Secondhand Smoke and Socio-Demographic Associated Factors: Results From the Vietnam Population-Based Provincial Global Adult Tobacco Survey in 2022.

Background: Secondhand smoke (SHS) has detrimental effects on community health, including coronary heart diseases, stroke, lung cancer etc. This manuscript exploited data from the Vietnam Population-based Provincial Global Adult Tobacco Survey (PGATS) in 2022 to update the prevalence of adult exposure to SHS and associated socio-demographic factors. Methods: With the sample size of 71,981 adults aged 15+ throughout 30 provinces and cities in Vietnam, data was collected using the Global Adult Tobacco Survey (GATS) questionnaire. Bivariate analysis and multivariate logistic regression modelling were performed. Results: In the past 30 days, 44.4% (95% CI: 44.0%-44.9%) adults aged 15+ exposed to SHS at home while 23.1% (95% CI: 22.6%-23.6%) exposed to SHS at work. Female exposure to SHS in the past 30 days was higher at homes but lower at indoor workplaces. Participants aged 15-24 were likely to have higher odds of SHS exposure in the past 30 days to other age groups. Those living in the urban areas had 1.15 times higher odds (95% CI: 1.08-1.22) of exposure to SHS than those in the rural areas. Current smokers tended to have 2.2 times higher odds of exposure to SHS at the indoor workplaces compared to non-smokers (95% CI: 2.05-2.37). Conclusions: The prevalence of exposure to SHS at home was still relatively high amongst the adult population. While there was a significant reduction of SHS exposure at indoor workplaces, there was a higher prevalence of women being exposed to SHS at home. The Government of Vietnam should continue to strictly implement the smoke-free environment resolution at indoor workplaces and appropriate communication campaigns to protect people, especially women from SHS exposure at homes.

Camellia annamensis (Theaceae): phytochemical analysis, cytotoxic, antioxidative, and antimicrobial activities.

Cytotoxic, antioxidative, and antimicrobial activities of Camellia annamensis, and its chemical compositions were first provided in the current study. Phenolic contents in the methanol extracts of its leaves and flowers were 222.73 ± 0.09 and 64.44 ± 0.08 mg GAE/g extract, whereas flavonoid contents in these parts were 108.80 ± 0.28 and 131.26 ± 0.39 mg rutin/g extract, respectively. By using HPLC-DAD analysis, gallic acid (43.72 ± 0.09 - 81.89 ± 1.83 mg/g) and (-)-epigallocatechin gallate (67.31 ± 1.26 - 70.68 ± 7.82 mg/g) were identified as the major compounds. C. annamensis leaf and flower extracts were moderately cytotoxic against A549, HT-29, SK-Mel-2, MCF-7, HepG2, HeLa, and MKN-7. Particularly, they are better than the standards trolox (IC50 7.57 ± 0.23 µg/mL) in lipid peroxidation inhibitory evaluation, and streptomycin (IC50/MIC = 45.34-50.34/128-256 µg/mL) in antimicrobial assay against the Gram-positive bacteria Enterococcus faecalis ATCC299212, Staphylococcus aureus ATCC25923, and the Gram-negative bacterium Salmonella enterica ATCC13076.

Multifunctional nanocarriers of Fe3O4@PLA-PEG/curcumin for MRI, magnetic hyperthermia and drug delivery.

Background: Despite medicinal advances, cancer is still a big problem requiring better diagnostic and treatment tools. Magnetic nanoparticle (MNP)-based nanosystems for multiple-purpose applications were developed for these unmet needs. Methods: This study fabricated novel trifunctional MNPs of Fe3O4@PLA-PEG for drug release, MRI and magnetic fluid hyperthermia. Result: The MNPs provided a significant loading of curcumin (∼11%) with controllable release ability, a high specific absorption rate of 82.2 W/g and significantly increased transverse relaxivity (r2 = 364.75 mM-1 s-1). The in vivo study confirmed that the MNPs enhanced MRI contrast in tumor observation and low-field magnetic fluid hyperthermia could effectively reduce the tumor size in mice bearing sarcoma 180. Conclusion: The nanocarrier has potential for drug release, cancer treatment monitoring and therapy.

In this study, the authors designed and fabricated novel magnetic trifunctional nanoparticles of Fe₃O₄@PLA-PEG. The 8.5 nm Fe₃O₄ core was covered with the polymeric matrix of PLA-PEG to encapsulate an anticancer agent of curcumin at a content of about 11%. Curcumin release from the nanoparticles (NPs) could be controlled by applying a remote alternating magnetic field. The NPs enhanced MRI contrast, which allowed the authors to better distinguish the tumor and surroundings in MR images, which would help monitor treatment. The heat that NPs generated when applied to a field at low intensity could effectively reduce the tumor size in mice bearing sarcoma 180. The nanocarrier, therefore, has potential for cancer treatment monitoring and drug release conjuvant with magnetic hyperthermia therapy.

