Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300

Yakushiji, Fumika; Muguruma, Kyohei; Hayashi, Yoshiki; Shirasaka, Takuya; Kawamata, Ryosuke; Tanaka, Hironari; Yoshiwaka, Yushi; Taguchi, Akihiro; Takayama, Kentaro; Hayashi, Yoshio

doi:10.1016/j.bmc.2017.04.024

Cited by 7 publications

(5 citation statements)

References 31 publications

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“…The development of plinabulin derivatives with aryl moieties is a research direction of interest due to the ability of these moieties to alter significantly the hydrophobicity and π-π interaction capacity of the compound. 10,11 In this study, the moieties of choice were nitroquinoline, 1,4-dihydroquinoline, 4-methoxybenzene, and 4-chlorobenzene. The quinoline ring is commonly acknowledged for its antimalarial potency, and the quinine derivative, Chloroquine, has been the most widely used anti-malarial drug since the 1940s.…”

Section: Resultsmentioning

confidence: 99%

“…The Npropargyl-plinabulin derivatives 5 and 6 were synthesized from 1,4-diacetyl-2,5-piperazinedione 1 through 2 steps [1][2][3][4][5][6][7][8]11,17 (Schemes 1 and 2, Supplemental Figures S6-S13). The first was aldol condensation between aldehyde derivatives and 1,4-diacetyl-2,5-piperazinedione via K 2 CO 3 -catalysis and methylation with propargyl bromide in one-pot 4 to give the Npropargyl-piperidinedione derivatives 3 in high yield 91% (Supplemental Figures S1 and 2).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

Tham¹,

Quynh²,

Tuyen³

et al. 2021

Natural Product Communications

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Seven novel N-alkyl-plinabulin derivatives with aryl groups moieties (nitroquinoline, 1,4-dihydroquinoline, 4-methoxybenzene, and 4-chlorobenzene) have been synthesized via aldol condensation and alkylation in one-pot, and tested for their cytotoxicity against 4 cancer cell lines (KB, HepG2, Lu, and MCF7). Compounds ( Z)−3-((6,8-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl)methylene)−6-(( Z)−4-methoxybenzylidene)−1-(prop-2-yn-1-yl)piperazine-2,5-dione (5a), ( Z)−6-(( Z)−4-methoxybenzylidene)−1-(prop-2-yn-1-yl)−3-((1,6,8-trimethyl-4-oxo-1,4-dihydroquinolin-2-yl)methylene)piperazine-2,5-dione (5b), and ( Z)−3-(( Z)−4-chlorobenzylidene)−1,4-dimethyl-6-((8-methyl-4-nitroquinolin-2-yl)methylene)piperazine-2,5-dione (8) showed strong cytotoxicity against 3 of the cancer cells lines (KB, HepG2 and Lu) with IC50 values ranging from 3.04 to 10.62 µM. The quinoline-derived compounds had higher cytotoxic activity than the benzaldehyde derivatives. The successful synthesis of these derivatives offers useful information for the development of more potent vascular disrupting agents based on plinabulin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

Tham¹,

Quynh²,

Tuyen³

et al. 2021

Natural Product Communications

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“…Given plinabulin's low water solubility [38,39] and the use of water immersion for compound administration (oral uptake and passive diffusion via skin and gills) to the larvae, a low bioavailability after a short exposure time seems plausible, but currently no pharmacokinetic data are present to support this. Plinabulin's poor pharmacokinetic properties in general, and low water solubility in particular, have been reported to limit its pharmaceutical advantages, and derivatives with improved pharmacokinetics have been developed [38,39]. In the absence of convulsant, an 18 h exposure to 1.25-5 µM plinabulin lowered the normal swimming behavior of zebrafish larvae, which was not observed at 10 µM.…”

Section: Discussionmentioning

confidence: 99%

Section: Plinabulin Ameliorates Seizures and Epileptiform Brain Activ...mentioning

confidence: 99%

“…Plinabulin (Figure 2), the commercially available structural analogue of halimide, was tested in the zebrafish PTZ seizure model after both 2 and 18 h of treatment to examine whether this 2,5-diketopiperazine also shows antiseizure activity. Given plinabulin's limited water solubility [38,39], the highest test concentration was determined not by its MTC but by its maximum soluble concentration in embryo medium (1% DMSO), which was 10 µM. After 2 h of exposure, significant antiseizure activity was observed at all concentrations tested (p ≤ 0.0001 and p ≤ 0.05, Figure 5A), though the efficacy was rather limited.…”

Section: Plinabulin Ameliorates Seizures and Epileptiform Brain Activ...mentioning

confidence: 99%

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From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin

et al. 2022

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PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin’s antiseizure action.

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An Efficient Method for the Conjugation of Hydrophilic and Hydrophobic Components by Solid‐Phase‐Assisted Disulfide Ligation

et al. 2018

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Chemical conjugation between hydrophilic and hydrophobic components is difficult because of their extremely different solubility. Herein, we report a new versatile method with a solid‐phase‐assisted disulfide ligation to overcome the difficulty of conjugation attributed to solubility. The method involves two steps in a one‐pot process: 1) loading of a hydrophobic molecule onto a resin in an organic solvent, and 2) release of the solid‐supported hydrophobic molecule as a conjugate with a hydrophilic molecule into an aqueous solvent. This strategy allows the use of a suitable solvent system for the substrates in each step. Conjugates of a water‐insoluble drug, plinabulin, with hydrophilic carriers that could not be prepared by solution‐phase reactions were obtained in moderate yields (29–45 %). This strategy is widely applicable to the conjugation of compounds with solubility problems.

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Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300

Cited by 7 publications

References 31 publications

Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin

An Efficient Method for the Conjugation of Hydrophilic and Hydrophobic Components by Solid‐Phase‐Assisted Disulfide Ligation

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