714273-84-4Relevant articles and documents
Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer
Ding, Zhongpeng,Li, Feifei,Li, Feng,Li, Wenbao,Liu, Yuqian,Wang, Shixiao,Zhao, Jianchun,Zhong, Changjiang
, (2020/04/15)
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.
(Z)-3-(3-formyl benzylidene) piperazinedione type compound and application thereof to preparation of anti-tumor medicine
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Paragraph 0048-0051, (2019/10/01)
The invention discloses a (Z)-3-(3-formyl benzylidene) piperazinedione type compound and application thereof to preparation of anti-tumor medicine. In a general formula (I) shown as the accompanying drawing, Rl is selected from substituted or nonsubstituted saturated nitrogen-containing multivariate heterocycles, substituted or nonsubstituted unsaturated sulfur-containing multivariate heterocycles, and substituted or nonsubstituted unsaturated oxygen containing multivariate heterocycles, and the multivariate heterocycles are 4 to 6 membered heterocycles. R2 is 5-tertiary butyl-1H-imidazole or pyridine. The invention also discloses a purpose of the compound to preparation of medicine composition aspects for treating tumor diseases, particularly, purposes to preparation of medicine compositions for treating pancreatic cancer and/or lung cancer aspects.
Design, synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure
Fu, Zhangyu,Hou, Yingwei,Ji, Cunpeng,Ma, Mingxu,Tian, Zhenhua,Deng, Mengyan,Zhong, Lili,Chu, Yanyan,Li, Wenbao
, p. 2061 - 2072 (2018/03/26)
Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC50 at 1.56 and 1.72 nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.
Plinabulin compound polycrystalline type and preparation method thereof
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Paragraph 0049; 0050, (2017/08/31)
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.
Preparation and purification method of high-purity Plinabulin compound
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Paragraph 0028; 0029, (2017/08/31)
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.
Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation
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Paragraph 0034; 0035, (2017/10/31)
The invention discloses and provides an acid addition salt of a deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation. The invention discloses and provides a preparation process of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)deuteration methylene) piperazidine-2,5-diketone compound acid addition salt. The salifying compound aims at obviously improving the solubility and the bioavailability of the active ingredients of the compound; further, the sufficient embodiment and application are achieved in aspects of curative effect and dosage form selection of the anti-tumor medicine.
Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure
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
experimental part, p. 1056 - 1071 (2012/04/04)
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.
ANALOGS OF DEHYDROPHENYLAHISTINS
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Page/Page column 38; 41-42, (2011/08/03)
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.
ANALOGS OF DEHYDROPHENYLAHISTINS AND THEIR THEAPEUTIC USE
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Page/Page column 19; 28, (2008/12/08)
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.