Chemical compositions, larvicidal and antimicrobial activities of Zingiber castaneum (Škorničk. & Q.B. Nguyễn) and Zingiber nitens (M.F. Newman) essential oils

Abstract In this paper, the chemical constituents, larvicidal and antimicrobial activities of hydrodistilled essential oils from Zingiber castaneum Škorničk. & Q.B. Nguyễn and Zingiber nitens M.F. Newman were reported. The main constituents of Z. castaneum leaf were bicyclogermacrene (24.8%), germacrene D (12.9%), cis-β-elemene (11.2%) and β-pinene (10.3%), while sabinene (22.9%) and camphene (21.2%) were the significant compounds in the rhizome. However, the dominant compounds in the leaf of Z. nitens includes β-pinene (45.8%) and α-pinene (10.7%). Terpinen-4-ol (77.9%) was the most abundant compound of the rhizome. Z. castaneum rhizome oil displayed larvicidal activity against Aedes aegypti and Culex quinquefasciatus with LC50 values of 121.43 and 88.86 µg/mL, respectively, at 24 h. The leaf oil exhibited activity with LC50 values of 39.30 µg/mL and 84.97 µg/mL, respectively. Also, the leaf and rhizome oils of Z. nitens displayed greater larvicidal action towards Ae. aegypti with LC50 values of 17.58 µg/mL and 29.60 µg/mL, respectively. Only the rhizome oil displayed toxicity against Cx. quinquefasciatus with LC50 value of 64.18 µg/mL. All the studied essential oils inhibited the growth of Pseudomonas aeruginosa ATCC25923 with minimum inhibitory concentration (MIC) value of 50.0 µg/mL. This paper provides information on the larvicidal and antimicrobial potentials of Z. castaneum and Z. nitens essential oils.

Nutritional Intervention Improves Nutrition Outcomes in Stomach and Colon Cancer Patients Receiving Chemotherapy: Finding from a Quasi-Experiment in Vietnam.

BACKGROUND: Evidence on the effects of nutritional interventions on gastrointestinal cancer patients receiving chemotherapy is not well documented. This study aims to assess the effects of nutritional intervention in patients diagnosed with stomach and colon cancer receiving chemotherapy in Vietnam. METHODS: A quasi-experiment with intervention and control groups for pre- and post-intervention was carried out in cancer patients receiving chemotherapy in a university hospital in Vietnam. Patients in the intervention group were provided nutritional counseling, personalized specific dietary advice, and received oral nutrition supplements (ONSs) while patients in the control group only received nutrition counseling. RESULTS: The weight in the intervention and control group after 2 months increased significantly by 1.4 ± 2.6 kg and 0.4 ± 2.3 kg, respectively. Muscle mass increased by 1.2 ± 4.1 cm in the intervention group, while those in the control group decreased by 0.55 ± 2.77 cm. There was no statistical significance between two groups after intervention in terms of Mid-Upper Arm Circumference (MUAC) and percentage of fat. The percentage of malnutrition based on the Scored Patient-Generated Subjective Global Assessment (PG-SGA) and Body Mass Index (BMI) declined after the intervention in both groups. According to the average treatment effect on the treated (ATT) using the propensity score matching and DiD method, participants receiving the intervention were more likely to have a higher score of weight (Coef = 0.84; 95%CI = 0.47; 2.16) and muscle mass (Coef = 1.08; 95%CI = 0.09; 2.06) between pre- and post-intervention. By contrast, the PG-SGA scores on treated participants were more likely to decrease after the intervention (Coef = -1.28; 95%CI = -4.39; -0.84). After matching, being female, living in rural areas, or having stomach cancer were still positively related to being moderately/severely malnourished by the PG-SGA, and these findings were statistically significant (p < 0.05). CONCLUSION: The nutritional interventions had a positive effect on weight gain, muscle mass, and reduced malnutrition. Further studies with a longer follow-up duration are needed to confirm the effects of the intervention.

Essential Oil Compositions of Three Invasive Conyza Species Collected in Vietnam and Their Larvicidal Activities against Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus.

