Dataset Information

Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1H)-one.

ABSTRACT: 3,4-dihydropyrimidin-2(1H)-one compounds (DHPMs) possess extensive biological activities and are mainly prepared via Biginelli reaction and N-alkylation. In the present study, selective alkylation of N¹ was investigated by using tetrabutylammonium hydroxide. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of the aryl chain in the R³ as well as the low electron-donating group in the R¹ of DHPMs contributed to the anti-proliferative potency. A larger value of the partition coefficient (Log P) and suitable polar surface area (PSA) values were both found to be important in order to maintain the antitumor activity. The results from in vivo study indicated the great potential of compound 3d to serve as a lead compound for novel anti-tumor drugs to treat glioma. Pharmacophore study regarding the structure-activity relations of DHPMs were also conducted. Our results here could provide a guide for the design of novel bioactive 3,4-dihydropyrimidin-2(1H)-one compounds.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6429579 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1<i>H</i>)-one.

Liu Ye Y Liu Jiaqi J Zhang Renmei R Guo Yan Y Wang Hongbo H Meng Qingguo Q Sun Yuan Y Liu Zongliang Z

Molecules (Basel, Switzerland) 20190303 5

3,4-dihydropyrimidin-2(1<i>H</i>)-one compounds (DHPMs) possess extensive biological activities and are mainly prepared via Biginelli reaction and N-alkylation. In the present study, selective alkylation of N¹ was investigated by using tetrabutylammonium hydroxide. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of the aryl chain in the R³ as well as the low electron-donating group in the R¹ of DHPMs contributed to the anti-proliferative potency. A larger ...[more]

PMID: 30832453

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Project description:Breast cancer is a complex heterogeneous disease and is one of the leading causes of death among women. In addressing the need for treatments of this life-threatening illness, we studied 3,4-dihydropyrimidin-2(1H)-one (or thione) derivatives (DHPMs), a class of inhibitor molecules of the Eg5 motor spindle protein that shows pronounced antitumor activity against several cancer cell lines.An in vitro screening was performed for identification of DHPMs with potent antitumor effects on MCF-7 and MDA-MB-231 cells and the selected DHPMs were evaluated for their inhibitory activity on Eg5 both in silico, using Molecular dynamics, and in vitro Eg5 inhibition assays. Analysis of cell death induction, proliferation, cell cycle and cancer stem cells (CSC) profile were performed by flow cytometry to assess the influence of the selected DPHMs on these important tumor features. Finally, the effects of DHPM treatment on tube formation were evaluated in vitro using HUVEC cells, and in vivo using a model on chorioallantoic membrane (CAM) of fertilized eggs.We identified five DHPMs with pronounced inhibitory activity on Eg5 motor protein interfering with the proper mitotic spindle assembly during cell division. These compounds impair the correct conclusion of cell cycle of the breast cancer cells and showed to be selective for tumor cells. Moreover, DHPMs modulate the CD44(+)/CD24(-) phenotype leading to a decrease in the CSC population in MDA-MB-231 cells, an important effect since CSC are resistant to many conventional cancer therapies and play a pivotal role in tumor initiation and maintenance. This observation was confirmed by the results which demonstrated that DHPM treated cells had impaired proliferation and were unable to sustain angiogenesis events. Finally, the DHMP treated cells were induced to apoptosis, which is one of the most pursued goals in drug development.The results of our study strongly suggest that DHPMs inhibit important tumorigenic features of breast cancer cells leading them to death by apoptosis. These findings firmly point to DHPM molecular architecture as a promising alternative against breast cancer.

Dataset Information

Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1H)-one.

Publications

Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1<i>H</i>)-one.

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