Unveiling Pre-Transmetalation Intermediates in Base-Free Suzuki-Miyaura Cross-Couplings: A Computational Study.

The pre-transmetalation intermediates are critically important in Suzuki-Miyaura cross-coupling (SMC) reactions and have become a hot spot of the current research. However, the pre-transmetalation intermediates under base-free conditions have not been clear. Herein, a comprehensive theoretical study is performed on the base-free Pd-catalyzed desulfonative SMC reaction. The fragile coordination feature and the acceleration role of the RuPhos chelate ligand are revealed. The hydrogen-bond complex between the Pd-F complex and aryl boronic acid is identified as an important pre-transmetalation intermediate, which increases the energy span to 32.5 kcal/mol. The controlling factor for the formation of the hydrogen-bond complexes is attributed to the electronegativities of halogen atoms in the metal halide complexes. What is more, other reported SMC reaction systems involving metal halide complexes and aryl boronic acids are reconsidered and suggest that the hydrogen-bond complexes widely exist as stable pre-transmetalation intermediates with influencing the catalytic activities. The earth-abundant Ni-catalyzed desulfonative SMC reaction is further designed and predicted to have a higher activity than the original Pd-catalyzed SMC reaction.

A novel Schiff base cobalt(III) complex induces a synergistic effect on cervical cancer cells by arresting early apoptosis stage.

A new schiff base cobalt(III) complex [N,N'-bis(2'-hydroxyphenylacetone)-o-ethanediamine] cobalt(III) (M3) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M3 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 by MTT assays. The IC50 is in the range of 6.27-22.68 µM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M3 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, western blot analysis indicated M3 dramatically decreased the target protein c-Myc and KLF5 expression levels, and activated many signaling pathways including ER stress, apoptosis, cell cycle and DNA damage in HeLa. M3 did not affect proteasomal activity.

A dual functional turn-on non-toxic chemosensor for highly selective and sensitive visual detection of Mg2+ and Zn2+: the solvent-controlled recognition effect and bio-imaging application.

A new dual functional turn-on chemosensor, 2,6-diformyl-4-methylphenol-di(isoquinolinyl-1-hydrazone) (HL), has been developed, which could highly selectively discriminate Mg2+ and Zn2+ in different solvent systems. The chemosensor HL exhibits rapid visual turn-on fluorescence enhancing recognition toward Mg2+/Zn2+, which is not interfered by other cations, especially for respective congeners Ca2+/Cd2+. The remarkable fluorescence enhancement (71-fold or 11-fold) was observed after adding Mg2+ in acetonitrile or Zn2+ in DMF-H2O solvent systems. Additionally such a solvent medium-controlled platform could achieve the quantitative determination of Mg2+ and Zn2+ quantitation with low detection limits of 2.97 × 10-8 M and 3.07 × 10-7 M, respectively. Furthermore, the turn-on fluorescence sensing mechanism is also investigated by 1H NMR, FT-IR and ESI-MS spectroscopy. Density functional theory (DFT) calculations derive optimized geometries of HL and its complexes. Notably, non-toxic HL also can be successfully applied as a visual probe for the practical determination of Mg2+/Zn2+ in MCF-7 cells, Zebrafish larvae, syrup and water samples, which might provide extensive application in biology and medicine fields.

Biomimetic Frustrated Lewis Pair Catalysts for Hydrogenation of CO to Methanol at Low Temperatures.

The industrial production of methanol through CO hydrogenation using the Cu/ZnO/Al2O3 catalyst requires harsh conditions, and the development of new catalysts with low operating temperatures is highly desirable. In this study, organic biomimetic FLP catalysts with good tolerance to CO poison are theoretically designed. The base-free catalytic reaction contains the 1,1-addition of CO into a formic acid intermediate and the hydrogenation of the formic acid intermediate into methanol. Low-energy spans (25.6, 22.1, and 20.6 kcal/mol) are achieved, indicating that CO can be hydrogenated into methanol at low temperatures. The new extended aromatization-dearomatization effect involving multiple rings is proposed to effectively facilitate the rate-determining CO 1,1-addition step, and a new CO activation model is proposed for organic catalysts.

Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo.

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

Enantioselective Synthesis of Fused Butyrolactones via Organocatalytic Formal [2 + 2 + 2] Annulation of γ-Butenolides, Methylene Indolinones, and Nitroolefins.

An organocatalyzed asymmetric synthesis of fused butyrolactones via formal [2 + 2 + 2] annulation between γ-butenolides, methylene indolinones, and nitroolefins in a one-pot process has been established. Products containing six contiguous stereocenters could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to >99% ee) catalyzed by a l-tert-leucine-derived bifunctional thiourea catalyst.

Rapid DNA interstrand cross-linking of Pt(IV) compound.

Pt(IV) anticancer compounds have been developed for several decades to overcome the drawbacks of their Pt(II) congeners, and the reduction of Pt(IV) to Pt(II) has been commonly regarded as a necessary step in the activation of Pt(IV) compounds prior to targeting DNA. However, blockage of glutathione (GSH) biosynthesis resulted in a slight effect on the cytotoxicity of oxoplatin in yeast Saccharomyces cerevisiae strains, urging us to reconsider the mechanism of actions for the "inert" Pt(IV) complexes. Using X-ray absorption near-edge spectroscopy (XANES), our data demonstrated that Pt(IV) complex oxoplatin could bind to DNA in a tetravalent state. Both alkaline denaturing agarose electrophoresis and thermal denaturation-renaturation assay revealed that oxoplatin could rapidly produce stable interstrand crosslinks (ICLs), which can further translate into a fast cell-killing process in cancer cells. Using quantitative real-time PCR and immunofluorescence analysis, we also proved that Pt(IV) complex oxoplatin could induce a quick intracellular response of the FA/BRCA pathway in cancer cells that involves the DNA interstrand crosslinking repair system, and this quick response to ICLs was independent with the intracellular GSH levels. Cell cycle analysis showed that short incubation with oxoplatin can induce a strong S phase arrest in HeLa cells, indicating that the rapid interstrand crosslinks produced by oxoplatin might stall the replication fork, result in the double-strand breaks, and eventually induce cell death. Our results implied that, besides the reduction mechanism to release the Pt(II) congeners, direct and rapid interstrand cross-linking with DNA by Pt(IV) compounds might be a unique mechanism for Pt(IV) compounds, which may provide new insight for the development of next-generation platinum-based drugs.

Ketoplatin in triple-negative breast cancer cells MDA-MB-231: High efficacy and low toxicity, and positive impact on inflammatory microenvironment.

Triple-negative breast cancer (TNBC) shares the molecular features facilitating epithelial-to-mesenchymal transition (EMT), which contributed to tumor invasion and metastasis. A platinum(IV) conjugate ketoplatin deriving from FDA-approved drugs cisplatin and ketoprofen was designed and prepared to enhance antitumor activity and suppress EMT in TNBC via positive impact on inflammatory microenvironment by modulating COX-2 signal. As a prodrug, ketoplatin afforded 50.26-fold higher cytotoxicity than cisplatin against TNBC mesenchymal-stem cell-like MDA-MB-231 cells, partly attributing to its dramatic increase of cellular uptake and DNA damage. More importantly, EMT progress in MDA-MB-231 was markedly restrained by ketoplatin, resulting from the suppression of vimentin and N-cadherin mediated by down-regulated COX-2. Further in vivo investigation exhibited that ketoplatin effectively inhibited tumor growth and reduced systemic toxicity compared to cisplatin. Overall, ketoplatin possessed high antitumor activity and low toxicity against TNBC MDA-MB-231 in vitro and in vivo.

Cu(ii)-TACN complexes selectively induce antitumor activity in HepG-2 cells via DNA damage and mitochondrial-ROS-mediated apoptosis.

