- Tetravalent platinum complex containing BET inhibitor and application
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The invention discloses a tetravalent platinum complex containing a BET inhibitor. The structure of the tetravalent platinum complex is as shown in a general formula I, wherein substituent groups are defined in the specification. The advantages of the tetravalent platinum complex are utilized, and the synergistic anti-tumor effect of the BET inhibitor and cis-platinum is exerted. The tetravalent platinum complex containing the BET inhibitor shows broad-spectrum and excellent in-vitro anti-tumor activity, the activity of the tetravalent platinum complex is obviously superior to that of cis-platinum, the BET inhibitor and the mixture of the cis-platinum and the BET inhibitor according to the ratio of 1: 1, and the tetravalent platinum complex has huge potential of being developed into a novel broad-spectrum anti-tumor drug.
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Paragraph 0036-0039
(2021/09/04)
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- Quadrivalent platinum prodrug bendazac platinum, preparation thereof, and preparation methods and applications of prodrug and preparation
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The invention belongs to the technical field of medicines, and particularly relates to a tetravalent platinum prodrug bendazac platinum, a preparation thereof, and preparation methods and applications of the prodrug and the preparation. The structural formula of the prodrug is shown in the specification. The preparation method of the prodrug comprises the following steps: (1) synthesizing hydroxyl platinum; (2) synthesizing bendazac platinum; and (3) purifying the bendazac platinum. The preparation method of the nano preparation comprises the following steps: (1) preparing a bendazac platinum solution; and (2) preparing the nano preparation by taking bovine serum albumin as a carrier. The tetravalent platinum prodrug bendazac platinum and the nano preparation thereof provided by the invention are good in water solubility, small in toxic and side effects and high in anti-tumor efficacy, can be passively targeted to a tumor site, can increase the drug uptake ability of tumor cells, and show a good anti-tumor effect, and the inhibition rates of the tetravalent platinum prodrug bendazac platinum to various tumors can be higher than 90%.
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Paragraph 0042-0043; 0045-0046; 0048-0049
(2021/06/21)
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- Human serum albumin loaded tetravalent platinum nanoparticles and preparation method thereof
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The invention relates to human serum albumin loaded tetravalent platinum nanoparticles and a preparation method thereof, the nanoparticles are formed by self-assembly of albumin and a tetravalent platinum drug modified with double aliphatic chains, the structural formula of the tetravalent platinum drug is as shown in formula I or formula II, and n and m are respectively and independently selected from integers of 1-15. The nanoparticles can respond to the environment in tumor cells to release platinum drugs, therefore effectively reduce the system toxicity, overcome the drug resistance of the tumor cells, and have the advantage of enhancing the killing effect on the tumor cells.
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Paragraph 0048-0050
(2021/06/21)
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- Low-toxicity Pt complex and preparation method and application thereof
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The invention discloses a low-toxicity Pt complex, and belongs to the technical field of anticancer chemical drugs. The structure of the complex is as shown in a general formula (1) or a general formula (2), pterostilbene is introduced into the platinum (IV) complex, and the anti-tumor effect of the platinum complex is improved and the toxic and side effects of the platinum complex on normal cells are reduced by utilizing the anti-inflammatory and anti-oxidation double functions of the pterostilbene.
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Paragraph 0022
(2021/07/08)
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- Tetravalent platinum complex containing artesunate as well as preparation method and application of tetravalent platinum complex
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The invention discloses a tetravalent platinum complex containing artesunate. The structure of the tetravalent platinum complex is shown as a general formula I or II, wherein R is shown in the specification, and R1 is a branched chain or straight chain saturated C1-C20 alkyl group, or a branched chain or straight chain unsaturated C1-C20 alkyl group. The tetravalent platinum complex containing artesunate provided by the invention has an obvious proliferation inhibition effect on liver cancer HepG2, lung cancer A549, intestinal cancer HCT116, breast cancer MDA-MB-231 and cis-platinum drug-resistant lung cancer, the anti-tumor activity of part of compounds is obviously superior to that of cis-platinum, and the tetravalent platinum complex containing artesunate can be used as anti-tumor candidate drugs for deeper research.
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Paragraph 0045; 0047; 0048
(2021/07/08)
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- Immunogenicity and cytotoxicity of a platinum(iv) complex derived from capsaicin
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Platinum-based anticancer drugs constitute the cornerstone of chemotherapy for various cancers. Although cytotoxic agents are considered to have immunosuppressive effects, increasing evidence suggests that some cytotoxic compounds can effectively stimulate the antitumor immune response by inducing a special type of apoptosis called immunogenic cell death (ICD). A platinum(iv) complex (DCP) modified with the derivative of synthetic capsaicin (nonivamide) was designed to elicit ICD. The complex exhibited high cytotoxicity against a panel of human cancer cell lines including pancreas (PANC-1), breast (MCF-7), and liver (HepG2) cancer cells, and osteosarcoma (MG-63) cells. In addition to causing DNA damage, DCP also triggered the translocation of calreticulin (CRT) as well as the release of ATP and HMGB1 protein in PANC-1 cells, thus manifesting an efficient ICD-inducing effect on cancer cells. Furthermore, the DCP-treated PANC-1 cell-conditioned culture medium promoted the release of IFN-γ and TNF-α to induce the immune response of human peripheral blood mononuclear cells, thereby increasing their cytotoxicity to cancer cells. Concurrently, the phagocytosis of PANC-1 cells by macrophages was also augmented by DCP. The results demonstrate that DCP is an effective inducer of ICD and a potential agent for chemoimmunotherapy of cancers.
- Sun, Yuewen,Yin, Enmao,Tan, Yehong,Yang, Tao,Song, Dongfan,Jin, Suxing,Guo, Zijian,Wang, Xiaoyong
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supporting information
p. 3516 - 3522
(2021/03/23)
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- The invention discloses an amphipathic conjugate anti-tumor nano drug and a preparation method thereof. Nano-assembly and application
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The anti-tumor prodrug comprises at least one of a cisplatin precursor, a carboplatin precursor and an oxaliplatin precursor. The amphipathic conjugate anti-tumor nano-drug is simple in chemical structure, can be assembled into a uniform nano structure in water, can greatly reduce the damage to normal cells by reducing cytotoxicity of an antitumor drug outside the tumor cells, and has EPR effect in vivo so as to promote blood circulation time in a human body. Compared with a small molecule anti-tumor drug, the conjugate can prolong the blood circulation time in the human body and has a passive targeting function, so that the enrichment of the conjugate in the tumor site is greatly improved.
