Discovery of a chiral fluorinated azetidin-2-one as a tubulin polymerisation inhibitor with potent antitumour efficacy

Tang, Hairong; Cheng, Jing; Liang, Yuru; Wang, Yang

doi:10.1016/j.ejmech.2020.112323

Cited by 24 publications

(10 citation statements)

References 22 publications

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“…Good physicochemical properties ( e.g. , aqueous solubility) is the key to the druggability of a candidate compound . Therefore, the aqueous solubility and other drug-like properties of compound P18 were evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Good physicochemical properties (e.g., aqueous solubility) is the key to the druggability of a candidate compound. 16 Therefore, the aqueous solubility and other druglike properties of compound P18 were evaluated. As shown in Table 3, the aqueous solubility of compound P18 was determined as 17.61 mg/mL at pH 7.4, which was significantly better than that of NP19 (12 μg/mL at pH 7.4), 17 a highly potent PD-L1 inhibitor identified by us before.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

et al. 2020

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A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t 1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

et al. 2020

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“…We assembled a dataset of 851 compounds tested as Tub-Mts inhibitors and with reported bioactivity in different cancer cell lines [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. All compounds were retrieved from original and review articles and patents over a period of 15 years (2005–2020).…”

Section: Methodsmentioning

confidence: 99%

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

2021

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Inhibiting the tubulin-microtubules (Tub-Mts) system is a classic and rational approach for treating different types of cancers. A large amount of data on inhibitors in the clinic supports Tub-Mts as a validated target. However, most of the inhibitors reported thus far have been developed around common chemical scaffolds covering a narrow region of the chemical space with limited innovation. This manuscript aims to discuss the first activity landscape and scaffold content analysis of an assembled and curated cell-based database of 851 Tub-Mts inhibitors with reported activity against five cancer cell lines and the Tub-Mts system. The structure–bioactivity relationships of the Tub-Mts system inhibitors were further explored using constellations plots. This recently developed methodology enables the rapid but quantitative assessment of analog series enriched with active compounds. The constellations plots identified promising analog series with high average biological activity that could be the starting points of new and more potent Tub-Mts inhibitors.

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“…1 , Eq 3) 40 . In this fluorination process, the in situ formed alkyl sulfonimidate (from SulfoxFluor and alcohol) serves as the real electrophilic alkylating agent to react with hydrogen-bonded fluoride ion, affording the desired alkyl fluoride 40 , 41 . We envisioned that since fluoride ion is a weak nucleophile 42 , if there is a strong nucleophile (namely, azide ion) existing in the reaction system, the deoxyazidation of alcohol could become the dominating reaction pathway, giving an alkyl azide as a major product.…”

Section: Introductionmentioning

confidence: 99%

SulfoxFluor-enabled deoxyazidation of alcohols with NaN3

Guo

Wang

et al. 2022

Nat Commun

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Direct deoxyazidation of alcohols with NaN3 is a straightforward method for the synthesis of widely used alkyl azides in organic chemistry. However, known methods have some limitations such as high reaction temperatures and narrow substrate scope. Herein, a general and practical method for the preparation of alkyl azides from alcohols using NaN3 has been developed. N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor) plays an important role in this deoxyazidation process, which converts a broad range of alcohols into alkyl azides at room temperature. The power of this deoxyazidation protocol has been demonstrated by successful late-stage deoxyazidation of natural products and pharmaceutically relevant molecules.

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Discovery of a chiral fluorinated azetidin-2-one as a tubulin polymerisation inhibitor with potent antitumour efficacy

Cited by 24 publications

References 22 publications

Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

SulfoxFluor-enabled deoxyazidation of alcohols with NaN3

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