A new 1,4,7-triazacyclononane derivative, 4-benzyloxy-benzyl-1,4,7-triazacyclononane (btacn), and three associated cyclen complexes, Cu(btacn)Cl2, Zn(btacn)Cl2 and [Cu(btacn)2]·(ClO4)2, were prepared to serve as DNA synthesis interferents. The compounds were characterized using IR, 1H and 13C NMR, ESI-MS, elemental analysis and X-ray single crystal diffraction methods, and their DNA damage mechanisms and cytotoxicities towards cancer and normal cells were studied. Among them, Cu(btacn)Cl2 and [Cu(btacn)2]·(ClO4)2 exhibit potent anti-proliferation activity in HepG-2 and HeLa cells, but low cytotoxicity in the normal cell models LO2 and HUVEC, giving SI values (IC50 ratios) ranging from 2.45 to 7.09-times higher than that of cisplatin. DNA binding and cleavage studies suggested that [Cu(btacn)2]·(ClO4)2 can more easily intercalate into CT-DNA than Cu(btacn)Cl2, which is consistent with the results of G2/S phase arrest and apoptosis in HepG-2 cells involving the complexes. In contrast, Zn(btacn)Cl2 demonstrated weak DNA binding and no obvious cytotoxicity. The results suggest that Cu(btacn)Cl2 and [Cu(btacn)2]·(ClO4)2 mainly undergo redox processes to produce reactive oxygen species (ROS) that induce DNA degradation and mitochondrial damage.

Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo.

Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3-6, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER+) cells, among which 3 presented the most potent cytotoxicity toward ER+ MCF-7 with nanomolar IC50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo, promoting lymphocyte proliferation in spleen to achieve immune modulation.

A new Schiff base copper(II) complex induces cancer cell growth inhibition and apoptosis by multiple mechanisms.

A new Schiff base copper(II) complex [N,N'-bis(2'-hydroxyphenylacetone)-o-ethanediamine] copper (II) (M1) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M1 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 and HUVEC, by MTT (3-(4,5-dimethylthiazoyl-2-yl)2,5-diphenyltetrazoliumbromide) assays. The IC50 (50% inhibition concentrations) is in the range of 5.13-11.68 µM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M1 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, M1 increased intracellular ROS (Reactive oxygen species) levels in a dose-dependent manner. Western blot analysis indicated M1 dramatically decrease c-Myc transcription factor and KLF5 (Krüppel-like factor 5) protein expression levels in HeLa. M1 did not inhibit proteasomal activity. Finally, M1 induced DNA damages and activated the DNA damage repair pathways.

Syntheses, characterization, DNA/HSA binding ability and antitumor activities of a family of isostructural binuclear lanthanide complexes containing hydrazine Schiff base.

Three dinuclear lanthanide complexes, [Ln2(L)2(µ3-OAc)4(H2O)2]⋅2H2O (Ln = La (1), Eu (2) and Dy (3), HL = N'-(2-hydroxybenzylidene) nicotinohydrazide), have been synthesized and characterized by IR, elemental analysis and X-ray single-crystal diffraction. Crystallographic study revealed that the representative complex 1 displays a discrete dinuclear structure with a distorted tricapped trigonal prismatic geometry around La(III) ion. The interaction of complexes 1-3 with CT-DNA was investigated by absorption spectra, fluorescence quenching and viscosity, which reveals that the complexes bind to CT-DNA with a moderate intercalative mode. The complexes exhibited obvious DNA cleavage activities in the presence of H2O2. All complexes could bind to human serum albumin (HSA) with medium affinity through static mode; thus, HSA could effectively transport complexes. Furthermore, three complexes exhibited specific cytotoxicity to A549 cancer cells in micromole magnitude than other cancer cells tested and less toxicity than cisplatin for normal human cells HUVEC, in which massive cell apoptosis was induced by complexes through producing DNA damage and suppressing DNA synthesis.Communicated by Ramaswamy H. Sarma.