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Paragraph 0072; 0073
(2021/11/17)
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- PLATINUM PRODRUG PERFLUOROARYL PEPTIDE CONJUGATES
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The disclosure provides platinum(IV) prodrug perfluoroaryl peptide conjugates that can be used to treat cell proliferative disorders, such as those associated with malignant tumor cells. The conjugates can improve the delivery of platinum(IV) prodrugs to glioma cells.
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Paragraph 0098; 0131
(2021/01/29)
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- Let-7i miRNA and platinum loaded nano-graphene oxide platform for detection/reversion of drug resistance and synergetic chemical-photothermal inhibition of cancer cell
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The drug resistance of chemotherapy is a major challenge to overcome for antineoplastic agents and the reverse of drug resistant is essential for cancer therapy. Herein, we developed a drug delivery system which can simultaneously detect/reverse the drug resistance and perform synergetic treatment of cancer. In this work, we integrated cyanine5 (Cy5) modified miRNA (let-7i) (Cy5-miRNA) and platinum onto nano-graphene oxide (NGO) (30-50 nm) platform to achieve simultaneously detection/reversion of drug resistance and synergetic treatment of cisplatin resistant SKOV3 cells (SKOV3DDP cells). The Cy5-miRNA adsorbed on NGO could selectively bind the drug resistance related mRNA follow by suppress the expression of drug resistance mRNA, and the binding simultaneously induced the release of Cy5-miRNA from the NGO, thus the fluorescence signal of Cy5 recovered and could be used for drug resistance monitoring. Moreover, the miRNA suppressed the Cyclin D1 protein expressions thus reversed the drug resistance. The loaded platinum(IV) (Pt(IV)) was converted to the therapeutic platinum(II) (Pt(II)) in both tumor acidic and reductive environment responsive behavior. NGO furtherly performed photothermal therapy under near infrared (NIR) laser irradiation and enhanced the therapeutic effect. All in all, this nanoplatform realized detection/reversion of the drug resistance as well as synergetic chemical-photothermal treatment of ovarian cancer cells, which holds great promise in the treatment of drug resistant cancer cells.
- Jiang, Ting,Liu, Xiaoqin,Liu, Yanfei,Liu, Zhenbao,Peng, Dongming,Wang, Ting,Wu, Yuwei,Yan, Jianhua,Zhang, Yixuan,Zheng, Lijuan
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supporting information
(2021/08/31)
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- Targeting ROS-AMPK pathway by multiaction Platinum(IV) prodrugs containing hypolipidemic drug bezafibrate
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Alterations in lipid metabolism, commonly disregarded in the past, have been accepted as a hallmark for cancer. Exploring cancer therapeutics that interrupt the lipid metabolic pathways by monotherapy or combination with conventional chemotherapy or immunotherapy is of great importance. Here we modified cisplatin with an FDA-approved hypolipidemic drug, bezafibrate (BEZ), via the well-established Pt(IV) strategy, affording two multi-functional Pt(IV) anticancer agents cis,cis,trans-[Pt(NH3)2Cl2(BEZ)(OH)] (CB) and cis,cis,trans-[Pt(NH3)2Cl2(BEZ)2] (CP) (BEZ = bezafibrate). The Pt(IV) prodrug CB exhibited an enhanced anticancer activity up to 187-fold greater than the clinical anticancer drug cisplatin. Both CB and CP had less toxicity to normal cells, showing higher efficacies and superior therapeutic indexes than cisplatin. Mechanism studies revealed that the bezafibrate-conjugated Pt(IV) complex CB, as a representative, could massively accumulate in A549 cells and genomic DNA, induce DNA damage, elevate intracellular ROS levels, perturb mitochondrial transmembrane potentials, activate the cellular metabolic sensor AMPK, and result in profound proliferation inhibition and apoptosis. Further cellular data also provided evidence that phosphorylation of AMPK, as a metabolic sensor, could suppress the downstream HMGB1, NF-κB, and VEGFA, which may contribute to the inhibition of angiogenesis and metastasis. Our study suggests that the antitumor action of CB and CP mechanistically distinct from the conventional platinum drugs and that functionalizing platinum-based agents with lipid-modulating agents may represent a novel practical strategy for cancer treatment.
- Ding, Xiao-Jing,Gao, Wei-Zhen,Gao, Yu-Yang,Hu, Juan-Juan,Qiao, Xin,Xu, Jing-Yuan,Xu, Ling-Wen,Zheng, Li-Xia
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- Berberine coupled cis-platinum compound as well as preparation method and application thereof
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The invention relates to the technical field of pharmaceutical chemicals, and in particular, relates to a berberine coupled cis-platinum compound as well as a preparation method and application thereof. The invention provides a berberine coupled cis-platinum compound. The berberine coupled cis-platinum compound has a structure represented by a formula I in the specification. Results of the embodiment show that the berberine coupled cis-platinum compound provided by the invention can effectively inhibit the proliferation activity of intestinal cancer cells and significantly reduce the killing ability of cis-platinum to normal intestinal epithelial cells, and in-vivo experiments of mice prove that the berberine coupled cis-platinum compound has a better tumor inhibition effect than cis-platinum.
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Paragraph 0045; 0066; 0070; 0075; 0079; 0082; 0086
(2021/06/12)
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- High-activity Pt complex as well as preparation method and application thereof
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The invention discloses a high-activity Pt (IV) complex, and belongs to the technical field of anticancer chemical drugs. The complex is represented by the general formula (1) or the general formula (2). General formula (1) (2) The invention introduces 6 - chloro -3 - methylbenzofuran -2 - formic acid or 5 -chloro -3 - methylbenzofuran -2 - formic acid into the platinum (IV) complex to significantly enhance the cytotoxicity of the platinum (IV) complex to cancer cells.
