- Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer
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Plinabulin, a synthetic analog of the marine natural product “diketopiperazine phenylahistin,” displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure–activity relationship study indicated that compounds 17o (IC50 = 14.0 nM, NCI-H460) and 17p (IC50 = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.
- Ding, Zhongpeng,Li, Feifei,Li, Feng,Li, Wenbao,Liu, Yuqian,Wang, Shixiao,Zhao, Jianchun,Zhong, Changjiang
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- Preparation method of plinabulin intermediate imidazole formaldehyde compound
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The invention discloses a preparation method of an imidazole formaldehyde compound. According to the preparation method, the operation danger level and the production cost are reduced by optimizing and improving a preparation route method, optimizing reaction conditions and improving a post-treatment and purification method; the requirement on the corrosion resistance grade of reaction container equipment is low, the operation safety is good, and the post-treatment is green and environment-friendly; and the preparation method has the advantages of simple operation of each step, safe and feasible solvent and process conditions, realization of environment-friendly production, and wide application prospect.
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Paragraph 0112-0115; 0120-0121
(2020/11/09)
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- Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent
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Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
- Ding, Zhongpeng,Cheng, Hejuan,Wang, Shixiao,Hou, Yingwei,Zhao, Jianchun,Guan, Huashi,Li, Wenbao
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p. 1416 - 1419
(2017/03/08)
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- Plinabulin compound polycrystalline type and preparation method thereof
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The invention provides a plinabulin compound polycrystalline type and a preparation method thereof, and particularly relates to a polycrystalline type of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) methylene)piperazidine-2,5-diketone and a preparation method thereof. Three kinds of crystalline types beta, gamma and delta are developed on the basis of the crystalline type alpha of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl) methylene)piperazidine-2,5-diketone, wherein the three kinds of crystalline types beta, gamma and delta can be prepared into monocrystallines; the three kinds of crystalline types have the advantages of clear conformation, high purity and high method repeatability; the important significance is realized on implementation of plinabulin biological effectiveness study and dosage form variety development.
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- Preparation and purification method of high-purity Plinabulin compound
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The invention provides a preparation and purification method of high-purity Plinabulin compound, which aims at mainly removing a trans-isomer. The preparation and purification method has the advantages that (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)methylene)piperazine-2,5-diketone monohydrate and (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)deuterated methylene)piperazine-2,5-diketone monohydrate are prepared; the purity of the prepared product is higher than 99.5%, and the content of the trans-isomer is smaller than 0.1%. The invention also relates to the preparation and purification of important intermediates, such as 5-(tert-butyl)-1H-imidazole-4-ethyl formate and 1,4-diacetylpiperazine-2,5-diketone. The preparation and purification method has the advantages that the production cost is reduced, the pos-treatment difficulty is decreased, and the technology more meets the requirements of industrialized production.
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- Ferrocenyl 2,5-Piperazinediones as Tubulin-Binding Organometallic ABCB1 and ABCG2 Inhibitors Active against MDR Cells
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The tubulin-microtubule system is a common target of many anticancer drugs. However, the use of chemotherapeutics frequently leads to the development of a clinically relevant phenomenon of multidrug resistance (MDR). One of the basic mechanisms involved in MDR involves elevated expression and/or activity of several ATP-binding cassette superfamily members (ABC transporters) which are normally responsible for the efflux of xenobiotics or secondary metabolites outside the cell. Here we present the synthesis and biological characteristics of ferrocenyl analogues of plinabulin, i.e. one of the so-called "spindle poisons". We found that replacement of the phenyl group of plinabulin by the ferrocenyl moiety turns this compound into a potent inhibitor of ABCB1 and ABCG2, thus making it possible to overcome the multidrug resistance phenomenon. We also demonstrated that the alkyl group attached to the imidazole moiety of ferrocenyl analogues of plinabulin strongly affects their potency to inhibit tubulin polymerization.
- Wieczorek, Anna,B?auz, Andrzej,Zakrzewski, Janusz,Rychlik, B?azej,Plazuk, Damian
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supporting information
p. 612 - 617
(2016/07/06)
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- Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus
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We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
- Dong, Jianghong,Chen, Shengwei,Li, Runfeng,Cui, Wei,Jiang, Haiming,Ling, Yixia,Yang, Zifeng,Hu, Wenhui
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p. 605 - 615
(2015/12/30)
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- Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure
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Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
- Yamazaki, Yuri,Tanaka, Koji,Nicholson, Benjamin,Deyanat-Yazdi, Gordafaried,Potts, Barbara,Yoshida, Tomoko,Oda, Akiko,Kitagawa, Takayoshi,Orikasa, Sumie,Kiso, Yoshiaki,Yasui, Hiroyuki,Akamatsu, Miki,Chinen, Takumi,Usui, Takeo,Shinozaki, Yuki,Yakushiji, Fumika,Miller, Brian R.,Neuteboom, Saskia,Palladino, Michael,Kanoh, Kaneo,Lloyd, George Kenneth,Hayashi, Yoshio
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p. 1056 - 1071
(2012/04/04)
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- ANALOGS OF DEHYDROPHENYLAHISTINS
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Analogs of dehydrophenylahistins are disclosed as are methods for making such compounds. Compositions and methods for treating various disease conditions including cancer and non-cancer diseases associated with vascular proliferation are also disclosed.
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- ANALOGS OF DEHYDROPHENYLAHISTINS AND THEIR THEAPEUTIC USE
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Compounds represented by the following structure (II) are disclosed: as are methods for making such compounds. Compositions and methods for treating various disease conditions including cancer and non-cancer diseases associated with vascular proliferation are also disclosed.
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- Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
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Compounds represented by the following structure (I) are disclosed: as are methods for making such compounds, wherein said methods comprise reacting a diacyldiketopiperazine with a first aldehyde to produce an intermediate compound; and reacting the intermediate compound with a second aldehyde to produce the class of compounds with the generic structure, where the first aldehyde and the second aldehydes are selected from the group consisting of an oxazolecarboxaldeyhyde, imidazolecarboxaldehyde, a benzaldehyde, imidazolecarboxaldehyde derivatives, and benzaldehyde derivatives, thereby forming the above compound wherein R1, R1′, R1″, R2, R3, R4, R5, and R6, X1 and X2, Y, Z, Z1, Z2, Z3, and Z4 may each be separately defined in a manner consistent with the accompanying description. Compositions and methods for treating vascular proliferation are also disclosed.
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