714272-27-2

Usage

Biological Activity

the ic50 values of npi-2358 is 9.8 ± 2.4 nmol/l, 18 ± 5 nmol/l, 13 ± 1 nmol/l, 14 ± 2 nmol/l, 18 ± 1 nmol/l and 11 nmol/l for ht-29, du 145, pc-3, mda-mb-231, ncl-h292 and jurkat cell lines, respectively[1].plinabulin (npi-2358) is a vascular disrupting agent which binds to the colchicine-binding site of tubulin. npi-2358 could destabilize tumor vascular endothelial architectural resulting in selective collapse of established tumor vasculature [1].

in vitro

npi-2358 exhibited anti-tumor activity against various human tumor cell lines. in proliferating human umbilical vein endothelial cells (huvecs), administration of npi-2358 at 10 nmol/l induced tubulin depolymerization within 30 min [1]. in an in-vitro model of tumor vascular collapse, npi-2358 increased huvec monolayer permeability in a dose-dependent manner. plinabulin had also shown the in-vitro cytotoxic activity with ic50 values of 11 ± 5 nmol/l and 4.3 ± 2.2 nmol/l for mes-sa and hl-60 tumor cell lines, respectively[1].

in vivo

in the foot implanted c3h mammary carcinomas or leg implanted kht sarcomas mice model, 7.5 mg/kg plinabulin (intraperitoneally injected) significantly reduced the transfer constant (k(trans)) and the initial area under curve (iauc) within 1 hour after injection, reaching a lowest point at 3 h, but returning to normal within 24 h. a dose-dependent decrease in iauc and k(trans) was seen at 3 h. 12.5 mg/kg and 1.5 mg/kg npi-2358 showed significant anti-tumour effects in the c3h tumours and the kht sarcoma, respectively .

references

nicholson b1, lloyd gk, miller br, palladino ma, kiso y, hayashi y, neuteboom st. npi-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent.anticancer drugs. 2006 jan; 17(1):25-31.bertelsen l b, shen y y, nielsen t, et al. vascular effects of plinabulin (npi-2358) and the influence on tumour response when given alone or combined with radiation[j]. international journal of radiation biology, 2011, 87(11): 1126-1134.millward m, mainwaring p, mita a, et al. phase 1 study of the novel vascular disrupting agent plinabulin (npi-2358) and docetaxel[j]. investigational new drugs, 2012, 30(3): 1065-1073.

InChI:InChI=1S/C19H20N4O2/c1-19(2,3)16-13(20-11-21-16)10-15-18(25)22-14(17(24)23-15)9-12-7-5-4-6-8-12/h4-11H,1-3H3,(H,20,21)(H,22,25)(H,23,24)/b14-9-,15-10-

Upstream product

• 1538-75-6 2,2-dimethylpropanoic anhydride 
• 51721-22-3 (5-(tert-butyl)-1H-imidazol-4-yl)methanol 
• 51721-21-2 5-(tert-butyl)-1H-imidazole-4-carboxylic acid ethyl ester 
• 714273-89-9 5-(tert-butyl)oxazole-4-carboxylic acid ethyl ester 
• 714273-83-3 5-(tert-butyl)-1H-imidazole-4-carbaldehyde 
• 1360790-08-4 (((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methyl hex-5-ynoate 
• 1360790-10-8 sodium (S)-2-(4-(4-((((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methoxy)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)-3-hydroxypropanoate 
• 1366139-26-5 sodium (R)-4-(4-(4-((((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methoxy)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutanoate 
• 1366139-24-3 (R)-4-(4-(4-((((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methoxy)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutanoic acid 
• 29509-07-7 2-chloro-4,4-dimethyl-3-oxopentanoic acid ethyl ester 
• 714273-83-3 4-tert-butyl-1H-imidazole-5-carbaldehyde 
• 51721-21-2 ethyl 4-(tert-butyl)-1H-imidazole-5-carboxylate 
• 51721-22-3 (4-(tert-butyl)-1H-imidazol-5-yl)methanol 
• 17094-34-7 ethyl pivaloylacetate 

Downstream Products

• 1360790-08-4 (((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methyl hex-5-ynoate 
• 1360790-10-8 sodium (S)-2-(4-(4-((((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methoxy)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)-3-hydroxypropanoate 
• 1360790-09-5 (S)-2-(4-(4-((((3Z,6Z)-6-benzylidene-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)-5-oxo-3,4,5,6-tetrahydropyrazin-2-yl)oxy)methoxy)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)-3-hydroxypropanoic acid 

Relevant academic research and scientific papers

Plinabulin compound polycrystalline type and preparation method thereof

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.

Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation

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.

Preparation and purification method of high-purity Plinabulin compound

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.

PLINABULIN PRODRUG ANALOGS AND THERAPEUTIC USES THEREOF

Compounds of Formula (I) and (I') 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.

Prodrug study of plinabulin using a click strategy focused on the effects of a replaceable water-solubilizing moiety

Plinabulin (1) is a potent anti-microtubule agent, however, its low water solubility has to be improved for the advantage in pharmacokinetics and chemotherapy. In this report, the replaceable water-solubilizing moiety of the water-soluble prodrug of plina

ANALOGS OF DEHYDROPHENYLAHISTINS

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

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.