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Paragraph 0013
(2021/09/22)
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- Tetravalent veratric acid platinum as well as preparation method and application thereof
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The invention belongs to the technical field of medicine, and particularly relates to tetravalent veratric acid platinum as well as a preparation method and application thereof, the structural formula of the tetravalent veratric acid platinum is shown in the specification, and the preparation method comprises the following steps: (1) synthesizing hydroxyl platinum; (2) synthesizing tetravalent platinum veratryl acid; and (3) purifying tetravalent platinum veratryl acid. The tetravalent veratric acid platinum provided by the invention belongs to a tetravalent platinum prodrug, is a novel efficient anti-tumor active compound, has a broad-spectrum anti-cancer effect, is small in killing effect on normal cells of a human body, is efficient and low in toxicity, has a relatively high medicinal value, and is simple in preparation method, low in cost and easy for industrial production.
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Paragraph 0031-0033; 0035-0036; 0038-0039
(2021/06/21)
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- Tetravalent platinum complex containing posaconazole Preparation method and application thereof
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The invention provides a tetravalent platinum complex containing posaconazole, a preparation method and application thereof, and the structure is shown in the formula I. The tetravalent platinum complex has obvious proliferation inhibition effect on liver cancer HepG2, lung cancer A549, colon cancer HCT116, breast cancer MDA-MB - 231 and cis-platinum drug-resistant lung adenocarcinoma, and the antitumor activity of the partial compound is obviously better than that of cisplatin. In addition, the complex has a remarkable inhibitory activity on common pathogenic fungi, shows significant inhibitory activity on posaconazole drug-resistant candida albicans, and can be used as a new drug for anti-tumor and antifungal candidate drugs.
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Paragraph 0085-0087
(2021/09/21)
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- Photothermal Therapy via NIR II Light Irradiation Enhances DNA Damage and Endoplasmic Reticulum Stress for Efficient Chemotherapy
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Ovarian cancer has the highest death rate in gynecologic tumors and the main therapy for patients with advanced is chemotherapy based on cisplatin. Additionally, hyperthermic intraperitoneal has been used in clinic to obtain better efficacy for patients. Hence, combined photothermal therapy with platinum drugs in a new delivery system might bring new hope for ovarian cancer. A reduction sensitive polymer encapsulating a Pt (IV) prodrug and a near infrared II (NIR II) photothermal agent IR1048 to form nanoparticles were reported to enhance the efficacy of ovarian cancer treatment. At the same time, endoplasmic reticulum stress indicates an imbalance in proteostasis which probably caused by extrinsic stress such as chemotherapy and the temperature changed. The efficacy of nanoparticles containing Pt (IV) and IR1048 under NIR II light might be caused via increased DNA damage and endoplasmic reticulum (ER) stress.
- Kong, Qingduo,Wei, Dengshuai,Xie, Peng,Wang, Bin,Yu, Kunyi,Kang, Xiang,Wang, Yongjun
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- Tetravalent platinum anticancer complex based on cis-platinum derivative containing ursodic acid ligand and preparation method and application thereof
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The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a tetravalent platinum anticancer complex based on cis-platinum-derived ursodic acid ligand and a preparation method and application thereof. Pt (IV) Complex containing the ursolic acid ligand disclosed by the invention adopts cisplatin as a basic mother nucleus, the ursolic acid derivative ligand is introduced at one end in the axial direction, Cl or - OH groups are introduced at the other end. The preparation of the series Pt (IV) complex is cheap and easily available, the method is simple and feasible, the operation is easy, and the method is suitable for large-scale production. In-vitro experiments show Pt (IV) complexes US-CIS-CL and US-CIS-OH show high anticancer activity, superior to cisplatin, and have good anticancer activity.
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Paragraph 0023; 0055; 0058
(2021/11/19)
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- trans-Platinum(iv) pro-drugs that exhibit unusual resistance to reduction by endogenous reductants and blood serum but are rapidly activated inside cells:1H NMR and XANES spectroscopy study
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Recent results have confirmed that protection of transplatin from reactions on the path to cancer cells substantially increases their activity, suggesting that such complexes have greater potential than previously thought. In this study we have investigated the use of the platinum(iv) oxidation state and the tetracarboxylate coordination sphere to determine whether these features could impart the same stability totrans-diammineplatinum complexes that they do tocis-diam(m)ineplatinum complexes. Theciscomplexes exhibit resistance to reduction byl-ascorbate and human blood serum, but are readily reduced inside cancer cells. Studies of reduction monitored by1H NMR revealed that oxidation oftrans-diammineplatinum(ii) complexes does not always result in significant stabilisation, but the complexestrans, trans, trans-[Pt(OAc)4(NH3)2] (OAc = acetate) andtrans, trans, trans-[Pt(OPr)2(OAc)2(NH3)2] (OPr = propionate) exhibit second order half-lives of 33 h and 5.9 days respectively in the presence of a ten-fold excess ofl-ascorbate. XANES spectroscopy studies of reduction in blood models showed thattrans, trans, trans-[Pt(OAc)4(NH3)2] is stable in blood serum for at least 24 hours, but is reduced rapidly in whole blood and was observed to have a half-life of approximately 4 hours in DLD-1 colon cancer cells. Consequently, the tetracarboxylatoplatinum(iv) moiety has the properties required to enable the delivery oftrans-diammine platinum complexes to cancer cells.
- Chen, Catherine K. J.,Gibson, Dan,Hambley, Trevor W.,Kappen, Peter
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supporting information
p. 7722 - 7736
(2020/06/26)
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- Intratumoral Cancer Chemotherapy with a Carrier-Based Immunogenic Cell-Death Eliciting Platinum (IV) Agent
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A carrier-based, immunogenic cell death (ICD)-eliciting platinum(IV) chemotherapeutic agent was synthesized via complexation between an axially derivatized Pt(IV)-tocopherol and hyaluronan (HA)-tocopherol nanocarrier. The resultant HA-Pt(IV) complex demonstrated antiproliferative activity and induced calreticulin translocation, an indicator of ICD, in murine and human head and neck cancer (HNC) cells. The intratumorally administered HA-Pt(IV) treatments were tolerable and efficacious in both immunocompetent and immunodeficient mice with HNC, partially because of the direct cytotoxicity. Superior efficacy and survival were observed in the immunocompetent group, suggesting a possible Pt(IV)-induced immunological response, which would only manifest in animals with an intact immune system. Subsequent imaging of tumor tissues demonstrated increased macrophage infiltration in the HA-Pt(IV)-treated tumors compared to the nontreated controls and the cisplatin-treated tumors, suggesting favorable inflammatory activation. RNA sequencing of HA-Pt(IV)-treated tumors indicated that carbohydrate and vitamin metabolisms were the most important Kyoto Encyclopedia of Genes and Genomes pathways, and molecular function, biological process, and cellular component were highly enriched gene ontology categories.