Mosquito-borne infectious diseases are a persistent problem in tropical regions of the world, including Southeast Asia. Vector control has relied principally on synthetic insecticides, but these have detrimental environmental effects and there is an increasing demand for plant-based agents to control insect pests. Invasive weedy plant species may be able to serve as readily available sources of essential oils, some of which may be useful as larvicidal agents for control of mosquito populations. We hypothesize that members of the genus Conyza (Asteraceae) may produce essential oils that may have mosquito larvicidal properties. The essential oils from the aerial parts of Conyza bonariensis, C. canadensis, and C. sumatrensis were obtained by hydrodistillation, analyzed by gas chromatography-mass spectrometry, and screened for mosquito larvicidal activity against Aedes aegypti, Ae. albopictus and Culex quinquefasciatus. The essential oils of C. canadensis and C. sumatrensis, both rich in limonene (41.5% and 25.5%, respectively), showed notable larvicidal activities against Ae. aegypti (24-h LC50 = 9.80 and 21.7 µg/mL, respectively) and Ae. albopictus (24-h LC50 = 18.0 and 19.1 µg/mL, respectively). These two Conyza species may, therefore, serve as sources for alternative, environmentally-benign larvicidal control agents.

Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

Background: The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. Objective: To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. Methods: The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. Results: A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI (r = -0.696, p = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI (r = -0.788, p < 0.001; r = -0.739, p = 0.002). HDI positively correlated with average testing level (r = 0.742, p = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. Conclusion: There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.

Premna Species in Vietnam: Essential Oil Compositions and Mosquito Larvicidal Activities.

Essential oils have emerged as viable alternatives to synthetic insecticides for control of mosquito-borne pathogens. The leaf essential oils of eight species of Premna (Lamiaceae) growing in central Vietnam have been obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry. Sesquiterpene hydrocarbons dominated most of the Premna essential oils, with the notable exception of Premnamekongensis from Ngoc Linh Nature Reserve, which had α-pinene as the major component. Larvicidal activities against Aedes aegypti have been determined and all of the Premna essential oils showed larvicidal activity with 24-h LC50 < 65 µg/mL. The leaf essential oils of Premnacambodiana from Chu Mom Ray National Park and Premnamekongensis from Ngoc Linh Nature Reserve showed the best larvicidal activities with 24-h LC50 of 16.8 and 18.0 µg/mL, respectively. The essential oil compositions and larvicidal activities of P. cambodiana, Premna flavescens, Premnamaclurei, P. mekongensis, and Premnapuberula are reported for the first time. Although the larvicidal activities of Premna leaf essential oils are promising, the essential oil yields are relatively low (0.10-0.25%).

Knowledge of Cervical Cancer and Human Papillomavirus Vaccines among Child-Bearing Aged Women in Hanoi, Vietnam.

OBJECTIVES: The study sought to examine knowledge of cervical cancer and human papillomavirus (HPV) vaccines among child-bearing aged women in Hanoi, Vietnam. METHODS: In 2016, 807 women aged 18 to 49 years were recruited from one urban area and one rural area in 2016 and were examined through face-to-face paper-based interviews. Pearson's chi-square test and an independent t-test were utilized to compare awareness of cervical cancer and HPV vaccination among women according residential status. RESULTS: Overall, 83.8% and 71.3% women had heard about cervical cancer and HPV vaccination, respectively. Mean knowledge scores for cervical cancer and HPV vaccination were 4.60±1.43 out of 7 and 1.53±1.35 out of 5, respectively. Women living in an urban area were more likely to be aware of cervical cancer and to be more knowledgeable of HPV vaccination than women in a rural area. CONCLUSIONS: Despite strong awareness, we found knowledge on cervical cancer and HPV vaccination to be alarmingly insufficient among Vietnamese women.
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Factors associated with the duration of hospitalisation among COVID-19 patients in Vietnam: A survival analysis.

BACKGROUND: The median duration of hospital stays due to COVID-19 has been reported in several studies on China as 10-13 days. Global studies have indicated that the length of hospitalisation depends on different factors, such as the time elapsed from exposure to symptom onset, and from symptom onset to hospital admission, as well as specificities of the country under study. The goal of this paper is to identify factors associated with the median duration of hospital stays of COVID-19 patients during the second COVID-19 wave that hit Vietnam from 5 March to 8 April 2020. METHOD: We used retrospective data on 133 hospitalised patients with COVID-19 recorded over at least two weeks during the study period. The Cox proportional-hazards regression model was applied to determine the potential risk factors associated with length of hospital stay. RESULTS: There were 65 (48.9%) females, 98 (73.7%) patients 48 years old or younger, 15 (11.3%) persons with comorbidities, 21 (16.0%) severely ill patients and 5 (3.8%) individuals with life-threatening conditions. Eighty-two (61.7%) patients were discharged after testing negative for the SARS-CoV-2 virus, 51 were still in the hospital at the end of the study period and none died. The median duration of stay in a hospital was 21 (IQR: 16-34) days. The multivariable Cox regression model showed that age, residence and sources of contamination were significantly associated with longer duration of hospitalisation. CONCLUSION: A close look at how long COVID-19 patients stayed in the hospital could provide an overview of their treatment process in Vietnam, and support the country's National Steering Committee on COVID-19 Prevention and Control in the efficient allocation of resources over the next stages of the COVID-19 prevention period.

Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Several novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 µM) and some compounds (e.g 5f, IC50, 0.010 µM) were even more potent than SAHA (IC50, 0.025 µM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.

Identification of novel missense mutations associated with non-syndromic syndactyly in two vietnamese trios by whole exome sequencing.

BACKGROUND AND METHODS: Syndactyly is a congenital disorder caused by an irregularity in limb formation during the embryonic development. Many studies have demonstrated the critical effect of genetic factor in controlling the outcome of non-syndromic syndactyly. However the signaling pathway causing this disease has not been fully understood. The aim of this study was to identify the genetic mutations that related to syndactyly type I-c and I-d by exome sequencing. RESULTS: The exome sequence from two patients revealed two novel heterozygous missense mutations: GLI3: cG1622A pT541M and GJA1: cT274C p.Y92H. Sanger sequencing result confirmed that these mutations were present under heterozygous form in the affected mothers, but not in the unaffected fathers. In-silico analyses by SIFT, Polyphen-2, PredictSNP, PhD-SNP, and PROVEAN did confirm the damaging effect of these mutations in the structure and function of the proteins. CONCLUSIONS: The result suggested that the two novel mutations may be pathogenic for the disease in these families under the dominant model, provided the initial data for further functional studies to investigate whether those mutations play a disturbing role in the molecular network of syndactyly.

New Acetohydrazides Incorporating 2-Oxoindoline and 4-Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity.

In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.

Callicarpa Species from Central Vietnam: Essential Oil Compositions and Mosquito Larvicidal Activities.

There are around 140 species in the genus Callicarpa, with 23 species occurring in Vietnam. The Vietnamese Callicarpa species have been poorly studied. In this work, the leaf essential oils of C. bodinieri, C. candicans, C. formosana, C. longifolia, C. nudiflora, C. petelotii, C. rubella, and C. sinuata, have been obtained from plants growing in central Vietnam. The chemical compositions of the essential oils were determined using gas chromatography - mass spectrometry. Mosquito larvicidal activities of the essential oils were carried out against Aedes aegypti. All of the Callicarpa leaf essential oils showed larvicidal activity, but two samples of C. candicans were particularly active with 48-h LC50 values of 2.1 and 3.8 µg/mL. Callicarpa candicans essential oil should be considered as a potential alternative mosquito control agent.

Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N'-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH3, 4-OCH3, and 4-N(CH3)2, were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH3 substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most of the compounds, in this series, especially compounds 5c, 5b and 5h, also significantly activated caspase-3 activity. Among these, compound 5c displayed 1.61-fold more potent than PAC-1 as caspase-3 activator. Cell cycle analysis showed that compounds 5b, 5c, and 5h significantly arrested the cell cycle in G1 phase. Further apoptotic studies also demonstrated compounds 5b, 5c, and 5h as strong apoptotic cell death inducers. The docking simulation studies showed that these compounds could activate procaspase via chelating Zn2+ ion bound to the allosteric site of the zymogen.

(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.

Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity.

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10-0.16 µm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29-3.67 µm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21-0.38 µm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.

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.

N'-[(E)-Arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)-acetohydrazides: Synthesis and Evaluation of Caspase Activation Activity and Cytotoxicity.

In our search for novel small cytotoxic molecules potentially activating procaspase-3, we have designed and synthesized a series of novel N'-[(E)-arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)acetohydrazides (5, 6). Biological evaluation revealed that seven compounds, including 5h, 5j, 5k, 5l, 5n, 6a, and 6b, exhibited moderate to strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Among these compounds, two most cytotoxic compounds (5h and 5j) displayed from 3- up to 10-fold higher potency than PAC-1 and 5-FU in three cancer cell lines tested. Three compounds 5j, 5k, and 5n were also found to display better caspases activation activity in comparison to PAC-1. Especially, compound 5k activated the level of caspases activity by 200% higher than that of PAC-1. From this study, three compounds 5j, 5k, and 5n could be considered as potential leads for further design and development of caspase activators and anticancer agents.