- Design, synthesis and activity evaluation of new phthalazinone parp inhibitors
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Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.
- Cai, Jin,Chen, Xixi,Huang, Mingqi,Ji, Min,Li, Xiaojing,Ren, Jinghui,Tang, Tu,Wang, Yuhong,Yang, Jia,Yang, Zhenyong
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p. 620 - 629
(2021/07/09)
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- Novel synthesis method of olaparib bulk drug
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The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.
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- Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
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Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
- Chang, Xinyue,Huang, Wenhai,Liang, Meihao,Ma, Zhen,Shen, Zhengrong,Wang, Zunyuan,Zeng, Shenxin,Zhang, Chixiao,Zhang, Zhimin
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p. 1606 - 1615
(2020/08/19)
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
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Page/Page column 136; 150; 151
(2020/11/30)
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- Pyridazinone derivative, and preparation method and medical application thereof
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The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.
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Paragraph 0026; 0030
(2019/10/07)
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- Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
- Gao, Cheng-Zhi,Dong, Wei,Cui, Zhi-Wen,Yuan, Qiong,Hu, Xia-Min,Wu, Qing-Ming,Han, Xianlin,Xu, Yao,Min, Zhen-Li
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p. 150 - 162
(2018/11/30)
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- Synthesis, Cytotoxicity, and Mechanistic Investigation of Platinum(IV) Anticancer Complexes Conjugated with Poly(ADP-ribose) Polymerase Inhibitors
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Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPi) have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. Herein, we obtained seven potential PARPi with structural diversity and then conjugated them with cisplatin-based platinum(IV) complexes. Both the synthesized PARPi ligands and PARPi-Pt conjugates [PARPi-Pt(IV)] show inhibitory effects against PARP-1's catalytic activity. The PARPi-Pt(IV) conjugates are cytotoxic in a panel of human cancer cell lines, and the leading ones display the ability to overcome cisplatin resistance. A mechanistic investigation reveals that the representative PARPi-Pt(IV) conjugates efficiently enter cells, bind to genomic DNA, disturb cell cycle distribution, and induce apoptotic cell death in both cisplatin-sensitive and-resistant cells. Our study provides a strategy to improve the cytotoxicity of platinum(IV)-based anticancer complexes and overcome cisplatin resistance by using a small-molecule anticancer complex that simultaneously damages DNA and inhibits PARP.
- Xu, Zoufeng,Li, Cai,Zhou, Qiyuan,Deng, Zhiqin,Tong, Zixuan,Tse, Man-Kit,Zhu, Guangyu
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p. 16279 - 16291
(2019/11/28)
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
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Page/Page column 191; 192; 210
(2019/12/04)
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- A micro-channel modular reaction device for continuously preparing aurar handkerchief nepal intermediates (by machine translation)
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The present invention discloses a micro-channel aurar handkerchief nepal modular reaction device for the continuous production of the intermediates, including 3 - hydroxy isobenzofuran - 1 (3 H) - ketone and dimethyl methylene chloride solution of dichloromethane solution in the micro-reactor in the 1st reaction, liquid obtained by (3 - oxo - 1, 3 - ISO-benzofuran - 1 - yl) dimethyl phosphate effluent; then with 2 - fluoro - 5 - formyl phenyl nitrile dichloromethane solution of triethylamine in methylene chloride solution and 2nd micro-reactor to react to generate 2 - fluoro - 5 - (3 - oxo - 3 H - isobenzofuran - 1 - yl methylene) reaction of the nitrile; finally the reaction liquid with the ethanol solution of sodium hydroxide is obtained by stirring with hydrazine hydrate of homogeneous mixed solution in the micro-reactor in the 3rd reaction, processing effluent to obtain the aurar handkerchief nepal intermediate 2 - fluoro - 5 - [(4 - oxo - 3, 4 - dihydrodi diazonaphthalene - 1 - yl) methyl] benzoic acid. (by machine translation)
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- Preparation method of olaparib drug intermediate
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The invention provides a preparation method of an olaparib drug intermediate, and particularly relates to the technical field of preparation of drug intermediates. The method comprises the steps thatS1, 2-carboxybenzaldehyde, triethylamine and dichloromethane are mixed and stirred, then dimethyl phosphite is added for a reaction at the room temperature, methane sulfonic acid is added, a reactionsolution is concentrated to dryness, water is added for beating, filtering and drying are conducted, and beating with petroleum ether is conducted to obtain a white solid; S2, the solid obtained in the first step, 3-cyano-4-fluorobenzaldehyde and dichloromethane are mixed and then cooled, triethylamine is added dropwise for a reaction, a reaction solution is concentrated to dryness, water is addedfor beating, filtering and drying are conducted, and beating with methyl tert-butyl ether is conducted to obtain a white solid; S3, the solid obtained in the second step is mixed with water, coolingis conducted, hydrazine hydrate is added for a reaction, then acetone is added, a NaOH aqueous solution is added for a reaction, cooling is conducted to the room temperature, extraction is conducted,the pH value is adjusted, the white solid is precipitated, and filtering, rinsing with cold water and recrystallization are conducted to obtain the white solid. The preparation method has the advantages that the yield is increased, the production cost is reduced, and the operation is simple and convenient.
