Synthesis and Structure–Activity Relationship Study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as Anticancer Agents

Kuroiwa, Kenta; Ishii, Hirosuke; Matsuno, Kenji; Asai, Akira; Suzuki, Yumiko

doi:10.1021/ml5004684

Cited by 38 publications

(22 citation statements)

References 20 publications

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“…1A) and its fluorescent derivative 1-(4-methoxyphenyl)-1-(2morpholinoquinazolin-4-yl)ethan-1-ol (PVHD277) ( Fig. 6A) had submicromolar anti-cell proliferative EC 50 values in various tumor-derived cell lines (Suzuki et al, 1998(Suzuki et al, , 2017Kuroiwa et al, 2015). We also showed that they directly bound to the colchicine site of tubulin and inhibited tubulin polymerization in vitro (Kuroiwa et al, 2015).…”

Section: Introductionmentioning

confidence: 80%

Selective Inhibition of Spindle Microtubules by a Tubulin-Binding Quinazoline Derivative

et al. 2019

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In the research field of tubulin-binding agents for the development of anticancer agents, hidden targets are emerging as a problem in understanding the exact mechanisms of actions. The quinazoline derivative 1-(4-methoxyphenyl)-1-(quinazolin-4yl)ethan-1-ol (PVHD121) has anti-cell proliferative activity and inhibits tubulin polymerization by binding to the colchicine site of tubulin. However, the molecular mechanism of action of PVHD121 in cells remains unclear. Here, we demonstrate that PVHD121 delays mitotic entry and efficiently causes mitotic arrest with spindle checkpoint activation, leading to subsequent cell death. The dominant phenotype induced by PVHD121 was aberrant spindles with robust microtubules and unseparated centrosomes. The microtubules were radially distributed, and their ends appeared to adhere to kinetochores, and not to centrosomes. Extensive inhibition by high concentrations of PVHD121 eliminated all microtubules from cells. PVHD277 [1-(4-methoxyphenyl)-1-(2-morpholinoquinazolin-4-yl)ethan-1-ol], a PVHD121 derivative with fluorescence, tended to localize close to the centrosomes when cells prepared to enter mitosis. Our results show that PVHD121 is an antimitotic agent that selectively disturbs microtubule formation at centrosomes during mitosis. This antimitotic activity can be attributed to the targeting of centrosome maturation in addition to the interference with microtubule dynamics. Due to its unique bioactivity, PVHD121 is a potential tool for studying the molecular biology of mitosis and a potential lead compound for the development of anticancer agents. SIGNIFICANCE STATEMENT Many tubulin-binding agents have been developed as potential anticancer agents. The aim of this study was to understand the subcellular molecular actions of a quinazoline derivative tubulinbinding agent, 1-(4-methoxyphenyl)-1-(quinazolin-4-yl)ethan-1ol (PVHD121). As expected from its binding activity to tubulin, PVHD121 caused aberrant spindles and inhibited mitotic progression. However, in addition to tubulin, PVHD121 also targeted an unexpected biomolecule involved in centrosome maturation. Due to targeting the biomolecule just before entering mitosis, PVHD121 preferentially inhibited centrosome-derived microtubules rather than chromosome-derived microtubules during spindle formation. This study not only revealed the molecular action of PVHD121 in cells but also emphasized the importance of considering possible tubulin-independent effects of tubulinbinding agents via hidden targeted biomolecules for future use.

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Section: Introductionmentioning

confidence: 80%

Selective Inhibition of Spindle Microtubules by a Tubulin-Binding Quinazoline Derivative

et al. 2019

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“…In addition to developing a novel anticancer drug, a series of compounds with various substituents at positions 2 and 4 of the quinazoline core were synthesized and evaluated for anticancer activities. 67 Structure-activity relationship studies suggested that the 2-chloroquinazoline derivative compound 16 was the most potent and most active compound of the series (Fig. 3) in the low micromolar range.…”

Section: Quinazoline Derivatives As Tubulin Polymerization Inhibitorsmentioning

confidence: 97%

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

2017

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Cancer is one of the major causes of worldwide human mortality. A wide range of cytotoxic drugs are available on the market, and several compounds are in different phases of clinical trials. Many studies suggest that these cytotoxic molecules are also associated with different types of adverse side effects; therefore researchers around the globe are involved in the development of more efficient and safer anticancer drugs. In recent years, quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors. The aim of this article is to comprehensively review and highlight the recent developments concerning the anticancer activity of quinazoline derivatives as well as offer perspectives on the development of novel quinazoline derivatives as anticancer agents in the near future.

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“…A data set of 45 quinazoline-based anticancer agents was collected [10] . Reported activity values (IC 50 ) of inhibitors were converted into pIC 50 values for 3D-QSAR analysis.…”

Section: Data Setmentioning

confidence: 99%

“…Recently, quinazoline-based anticancer agents were reported [10] . However, a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis on these inhibitors has not been performed to establish exactly how their chemical structures relate to the inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

A CoMFA Study of Quinazoline-based Anticancer Agents

Balupuri¹,

Balasubramanian²,

Cho³

2015

Journal of the Chosun Natural Science

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Cancer has emerged as one of the leading cause of deaths worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of quinazoline-based anticancer agents. Purpose of the study is to understand the structural basis for their inhibitory activity. Comparative molecular field analysis (CoMFA) technique was employed to develop 3D-QSAR model. Ligand-based alignment scheme was used to generate a reliable CoMFA model. The model produced statistically significant results with a cross-validated correlation coefficient (q 2 ) of 0.589 and a non-cross-validated correlation coefficient (r 2 ) of 0.928. Model was further validated by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel and more potent anticancer agents.

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Synthesis and Structure–Activity Relationship Study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as Anticancer Agents

Cited by 38 publications

References 20 publications

Selective Inhibition of Spindle Microtubules by a Tubulin-Binding Quinazoline Derivative

Selective Inhibition of Spindle Microtubules by a Tubulin-Binding Quinazoline Derivative

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

A CoMFA Study of Quinazoline-based Anticancer Agents

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