Evaluation and molecular docking study of two flavonoids from Oroxylum indicum (L.) Kurz and their semi-synthetic derivatives as histone deacetylase inhibitors.

Chrysin (5,7-dihydroxyflavone, 6) and galangin 3-methyl ether (5,7-dihydroxy-3-methoxy flavone, 7) were obtained from the leaves of Oroxylum indicum (L.) Kurz in 4% and 6% yields, respectively. Both compounds could act as pan-histone deacetylase (HDAC) inhibitors. Structural modification of these lead compounds provided thirty-eight derivatives which were further tested as HDAC inhibitors. Compounds 6b, 6c, and 6q were the most potent derivatives with the IC50 values of 97.29 ± 0.63 µM, 91.71 ± 0.27 µM, and 96.87 ± 0.45 µM, respectively. Molecular docking study indicated the selectivity of these three compounds toward HDAC8 and the test against HDAC8 showed IC50 values in the same micromolar range. All three compounds were further evaluated for the anti-proliferative activity against HeLa and A549 cell lines. Compound 6q exhibited the best activity against HeLa cell line with the IC50 value of 13.91 ± 0.34 µM. Moreover, 6q was able to increase the acetylation level of histone H3. These promising HDAC inhibitors deserve investigation as chemotherapeutic agents for treating cancer.

Multifunctional effect of flavonoids from Millettia brandisiana against Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. Fifteen flavonoids from Millettia brandisiana were evaluated for the multifunctional effect against AD pathogenesis, including butyrylcholine esterase (BuChE) inhibition, anti-amyloid beta (Aß) aggregation and neuroprotection against hydrogen peroxide (H2O2) toxicity in differentiated human neuroblastoma SH-SY5Y cell. To understand the mechanism and structure-activity relationship, binding interactions between flavonoids and the BuChE and Aß were investigated in silico. Furthermore, drug-likeness properties and ADMET parameters were evaluated in silico using SwissADME and pKCSM tools. All flavonoids exhibit a good drug-likeness profile. Six flavonoids have potency in BuChE inhibition, and four flavonoids show potency in anti-Aß aggregation. Flavonoids with the 6″,6″-dimethylchromeno- [2″,3″:7,8]-flavone structure show a favorable multifunctional effect. In silico analysis showed that flavonoids can bind in various positions to the catalytic triad, anionic site, and acyl pocket. In Aß1-42, potential flavonoids can attach to the central hydrophobic region and the C terminal hydrophobic and interfere with Aß interchain hydrogen binding. When compared together, it can inhibit multifunctional action with a favorable ADMET parameter and drug-likeness profile. In addition, candidine can prevent neuronal damage in differentiated SH-SY5Y neuroblastoma cells induced by H2O2 in a dose-dependent manner.

7-Methoxyheptaphylline Enhances TRAIL-Induced Apoptosis of Colorectal Adenocarcinoma Cell via JNK-Mediated DR5 Expression.

A cytokine known as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has the ability to precisely cause the death of cancer cells, while normal cells are left undisturbed. Recent studies show that certain cancer cells are sensitive to the apoptotic effect of TRAIL. In this study, HT29 colorectal adenocarcinoma cells exposed to TRAIL were treated with heptaphylline and 7-methoxyheptaphylline from Clausena harmandiana in an effort to comprehend the mechanisms involved behind this activity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test was utilized to determine cell survival, and phase contrast microscopy was used to examine cell morphology. Through using real-time RT-PCR, Western blotting, and RT-PCR, the molecular mechanisms were investigated. According to the findings, whilst hepataphylline caused cytotoxicity in normal colon FHC cells, in comparison to healthy colon FHC cells, 7-methoxyheptaphylline inhibited cancer cells in a concentration-dependent manner. Heptaphylline alone or in conjunction with TRAIL showed no discernible effect on TRAIL-induced HT29 cell death, but 7-methoxyheptaphylline boosted caspase-3 cleavage. The study showed that the c-Jun N-terminal kinase (JNK) pathway was responsible for the 7-methoxyheptaphylline's enhancement of the death receptor 5 (DR5) mRNA, TRAIL receptor, and protein. The results demonstrated that the 7-methoxyheptaphylline of Clausena harmandiana increased the expression of DR5 via the JNK pathway, intensifying TRAIL-induced HT29 cell death.

Anti-inflammatory effects of Derris scandens extract on narrowband-ultraviolet B exposed HaCaT human keratinocytes.

Narrowband-ultraviolet B (NB-UVB) has been used to treat skin diseases such as psoriasis. Chronic use of NB-UVB might cause skin inflammation and lead to skin cancer. In Thailand, Derris Scandens (Roxb.) Benth. is used as an alternative medicine to nonsteroidal anti-inflammatory drugs (NSAIDs) for low back pain and osteoarthritis. Therefore, this study aimed to evaluate the potential anti-inflammatory effect of Derris scandens extract (DSE) on pre- and post exposed NB-UVB human keratinocytes (HaCaT). The results indicated that DSE could not protect HaCaT from cell morphology changes or DNA fragmentation and could not recover cell proliferation ability from the NB-UVB effects. DSE treatment reduced the expression of genes related to inflammation, collagen degradation, and carcinogenesis, such as IL-1α, IL-1ß, IL-6, iNOS, COX-2, MMP-1, MMP-9, and Bax. These results indicated the potential use of DSE as a topical preparation against NB-UVB-induced inflammation, anti-aging, and prevention of skin cancer from phototherapy.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 µM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 µM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

Neuroprotective and anticancer effects of 7­Methoxyheptaphylline via the TAK1 pathway.