Fuplatin: An Efficient and Low-Toxic Dual-Prodrug.

As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10-17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower cytotoxicity toward the human normal lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62- and 825-fold amount of oxaliplatin and 8 at 9 h, respectively, significantly induced DNA damage and cell apoptosis, and inhibited migration and invasion in HCT-116 cells. Compound 14 arrested the cell cycle at S and G2 phases and up-regulated thymidylate synthase and p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to kill cancer cells. In vivo, compound 14 showed high antitumor effect and no observable toxicity in NOD/SCID mice bearing HCT-116 tumors.

New NSAID-Pt(IV) prodrugs to suppress metastasis and invasion of tumor cells and enhance anti-tumor effect in vitro and in vivo.

The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3 h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells. Among of them, Eto-Pt(IV) and Car-Pt(IV) exhibited more excellent activity than Sul-Pt(IV), arising from their reduction-labile and favorable lipophilicity. Most strikingly, Eto-Pt(IV) markedly inhibited metastasis and invasion of MCF-7 cells, owing to its COX-2 suppression that down-regulated active MMP-2, vimentin protein and up-regulated E-cadherin. In vivo, Eto-Pt(IV) displayed potent antitumor activity and no observable toxicity in BALB/c nude mice bearing MCF-7 tumors.

Chlorambucil-conjugated platinum(IV) prodrugs to treat triple-negative breast cancer in vitro and in vivo.

Modification of platinum (II) into lipophilic platinum (IV) compounds by introducing biologically active molecules were widely employed to develop new platinum-based prodrugs in the past decade. In this paper, two chlorambucil platinum (IV) complexes, CLB-Pt and CLB-Pt-CLB, were synthesized and displayed very potent antiproliferative activity against all the tested cancer cell lines, such as A549, HeLa and MCF-7, especially to treat the well-known refractory triple-negative breast cancer. CLB-Pt-CLB significantly improved cell-killing effect in triple-negative subtype MDA-MB-231 cells, and showed much stronger cytotoxicity than either monotherapy or combination of cisplatin and chlorambucil. CLB-Pt-CLB prodrug entered cells in dramatically increased amount compared with cisplatin and enhanced DNA damage, inducing cancer cell apoptosis. It exhibited high anticancer activity and no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. The chlorambucil moiety not only greatly assisted the passive diffusion of CLB-Pt-CLB into cells, but also produced the synergism with cisplatin in targeting DNA.

Rapid induction of apoptosis in tumor cells treated with a new platinum(II) complex based on amino-thiazolidinone.

Thiazolidinone derivatives have been previously shown significant anti-cancer activities. Two amino-thiazolidinone complexes, [Pt(HTone)Cl] (1) and [Cu(HTone)Cl] (3) (HTone = (Z)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one) and one ethyl-modified [Pt(ETone)Cl2] (2) (ETone = (Z)-3-ethyl-2-((E)-(1-(pyridin-2-yl)ethylidene) hydrazono)thiazolidin-4-one)], were designed and synthesized in order to explore novel metal-based antitumor agents. MTT assay indicated that 1 and 3 were markedly cytotoxic to MCF-7, HepG-2 and NCI-H460 tumor cells, superior to both cisplatin and the HTone ligand. Massive dead cells were observed as early as 6 h when treated with 1, indicating rapid action of 1 as compared to that of other compounds. More interestingly, Hoechst 33342 staining and flow cytometry analysis illustrated that only complex 1 could induce obvious cell apoptosis within 12 h, which was associated with the high-expression of Bax and cleavage of caspase-3 from 35 kDa to 17 kDa. By means of ICP-MS assay, we found complex 1 could largely accumulate in tumor cells in a short time. Additionally, complex 1 showed no cross resistance against the cisplatin-resistant cells.