- Groer, Chad,Zhang, Ti,Lu, Ruolin,Cai, Shuang,Mull, Derek,Huang, Aric,Forrest, Melanie,Berkland, Cory,Aires, Daniel,Forrest, Marcus Laird
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p. 4334 - 4345
(2020/12/13)
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- Synthesis of 2-deoxy-d-glucose coated Fe3O4nanoparticles for application in targeted delivery of the Pt(iv) prodrug of cisplatin-a novel approach in chemotherapy
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A water soluble Pt(iv) prodrug of cisplatin was synthesized by oxidation of cisplatin followed by treatment with succinic anhydride to achieve easily reducible ester linkage at axial positions which was evidenced from cyclic voltammetric analyses. Because of this modification the Pt(iv) prodrug achieved better physicochemical and pharmacological properties like water solubility and reduced toxicity for normal (non-cancerous) CHO cells respectively, as compared to cisplatin. Later, this Pt(iv) prodrug was loaded on 2-deoxy-d-glucose (2DG) functionalized over silica coated Fe3O4 magnetic nanoparticles (MNPs) to achieve the desired formulation. It exhibited potency as evidenced from the cytotoxicity evaluation against MCF-7 human breast cancer cell lines (IC50 ~ 14 μM). This encouraged us to further study the percentage viability, apoptosis and cell death evaluations on MCF-7, Colo-205 and CHO cells by flow cytometry. The cytotoxic potency of the formulation towards cancer cells, Colo-205 and MCF-7 (22-30% apoptosis), was revealed while the parent formulation was non-toxic to non-cancerous, CHO cell lines (3% apoptosis) as compared to cisplatin. It revealed that the formulation is comparable to cisplatin in its cell killing efficiency. Additionally the FITC labeled MNPs coated with 2DG exhibited efficient cell uptake and fast internalization (within 3 h) accumulating mainly in the cytoplasm and at the cell surface. Besides this, the formulation exhibited heating efficacy suggesting its possible application for hyperthermia treatment also. These results indicate the possible utility of the formulation for site specific delivery of the Pt(iv) prodrug of cisplatin. This journal is
- Ballal, Anand,Dubey, Akhil K.,Koijam, Arunkumar S.,Kumar, Chandan,Mukherjee, Sudip,Phadnis, Prasad P.,Sharma, K. Shitaljit,Vatsa, Rajesh K.
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p. 13863 - 13874
(2020/09/07)
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- Modified platinum compound as well as preparation method and application thereof
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The invention relates to a modified platinum compound as well as a preparation method and application thereof and belongs to the technical field of antit-umor drugs. The preparation method comprises the following steps: oxidizing a divalent platinum compound into a tetravalent platinum compound; carrying out condensation reaction on 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide and 4-formylbenzoic acid to obtain carboxyl modified 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide; adding the carboxyl modified 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide into the tetravalent platinum compound to obtain an intermediate product; and carrying out a reaction on the intermediate product and isocyanate to obtain a 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide modified platinum compound. The compound provided by the invention has good self-assembly performance, can greatly reduce the usage amount of a carrier and improve the encapsulation efficiency and drug loading capacity of a drug, and the compound is simple to prepare, high in controllability and good in stability. Meanwhile, the compound and the nano particles show a remarkably enhanced anti-tumor effect, thekilling index of the compound and the nano particles in drug-resistant cells can be enhanced by 266.4 times to the maximum extent, and the drug resistance problem of platinum drugs can be greatly relieved.
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Paragraph 0042-0046
(2020/05/01)
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- Compound with naproxen tetravalent platinum structure, preparation method and application of compound in preparation of antitumor drugs
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The invention provides a compound with a naproxen tetravalent platinum structure, a preparation method and application of the compound in preparation of antitumor drugs, the structural formula of thecompound is as follows: naproxen with COX enzyme inhibition capability is introduced into a tetravalent platinum structure, and the naproxen tetravalent platinum compound is designed and prepared. Themedicine can inhibit tumor-related inflammation while damaging DNA to kill cancer cells.
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Paragraph 0090-0093
(2020/05/08)
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- CIS-OXOPLATIN FOR TREATING STOMACH CANCER
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The invention relates to a pharmaceutical composition comprising cis-oxoplatin, or a salt and/or derivative thereof, for use as a medicament in the treatment and/or preventation of stomach cancer. The invention further relates to the pharmaceutical composition as described for use in the treatment of stomach cancer, wherein the cis-oxoplatin or derivative thereof is administered in a form that is transformed under acidic pH to a tetrachloro-oxoplatin (IV).
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Page/Page column 24
(2020/01/24)
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- Bromocoumarinplatin, targeting simultaneously mitochondria and nuclei with p53 apoptosis pathway to overcome cisplatin resistance
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Mitochondria as one of potential anticancer target, alternatively damaging mtDNA other than nDNA is a potential method for platinum-based anticancer drugs to overcome cisplatin resistance. We herein report that bromocoumarinplatin 1, a coumarin-Pt(IV) prodrug, targeted simultaneously mitochondria and nuclei with the contents of Pt in nDNA and mtDNA were 25.75% and 65.91%, respectively, which demonstrated mtDNA apoptosis played a key role in overcoming cisplatin resistance. Moreover, 1 promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity of 1 through p53 pathway. The property of preferential accumulation in cancer cells (Snu-368 and Snu-739) compared to the matched normal cells (HL-7702 cells) demonstrated that 1 was potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 1 for HCT-116 cells in vivo indicated that bromocoumarinplatin behaved a vital function in the treatment of colon cancer.
