation of flow electrolysis for the on-demand synthesis and release of ammonia with >70% selectivity, resulting in significantly increased yields and survival rates when applied to plant cultivation. The results of this study show significant promise for remediating nitrate-polluted water and completing the NOx cycle.

Production of 2-aminophenoxazin-3-one by Staphylococcus aureus causes false-positive results in ß-galactosidase assays.

Staphylococcus aureus can be distinguished from similar coagulase-positive staphylococci by its absence of ß-galactosidase activity. This is commonly tested using o-nitrophenyl-ß-D-galactopyranoside (ONPG) as the substrate. Unexpectedly, 111 and 58 of 123 isolates displayed apparent ß-galactosidase activity in the ONPG assay and on the Vitek 2 system, respectively. Compositional analysis showed that the yellow coloration of the positive ONPG assay resulted from production of 2-aminophenoxazin-3-one. Alternative ß-galactosidase substrates like X-Gal (5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside) should be used for testing staphylococci.

The influence of different carbonate ligands on the hydrolytic stability and reduction of platinum(IV) prodrugs.

Pt(IV) complexes bearing axial carbonate linkages have drawn much attention recently. A synthetic method behind this allows the hydroxyl group of bioactive ligands to be attached to the available hydroxyl group of Pt(IV) complexes, and the rapid release of free drugs is achieved after the reduction of carbonate-linked Pt(IV) complexes. Further understanding on the properties of Pt(IV) carbonates such as hydrolytic stability and reduction profiles, however, is hindered by limited research. Herein, six mono-carbonated Pt(IV) complexes in which the carbonate axial ligands possess various electron-withdrawing powers were synthesized, and the corresponding mono-carboxylated analogues were also prepared as references to highlight the different properties. The influence of the coordination environment towards the hydrolysis and reduction rate of Pt(IV) carbonates and carboxylates was explored. The mono-carbonated Pt(IV) complexes are both less stable and reduced faster than the corresponding mono-carboxylated ones. Moreover, the hydrolysis and reduction profiles are dependent not only on the electron-withdrawing ability of the carbonates but also on the nature of the opposite axial ligands. Besides, the exploration of the hydrolytic pathway for Pt(IV) carbonates suggests that the process proceeds by an attack of OH- on the carbonyl carbon, followed by elimination, which is different from that of Pt(IV) carboxylates. This study provides some information on the influence of axial carbonate ligands with different electron-withdrawing abilities on the properties of the Pt(IV) center, which may inspire new thoughts on the design of "multi-action" Pt(IV) prodrugs.