Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents.

In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure-activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.

Intention to Quit and Predictive Factors Among Current Smokers in Vietnam: Findings From Adult Tobacco Survey 2020.

BACKGROUND: Smoking leads to many smoking-attributable diseases. The promotion of quitting tobacco smoking is urgent as it has significant and immediate health benefits and improves the impacts of other tobacco control strategies. Intention to quit smoking is considered the first step before quitting smoking. METHODOLOGY: This paper used data from Vietnam provincial GATS 2020 on 80,166 participants who were 15-year-old or older. Data were collected from 34 provinces and cities throughout Vietnam and managed using REDCap. RESULTS: Among those who were current smokers, 50.3% (95% CI: 49.1%-51.4%) had the intention to quit smoking. Some predictive factors found to be positively associated with the intention to quit smoking were age (from 45-64), education level, received information about harmful effects or encouragement to quit smoking from media channels (from 6 channels), hearing about the Tobacco Control Law and noticing health warnings on the cigarette package. There was no significant difference in intention to quit smoking between current smokers from urban and rural areas or among different age groups to start smoking. CONCLUSIONS: Interventions or health promotion programs on smoking cessation should be focused on current smokers who have low education levels as they have a higher smoking rate and are less motivated to stop smoking. Received information about harmful effects or encouragement to quit smoking from media channels is also associated with stopping smoking in the future. The importance of health warning pictures on tobacco packages should be maintained and promoted as it has a specific effect on one's intention to stop smoking.

Design, synthesis and evaluation of novel 2-oxoindoline-based acetohydrazides as antitumor agents.

In our search for novel small molecules activating procaspase-3, we have designed and synthesized two series of novel (E)-N'-arylidene-2-(2-oxoindolin-1-yl)acetohydrazides (4) and (Z)-2-(5-substituted-2-oxoindolin-1-yl)-N'-(2-oxoindolin-3-ylidene)acetohydrazides (5). Cytotoxic evaluation revealed that the compounds showed notable cytotoxicity toward three human cancer cell lines: colon cancer SW620, prostate cancer PC-3, and lung cancer NCI-H23. Especially, six compounds, including 4f-h and 4n-p, exhibited cytotoxicity equal or superior to positive control PAC-1, the first procaspase-3 activating compound. The most potent compound 4o was three- to five-fold more cytotoxic than PAC-1 in three cancer cell lines tested. Analysis of compounds effects on cell cycle and apoptosis demonstrated that the representative compounds 4f, 4h, 4n, 4o and 4p (especially 4o) accumulated U937 cells in S phase and substantially induced late cellular apoptosis. The results show that compound 4o would serve as a template for further design and development of novel anticancer agents.

Novel 4-Oxoquinazoline-Based N-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation.

Two series of novel 4-oxoquinazoline-based N-hydroxypropenamides (9a-m and 10a-m) were designed, synthesized, and evaluated for their inhibitory and cytotoxicity activities against histone deacetylase (HDAC). The compounds showed good to potent HDAC inhibitory activity and cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). In this series, compounds with the N-hydroxypropenamide functionality impeded at position 7 on the 4-oxoquinazoline skeleton (10a-m) were generally more potent than compounds with the N-hydroxypropenamide moiety at position 6 (9a-m). Also, the N 3-benzyl-substituted derivatives (9h-m, 10h-m) exhibited stronger bioactivity than the N 3-alkyl-substituted ones (9a-e, 10a-e). Two compounds 10l and 10m were the most potent ones. Their HDAC inhibitory activity (IC50 values, 0.041-0.044 µM) and cytotoxicity (IC50 values, 0.671-1.211 µM) were approximately 2- to 3-fold more potent than suberoylanilide hydroxamic acid (SAHA). Some compounds showed up to 10-fold more potent HDAC6 inhibition compared to their inhibitory activity in total HDAC extract assay. Analysis of selected compounds 10l and 10m revealed that these compounds strongly induced both early and late apoptosis and arrested SW620 cells at the G2/M phase. Docking studies were carried out on the HDAC6 isoform for series 10a-m and revealed some important features contributing to the inhibitory activity of synthesized compounds.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents.

BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. CONCLUSIONS: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.