- Li, Linrong,Li, Yingguang,Liu, Hanfang,Luo, Wen,Ma, Jing,Wang, Chaojie,Wang, Jiajia,Wang, Peng George,Xie, Songqiang,Yue, Kexin
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-
- In-situ self-assembled tetravalent platinum drug, preparation method and application thereof
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The invention discloses an in-situ self-assembled tetravalent platinum drug, a preparation method and application thereof. Cis-platinum is subjected to chemical reaction to generate cis-platinum oxide, and the cis-platinum oxide is further subjected to reaction with lysine residue to covalently modify tyrosine phosphorylated self-assembled short peptide to construct the tetravalent platinum drug.The tetravalent platinum drug can be self-assembled in situ to form supramolecular hydrogel with a nanofiber microstructure under the action of high-expression phosphatase on the surface of a tumor cell. Under the action of glutathione highly expressed in tumor cells, the platinum-containing nanofibers taken by the cells release a bivalent platinum drug to play a role in treatment. The formation of the hydrogel promotes the uptake of platinum drugs by tumor cells and increases the residence time of the platinum drugs in the tumor cells. Compared with traditional cis-platinum, the killing effect of the tetravalent platinum drug on tumor cells is not influenced by cell drug resistance, and the systematic toxicity is obviously reduced.
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Paragraph 0029
(2020/08/22)
-
- Preparation method of double-response nano prodrug for cancer synergistic treatment
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The invention discloses a preparation method of a double-response nano prodrug for cancer synergistic treatment. The preparation method comprises the following steps: with cis-platinum as a precursor,performing carboxylation modification and then carboxyl activation on the cis-platinum; mixing the activated carboxyl cis-platinum with L-arginine; and forming a double-response nano prodrug with thecis-platinum/arginine composite structure through dehydration condensation of intermolecular carboxyl and amino. The method has advantages of being simple, green, and mild and being low in cost. Thecis-platinum can effectively inhibit DNA transcription to realize the effect of treating cancer; cis-platinum can promote H2O2 generation under the induction of NOX enzyme in vivo and the arginine serving as human amino acid can react with H2O2 to generate NO, so that tumor extinction is further induced. Therefore, the nano prodrug is expected to be developed into an efficient anticancer drug.
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Paragraph 0015
(2020/04/02)
-
- Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof
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The invention discloses a novel Pt (IV) complex based on cis-platinum and a preparation method and application thereof, and belongs to the field of chemical synthesis of medicines. The preparation method comprises the following steps: with cis-platinum, hydrogen peroxide and mycophenolic acid as raw materials, oxidizing cis-platinum into dihydroxy cis-platinum (IV) through hydrogen peroxide; carrying out esterification reaction on the dihydroxy cis-platinum (IV), TBTU, triethylamine and mycophenolic acid in the presence of DMF serving as a solvent to obtain a novel Pt (IV) complex mother solution; and carrying out reverse separation on the mother solution by using methanol, acetone or diethyl ether to obtain the novel Pt (IV) complex. The novel Pt (IV) complex prepared by the method has certain anti-tumor activity and can be used for preparing an oral targeted anti-tumor drug. The preparation method is simple, easy to operate and mild in reaction condition, and has the characteristicsof high purity, good stability, high yield and the like.
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Paragraph 0023; 0027-0030; 0035-0038; 0045-0046
(2020/12/30)
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- BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity
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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.
- Chen, Shu,Deng, Zhiqin,Matsuda, Yudai,Tse, Man-Kit,Yao, Houzong,Zhu, Guangyu
-
-
- Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof
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The invention provides an anti-tumor tetravalent platinum complex with an anti-drug resistance function and a preparation method thereof. The structural formula of the compound is shown as a formula Ior a formula II, and the compound is one of the following structures: the compound has excellent cytotoxic activity to tumor cells, especially to cisplatin-resistant tumor cells, and shows excellenttumor inhibition effect and relatively low toxicity in vivo.
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Paragraph 0027-0030
(2020/06/16)
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- DNA Nanostructures as Pt(IV) Prodrug Delivery Systems to Combat Chemoresistance
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Cisplatin is a first-line drug in clinical cancer treatment but its efficacy is often hindered by chemoresistance in cancer cells. Reduced intracellular drug accumulation is revealed to be a major mechanism of cisplatin resistance. Nanoscale drug delivery systems could help to overcome this problem because of their more active cellular uptake and more accurate tumor localization. DNA nanostructures have emerged as promising drug delivery systems because of their intrinsic biocompatibility and structural programmability. Herein, three diverse DNA nanostructures are constructed and their potential for cisplatin prodrug delivery is investigated. Results found that these DNA nanostructures could remarkably enhance the cellular internalization of platinum drugs and thus increase the anticancer activity, not only to regular lung cancer cells (A549), but more importantly to cisplatin-resistant cancer cells (A549cisR). Further, in vivo studies also demonstrate that cisplatin prodrug loaded DNA nanostructures could effectively suppress tumor growth in both regular and cisplatin-resistant tumor models. This study suggests that DNA nanostructures are effective carriers for platinum prodrug delivery to combat chemoresistance.
- Zhong, Yi-Fang,Cheng, Jin,Liu, Yan,Luo, Tao,Wang, Yuqi,Jiang, Kai,Mo, Fangli,Song, Jie
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- Anti-cancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof
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The invention provides an anti-cancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and a preparation method, and particularly relates to the field of biological medicine. The molecular structure of the anti-cancer tetravalent platinum complex is as follows: S1, reacting a divalent platinum complex with hydrogen peroxide H2O2 to obtain a tetravalent platinum complex; S2, mixing the tetravalent platinum complex obtained in the step S1 with O-benzotriazole-N, N, N ', N'-tetramethylurea tetrafluoroboric acid (TBTU) and triethylamine (TEA) in an N, N-dimethylformamide (DMF) solution, and uniformly stirring and mixing; S3, after the reaction is finished, collecting a filtrate, concentrating the filtrate to 0.5-5mL, dropwise adding a mixture of ethanol and water, and centrifugally collecting precipitates; and dissolving the precipitate in methanol, washing the precipitate with diethyl ether for three times, and carrying out vacuum drying to obtain the target product. The tetravalent platinum complex disclosed by the invention not only has very strong toxic activity to tumor cells, but also inhibits inflammation and immune escape through a plurality ofaction targets, and shows an excellent anti-tumor effect in vivo.
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Paragraph 0031-0034
(2020/11/10)
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- Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX-2 and PD-L1
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Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase-2 (COX-2) plays a vital role in the progression of BC, correlating with the expression of programmed death-ligand 1 (PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple-negative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo, inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.