Four Cu(ii) complexes based on antitumor chelators: synthesis, structure, DNA binding/damage, HSA interaction and enhanced cytotoxicity.

Four novel copper(ii) complexes [Cu(II)(Bp4mT)(µ-Cl)]2 (), [Cu(II)(µ-Bp4mT)Br]2 (), [Cu(II)(HBpT)Cl] (), and [Cu(II)(HBpT)Br] () (Bp4mT = 2-benzoylpyridine-4-methylthiosemicarbazone, HBpT = 2-benzoylpyridine thiosemicarbazone), were synthesized and characterized using single-crystal X-ray diffraction, elemental analysis, infrared, and ultraviolet-visible spectroscopy. X-ray analysis revealed that complexes and based on the Bp4mT ligand presented dimeric structures in which the Cu(ii) ions were located in a five-coordinated distorted square-pyramidal geometry, whereas both and complexes were mononuclear with the Cu(ii) ions exhibiting a tetracoordinated square planar configuration. Their interactions with calf thymus DNA (CT-DNA) were investigated using viscosity measurements and fluorescence spectroscopy. Multispectroscopic evidence has shown interactions between these complexes and human serum albumin (HSA). All these complexes have exhibited efficient oxidative cleavage of supercoiled DNA in the presence of hydrogen peroxide, presumably via an oxidative mechanism. Furthermore, in vitro cytotoxicity studies of against human liver hepatocellular carcinoma cells (HepG-2), human large cell lung carcinoma cells (NCI-H460), and human cervical carcinoma cells (HeLa) indicated their promising antitumor activity with quite low IC50 values in the range of 0.08-1.98 µM, which are 83 times lower than those of cisplatin. The mechanistic studies revealed that four complexes, which induced early apoptosis, were involved in reactive oxygen species generation and DNA cleavage for their antitumor activities.

Mixed-ligand copper(ii) Schiff base complexes: the role of the co-ligand in DNA binding, DNA cleavage, protein binding and cytotoxicity.

Four novel mononuclear Schiff base copper(ii) complexes, namely, [Cu(L)(OAc)]·H2O (), [Cu(HL)(C2O4)(EtOH)]·EtOH (), [Cu(L)(Bza)] () and [Cu(L)(Sal)] () (HL = 1-(((2-((2-hydroxypropyl)amino)ethyl)imino)methyl)naphthalene-2-ol), Bza = benzoic acid, Sal = salicylic acid), were synthesized and characterized by X-ray crystallography, elemental analysis and infrared spectroscopy. Single-crystal diffraction analysis revealed that all the complexes were mononuclear molecules, in which the Schiff base ligand exhibited different coordination modes and conformations. The N-HO and O-HO inter- and intramolecular hydrogen bonding interactions linked these molecules into multidimensional networks. Their interactions with calf thymus DNA (CT-DNA) were investigated by UV-visible and fluorescence spectrometry, as well as by viscosity measurements. The magnitude of the Kapp values of the four complexes was 10(5), indicating a moderate intercalative binding mode between the complexes and DNA. Electrophoresis results showed that all these complexes induced double strand breaks of pUC19 plasmid DNA in the presence of H2O2 through an oxidative pathway. In addition, the fluorescence spectrum of human serum albumin (HSA) with the complexes suggested that the quenching mechanism of HSA by the complexes was a static process. Moreover, the antiproliferative activity of the four complexes against HeLa (human cervical carcinoma) and HepG-2 (human liver hepatocellular carcinoma) cells evaluated by colorimetric cell proliferation assay and clonogenic assay revealed that all four complexes had improved cytotoxicity against cancer cells. Inspiringly, complex , with salicylic acid as the auxiliary ligand, displayed a stronger anticancer activity, suggesting that a synergistic effect of the Schiff base complex and the nonsteroidal anti-inflammatory drug may be involved in the cell killing process. The biological features of mixed-ligand copper(ii) Schiff base complexes and how acetic auxiliary ligands manipulate these features are also discussed.