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Paragraph 0020; 0022; 0025
(2018/10/19)
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- PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
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The present invention is directed to process for preparation of Olaparib of formula (I). The present invention further relates to novel polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
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Page/Page column 14; 15
(2017/12/14)
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- A method for preparing aurar handkerchief Nepal (by machine translation)
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The invention discloses a method for preparing aurar handkerchief Nepal, comprises the following steps: step one: synthesis of (3 - oxo - 1, 3 - dihydro - isobenzofuran - 1 - yl) phosphonic acid dimethyl ester; step two: synthesis of 2 - fluoro - 5 - (3 - oxo - 1, 3H - ISO-benzofuran asian base methyl) benzonitrile; step three: synthesis of 2 - fluoro - 5 - ((4 - oxo - 3, 4 - dihydro taitai qin - 1 - yl) methyl) benzoic acid; step four: synthetic aurar handkerchief Nepal. Compared with the prior art, the invention of the preparation method of the aurar handkerchief Nepal, cheap raw materials, has little influence to environment, the equipment requirement is low, the reaction time is short, the purity of the product after the purification and the like, can improve the production efficiency. (by machine translation)
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Paragraph 0062; 0063
(2017/07/21)
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- Heterocycle and imidazole compounds, pharmaceutical composition comprising heterocycle and imidazole derivatives as well as preparation method and application of heterocycle and imidazole compounds
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The invention relates to heterocycle and imidazole derivatives as well as a preparation method and a pharmaceutical application of heterocycle and imidazole derivatives, in particular to novel heterocycle and imidazole derivatives as shown in the general formula (I), a preparation method of the heterocycle and imidazole derivatives, pharmaceutical composition comprising the heterocycle and imidazole derivatives as well as an application of the heterocycle and imidazole derivatives as a therapeutic agent and particularly as a PARP (poly (ADP-ribose) polymerase) inhibitor.
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Paragraph 0136; 0137; 0138; 0149; 0150
(2017/07/20)
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- Synthesis and evaluation of a radioiodinated tracer with specificity for poly(ADP-ribose) polymerase-1 (PARP-1) in vivo
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Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An 123I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [123I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [123I]5 as a noninvasive PARP-1 SPECT imaging agent.
- Zmuda, Filip,Malviya, Gaurav,Blair, Adele,Boyd, Marie,Chalmers, Anthony J.,Sutherland, Andrew,Pimlott, Sally L.
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supporting information
p. 8683 - 8693
(2015/11/25)
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- HETEROCYCLIC DERIVATES, PREPARATION PROCESSES AND MEDICAL USES THEREOF
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Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.
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- HETEROCYCLIC DERIVATES,PREPARATION PROCESSES AND MEDICAL USES THEREOF
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Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.
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- TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
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The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-l(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP- ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.
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Page/Page column 70
(2013/02/27)
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- PHTHALAZINONE DERIVATIVE
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4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one as crystalline Form A.
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Page/Page column 27
(2008/12/05)
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