- Guo, Zijian,Jin, Suxing,Muhammad, Nafees,Song, Dongfan,Sun, Yuewen,Tan, Yehong,Wang, Xiaoyong,Yuan, Hao
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supporting information
p. 23313 - 23321
(2020/10/19)
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- Lung cancer combination treatment: Evaluation of the synergistic effect of cisplatin prodrug, vinorelbine and retinoic acid when co-encapsulated in a multi-layered nano-platform
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Purpose: Lung cancer remains the leading cancer-associated deaths worldwide. Cisplatin (CIS) was often used in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). Prodrug is an effective strategy to improve the efficiency of drugs and reduce the toxicity. The aim of this study was to prepare and characterize CIS prodrug, vinorelbine (VNR), and all-trans retinoic acid (ATRA) co-delivered multi-layered nano-platform, evaluating their antitumor activity in vitro and in vivo. Methods: Cisplatin prodrug (CISP) was synthesized. A multi-layered nano-platform contained CISP, VNR and ATRA were prepared and named CISP/VNR/ATRA MLNP. The physicochemical properties of CISP/VNR/ATRA MLNP were investigated. In vitro cytotoxicity against CIS-resistant NSCLC cells (A549/CIS cells) and Human normal lung epithelial cells (BEAS-2B cells) was investigated, and in vivo anti-tumor efficiency was evaluated on mice bearing A549/CIS cells xenografts. Results: CISP/VNR/ATRA MLNP were spherical particles with particle size and zeta potential of 158 nm and 12.3 mV. CISP/VNR/ATRA MLNP (81.36%) was uptake by cancer cells in vitro. CISP/VNR/ATRA MLNP could significantly inhibit the in vivo antitumor growth and suspended the tumor volume from 1440 mm3 to 220 mm3. Conclusion: It could be concluded that the CISP/VNR/ATRA MLNP may be used as a promising system for lung cancer combination treatment.
- Liang, Zhen,Li, Juan,Zhu, Budong
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p. 4519 - 4531
(2020/11/09)
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- Photochemotherapy platinum prodrug and preparation method and application thereof
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The invention discloses a photochemical therapy platinum prodrug, the structure formula of the photochemical therapy platinum prodrug is shown in a formula (I), wherein R1 is one of H, OC(CH2)mCOOH, OCNH(CH2)nOCOCH3CH=CH2 or OCNH(CH2)kOCOCH3CH-CH2R3, R2 is OC(CH2)mCOOH, OCNH(CH2)nOCOCH3CH=CH2 or OCNH(CH2)kOCOCH3CH-CH2R3, R3 is a polymer structure of monomers and is a structure polymerized from the compound in the formula (I) and one or more of monomers of 2-methylacryloyl yloxyethyl (acyl) phosphorylcholine or methacrylic acid, and m, n and k are respectively 0-10. Under the illumination condition, the photochemical therapy platinum prodrug releases the cisplatin chemotherapy drug through photodegradation, an active oxygen specie also released and produced by the photochemical therapy platinum prodrug is used for photodynamic therapy, the photochemical therapy platinum prodrug integrates dynamic therapy and chemical therapy, and the curative effect of the whole treatment of cancers is improved through the synergistic treatment of the dynamic therapy and the chemical therapy.
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Paragraph 0052-0053
(2020/12/05)
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- Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV) complexes as antitumor agents
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A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.
- Wang, Qingpeng,Chen, Yan,Li, Guoshuai,Liu, Zhifang,Ma, Jing,Liu, Min,Li, Dacheng,Han, Jun,Wang, Bingquan
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supporting information
p. 2112 - 2121
(2019/04/10)
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- Compound with asymmetric monosubstituted naphthalimide tetravalent platinum structure, preparation method and application of method in preparing antitumor drugs
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The invention provides a compound with an asymmetric monosubstituted naphthalimide tetravalent platinum structure, a preparation method and application of the method in preparing antitumor drugs, thestructural formula of the compound is as shown in the description, and the compound has excellent anticancer and antitumor effects.
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Paragraph 0065-0068
(2019/08/06)
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- New NSAID-Pt(IV) prodrugs to suppress metastasis and invasion of tumor cells and enhance anti-tumor effect in vitro and in vivo
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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.
- Song, Xue-Qing,Ma, Zhong-Ying,Wu, Yi-Gang,Dai, Miao-Liang,Wang, Dong-Bo,Xu, Jing-Yuan,Liu, Yangzhong
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p. 377 - 387
(2019/02/20)
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- Compound having asymmetric mono-substituted coumarin tetravalent platinum structure, preparation method thereof and use thereof in preparation of antitumor drugs
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A compound having an asymmetric mono-substituted coumarin tetravalent platinum structure has a structural formula as shown in the description. A preparation method of the compound having an asymmetricmono-substituted coumarin tetravalent platinum structure specifically comprises the following steps: adding TBTU and a coumarin derivative to a reaction container, replacing air in the system with nitrogen, adding dried DMF for stirred reaction for about 10 minutes at room temperature, adding dried triethylamine to the reaction system for stirred reaction for about 10 minutes at room temperature,finally adding a tetravalent platinum compound to the reaction system, replacing air in the flask with N2 and putting the reaction system at 25-120 DEG C for light-shielded reaction for 12-72 hours,removing the solvent under reduced pressure, and carrying out column chromatography to obtain an asymmetric mono-substituted coumarin modified tetravalent platinum compound having the general formula(1).
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Paragraph 0043-0045
(2019/11/19)
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- Targeting Energy Metabolism by a Platinum(IV) Prodrug as an Alternative Pathway for Cancer Suppression
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Cancer is characterized by abnormal cellular energy metabolism, which preferentially switches to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism. Many key enzymes involved in the abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV) complexes are potential anticancer prodrugs and kinetically more inert than the platinum(II) counterparts, which offer an opportunity to be modified by functional ligands for activation or targeted delivery. A novel platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on tumor energy metabolism. The complex was characterized by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy. The introduction of dichloroacetate (DCA) markedly increases the lipophilicity, reactivity, and cytotoxicity of the complex and blocks the growth of cancer cells having active glycolysis, and the introduction of biotin (C10H16N2O3S) enhances the tumor-targeting potential of the complex. The cytotoxicity of DPB is increased dramatically in a variety of cancer cell lines as compared with the platinum(IV) complex PB without the DCA group. DPB alters the mitochondrial membrane potential and disrupts the mitochondrial morphology. The levels of mitochondrial and cellular reactive oxygen species are also decreased. Furthermore, the mitochondrial function of tumor cells was impaired by DPB, leading to the inhibition of both glycolysis and glucose oxidation and finally to the death of cancer cells via a mitochondria-mediated apoptotic pathway. These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways and highlight the importance of dual-targeting for the efficacy of anticancer drugs.
- Jin, Suxing,Guo, Yan,Song, Dongfan,Zhu, Zhenzhu,Zhang, Zhenqin,Sun, Yuewen,Yang, Tao,Guo, Zijian,Wang, Xiaoyong
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supporting information
p. 6507 - 6516
(2019/05/15)
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- Cisplatin-modified isonicotinic acid as a?potential linker in bio-MOFs: synthesis and characterization
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Abstract: The platinum derivative cisplatin is widely used against many types of cancers effectively. However, cisplatin has limitations such as toxicity, resistances, and being thermally labile, non-volatile, and highly insoluble. To overcome these limitations, cisplatin with platinum(II) as metal centers needs to be modified to platinum(IV). Modification of platinum(IV) of cisplatin ligated to an organic ligand in the axial position could be a strategy to reduce its toxicity and increase the lifetime in blood when administered as an oral prodrug as an anti-cancer agent. The complex also has potential to be employed as a linker in bio-metal–organic frameworks (bioMOFs) synthesis and has good stability. Cisplatin-modified ligand also has a large size which can affect to the pore size on bioMOFs. Isonicotinic acid is a pyridine derivative with pyridine and carboxyl as an active group that can make coordination with metal ions on bioMOF assemblies. In this study, a simple and efficient method for the synthesis of a novel cisplatin-modified isonicotinic acid, nicoplatin, was reported. A substitution reaction possibly occurs on the axial position of oxoplatin by isonicotinic acid ligand. The obtained compound was fully characterized with FTIR, 1H-NMR, 13C-NMR, ESI–MS and elemental analyses. Graphical abstract: [Figure not available: see fulltext.].
- Rosari, Venansia Avelia,Lestari, Witri Wahyu,Firdaus, Maulidan
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p. 3155 - 3164
(2019/03/13)
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- 5 - Fluorouracil - platinum (IV) complex, intermediate, preparation method and application thereof (by machine translation)
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The present invention provides 5 - fluoro uracil - platinum (IV) complex, intermediate and preparation method, by formula (1) expressed, wherein Is selected from cisplatin, oxaliplatin, carboplatin, age platinum, nedaplatin or Miboplatin, preferred, For cisplatin or oxaliplatin; R1 For - Cn H2 N -, N is an integer and n ≥ 1, preferred, - Cn H2 N - Straight chain group, R2 For - Cm H2 M + 1 , M is an integer and m ≥ 1, preferred, - Cm H2 M + 1 Straight chain group. The invention of 5 - Fluorouracil - platinum (IV) complex can be reduced cisplatin, oxaliplatin with 5 - Fluorouracil toxic side effect, and at the same time used for the treatment of cancer and in anti-tumor drugs have the synergistic the sensitivity. (by machine translation)
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Paragraph 0096; 0104; 0105; 0106; 0107; 0108; 0109
(2019/04/09)
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- Carbonic anhydrase-targeted Pt (IV) complex, preparation method and application thereof
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The invention discloses a carbonic anhydrase (CAIX) targeted Pt (IV) complex as well as a preparation method and application thereof. The invention firstly provides the CAIX-targeted Pt (IV) complex which has the targeting characteristic of CAIX, can specifically identify tumor cells, effectively inhibit the activity of CAIX, is non-toxic to normal cells, enhances the toxicity under the conditionof anoxia, and has remarkable antitumor activity. Compared with a Pt (II) drug, the complex has the characteristics of improving tumor selectivity, reducing liver injury, reducing renal toxicity and having no toxic or side effect, and can be specifically combined with an anti-tumor target, so that the sensitivity of the platinum drug in a hypoxia environment is improved. The invention also provides a preparation method of the complex, which comprises the following steps of: mixing CAIXi and Pt (IV) - COOHx in a DMF solution containing N,N-diisopropylethylamine, and carrying out condensation reaction to obtain the complex. The preparation method is simple and low in cost. The product has a good antitumor drug application prospect and a wide development space.
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Paragraph 0061; 0063
(2019/10/01)
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- Biodegradable and pH-Responsive Acetalated Dextran (Ac-Dex) Nanoparticles for NIR Imaging and Controlled Delivery of a Platinum-Based Prodrug into Cancer Cells
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Nanoparticles (NPs) based on the biodegradable acetalated dextran polymer (Ac-Dex) were used for near-infrared (NIR) imaging and controlled delivery of a PtIV prodrug into cancer cells. The Ac-Dex NPs loaded with the hydrophobic PtIV prodrug 3 (PtIV/Ac-Dex NPs) and with the novel hydrophobic NIR-fluorescent dye 9 (NIR-dye 9/Ac-Dex NPs), as well as Ac-Dex NPs coloaded with both compounds (coloaded Ac-Dex NPs), were assembled using a single oil-in-water nanoemulsion method. Dynamic light scattering measurements and scanning electron microscopy images showed that the resulting Ac-Dex NPs are spherical with an average diameter of 100 nm, which is suitable for accumulation in tumors via the enhanced permeation and retention effect. The new nanosystems exhibited high drug-loading capability, high encapsulation efficiency, high stability in physiological conditions, and pH responsiveness. Drug-release studies clearly showed that the PtIV prodrug 3 release from Ac-Dex NPs was negligible at pH 7.4, whereas at pH 5.5, this compound was completely released with a controlled rate. Confocal laser scanning microscopy unambiguously showed that the NIR-dye 9/Ac-Dex NPs were efficiently taken up by MCF-7 cells, and cytotoxicity assays against several cell lines showed no significant toxicity of blank Ac-Dex NPs up to 1 mg mL-1. The IC50 values obtained for the PtIV prodrug encapsulated in Ac-Dex NPs were much lower when compared with the IC50 values obtained for the free PtIV complex and cisplatin in all cell lines tested. Overall, our results demonstrate, for the first time, that Ac-Dex NPs constitute a promising drug delivery platform for cancer therapy.
- Braga, Carolyne B.,Perli, Gabriel,Becher, Tiago B.,Ornelas, Catia
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p. 2083 - 2094
(2019/04/16)
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- Preparation methods and application of platinum derivative and platinum-containing nanoparticle
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The invention relates to the field of chemical synthesis, and particularly relates to a platinum derivative which is obtained by modifying and introducing a charged group by a covalent bond on the basis of tetravalent platinum, wherein the modification does not affect pharmaceutical activity of divalent platinum. Compared with the prior art, a high molecular polymer and a platinum derivative are electrostatically compounded to form nanoparticles through self-assembly in water in the invention. The nanoparticles have a relatively low critical micelle concentration, high colloidal stability, narrow and size-adjustable particle size distribution, and high hydrophobic drug loading efficiency, can protect the activity of platinum drugs during circulation and transportation to target organs or tissues, prevents the platinum drugs from inactivating before reaching target cancer cells, and increases accumulation of the platinum drugs in the cancer cells, thereby reducing toxic or side effectsof the platinum drugs and overcoming drug resistance.
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Paragraph 0084-0086
(2019/05/08)
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- Compound with tetravalent platinum structure of quinolinone, preparation method and application of compound in preparation of anti-tumor drug
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The invention provides a compound with a tetravalent platinum structure of quinolinone, a preparation method and application of the compound in preparation of an anti-tumor drug. The structural formula of the compound is shown in the original specification. The compound has excellent anti-cancer and anti-tumor effect.
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Paragraph 0091-0094
(2019/09/17)
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- Naphthalimide Platinum(IV) Compounds as Antitumor Agents with Dual DNA Damage Mechanism to Overcome Cisplatin Resistance
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A new series of naphthalimide platinum(IV) compounds with dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The platinum(IV) compounds could combine with DNA and cause DNA damage via naphthalimide fragment. Then the platinum(II) complexes released in reductive microenvironment would cause remarkable secondary DNA lesions. Some title compounds exhibit good antitumor activities and are of great potential in overcoming the drug resistance of cisplatin. Furthermore, naphthalimide platinum(IV) complexes could effectively combine with HSA by electrostatic force, which would influence the drug distribution and bioactivities in vivo. Moreover, the accumulation of the tested platinum(IV) compounds in whole cells and DNA is remarkably enhanced in comparison with cisplatin and oxaliplatin.
- Wang, Qingpeng,Li, Guoshuai,Liu, Zhifang,Tan, Xiaoxiao,Ding, Zhuang,Ma, Jing,Li, Lanjie,Li, Dacheng,Han, Jun,Wang, Bingquan
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supporting information
p. 4442 - 4451
(2018/10/25)
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- Impact of Mitochondrion-Targeting Group on the Reactivity and Cytostatic Pathway of Platinum(IV) Complexes
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Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum(IV) complexes, namely, c,c,t-[Pt(NH3)2Cl2(OH)(OCOCH2CH2CH2CH2PPh3)]Br and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2CH2CH2PPh3)2]Br2, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (1H, 13C, 31P, and 195Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.
- Jin, Suxing,Hao, Yigang,Zhu, Zhenzhu,Muhammad, Nafees,Zhang, Zhenqin,Wang, Kun,Guo, Yan,Guo, Zijian,Wang, Xiaoyong
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supporting information
p. 11135 - 11145
(2018/09/14)
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- Cis-dammine dichloroplatinum prodrug, preparation method and application
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The invention discloses a cis-dammine dichloroplatinum (CDDP) prodrug, a preparation method and application. The structural formula of the CDDP prodrug is shown as formula (I), and is generated by theesterification reaction of activated dihydroxy cisplatin with hydrophobic molecules. Characterization of the nano-preparation by dynamic light scattering and transmission electron microscopy indicates that the nanoparticles involved in the invention are uniformly distributed and are at about 30nm. In vitro cytotoxicity experiments show that the nano-drug can significantly inhibit the proliferation of tumor cells (A549 and LoVo). In vivo experiments show that compared with CDDP injections, on the basis of reducing the systemic toxicity, the nano-drug has the effect of inhibiting the non-smallcell lung cancer A549 subcutaneous tumor, and has good market prospects and clinical application value.
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Paragraph 0044; 0060; 0061
(2019/01/08)
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- Chlorambucil-conjugated platinum(IV) prodrugs to treat triple-negative breast cancer in vitro and in vivo
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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.
- Ma, Zhong-Ying,Wang, Dong-Bo,Song, Xue-Qing,Wu, Yi-Gang,Chen, Qian,Zhao, Chun-Lai,Li, Jing-Yi,Cheng, Shi-Hao,Xu, Jing-Yuan
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p. 1292 - 1299
(2018/09/12)
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- Platinum(iv) prodrugs with long lipid chains for drug delivery and overcoming cisplatin resistance
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Platinum(iv) prodrugs of clinically used cisplatin and oxaliplatin with two axial long lipid chains were developed for nanoparticle delivery to combat cisplatin resistance.
- Chen, Qiling,Yang, Yuanyuan,Lin, Xun,Ma, Wen,Chen, Gui,Li, Wenliang,Wang, Xuefeng,Yu, Zhiqiang
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supporting information
p. 5369 - 5372
(2018/06/01)
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- Immobilization of Platinum(II) and Platinum(IV) Complexes on Oxidized Nanoporous Carbon Material and Evaluation of the Enthalpy of Adsorption
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Physicochemical study of cis-[Pt(NH3)2Cl2] and cis-[Pt(NH3)2Cl2(OH)2] is carried out, and immobilization of platinum complexes on the nanoporous carbon substrate is investigated. The solubility of cis-[Pt(NH3)2Cl2] in 1 M HCl solution is determined, and the average enthalpy of dissolution is calculated: ΔsolH° = 27.3 ± 0.9 kJ/mol. The batch capacity is determined experimentally for cis-[Pt(NH3)2Cl2] and cis- [Pt(NH3)2Cl2(OH)2] to be 32.9 mg/g (0.17 mg-equiv/g) and 47.6 mg/g (0.24 mg-equiv/g), respectively. Immobilization of platinum complexes on the oxidized carbon surface is found to take place due to interaction between carboxy groups and ammine groups of platinum complexes. The resulting heat capacity curves are used to calculate the enthalpies of adsorption for cis-[Pt(NH3)2Cl2] and cis-[Pt(NH3)2Cl2(OH)2] on the oxidized carbon surface, equal to 24.46 and 27.46 kJ/mol, respectively.
- Levchenko,Matskevich,Kerzhentseva,Pishchur,Mikheev,Gel’fond,Korol’kov
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p. 923 - 929
(2018/08/16)
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