7­Methoxyheptaphylline (7­MH) is a carbazole extracted from Clausena harmandiana, a medicinal plant that is used to treat headaches and stomachaches. The aim of the present study was to examine the neuroprotective effects and anticancer activity of 7­MH. Cell death was assessed using an MTT assay and flow cytometry. The expression of apoptosis­related proteins was determined by western blot analysis. An animal model was used to test anti­metastasis. The interactions between 7­MH and the molecular target were observed using molecular docking. The results revealed that 7­MH provided protection against hydrogen peroxide (H2O2)­induced neuronal cell death. In cancer cells, 7­MH induced SH­SY5Y, 4T1, HT29, HepG2, and LNCaP cell death. 7­MH inhibited metastasis of HT29 cells in vitro and 4T1­Luc cells in vitro and in vivo. 7­MH inhibited proteins, including P­glycogen synthase kinase (GSK)­3, and cleaved caspase­3, but it activated anti­apoptotic proteins in H2O2­induced SH­SY5Y cell death. By contrast, 7­MH activated the cleaving of caspase­3 and GSK­3, but it suppressed anti­apoptotic proteins in SH­SY5Y cells. 7­MH reduced the levels of NF­κB and STAT3 in 4T1 cells; phospho­p65, Erk, and MAPK13 in LNCaP cells; and phospho­Erk and matrix metalloproteinase­9 in HT29 cells. Molecular docking analysis showed that 7­MH targets TAK1 kinase. The present study indicated that 7­MH induced apoptosis of cancer cells and provided protection against H2O2­induced neuron cell death via TAK1 kinase.

Five new quinoline alkaloids from Sauropus hirsutus Beille and their cytotoxicity.

Chemical investigation of the whole plant of Sauropus hirsutus Beille led to the isolation of eight quinolines and two known flavonoids. Furthermore, five quinolines were new, two were reported in plant for the first time and one was known. Cytotoxicity evaluation against cholangiocarcinoma, KKU-M156, showed that the most active compound was 4-hydroxy-6-methoxy-7,8-methylenedioxyquinaldine (IC50 20.54 ± 6.82 µM) which was a little more active than the cisplatin standard (IC50 24.39 ± 1.14 µM).

Nordentatin Inhibits Neuroblastoma Cell Proliferation and Migration through Regulation of GSK-3 Pathway.

Cancer is caused by abnormal cell changes leading to uncontrolled cell growth. The specific characteristics of cancer cells, including the loss of apoptotic control and the ability to migrate into and invade the surrounding tissue, result in cancer cell metastasis to other parts of the body. Therefore, the inhibition of the proliferation, migration, and invasion of cancer cells are the principal goals in the treatment of cancer. This study aimed to investigate the inhibitory activity of nordentatin, a coumarin derivative isolated from Clausena harmandiana, regarding the proliferation and migration of human neuroblastoma cells (SH-SY5Y). Nordentatin at a concentration of 100 µM showed cell cytotoxicity toward SH-SY5Y that was significantly different from that of the control group (p < 0.01) at 24, 48, and 72 h. Moreover, nordentatin inhibited SH-SY5Y proliferation by inhibiting the antiapoptotic protein Mcl-1, leading to the cleavage of caspase-3 and resulting in the inhibition of a migratory protein, MMP-9, through the GSK-3 pathway (compared with cells treated with a GSK inhibitor). These results suggest that nordentatin inhibited the proliferation and migration of neuroblastoma cells through the GSK-3 pathway.

Acridone Derivatives from Atalantia monophyla Inhibited Cancer Cell Proliferation through ERK Pathway.

The present study aimed to investigate the effect of acridone alkaloids on cancer cell lines and elucidate the underlying molecular mechanisms. The ten acridone alkaloids from Atalantia monophyla were screened for cytotoxicity against LNCaP cell lines by a WST-8 assay. Then, the most potential acridone, buxifoliadine E, was evaluated on four types of cancer cells, namely prostate cancer (LNCaP), neuroblastoma (SH SY5Y), hepatoblastoma (HepG2), and colorectal cancer (HT29). The results showed that buxifoliadine E was able to significantly inhibit the proliferation of all four types of cancer cells, having the most potent cytotoxicity against the HepG2 cell line. Western blotting analysis was performed to assess the expression of signaling proteins in the cancer cells. In HepG2 cells, buxifoliadine E induced changes in the levels of Bid as well as cleaved caspase-3 and Bax through MAPKs, including Erk and p38. Moreover, the binding interaction between buxifoliadine E and Erk was investigated by using the Autodock 4.2.6 and Discovery Studio programs. The result showed that buxifoliadine E bound at the ATP-binding site, located at the interface between the N- and C-terminal lobes of Erk2. The results of this study indicate that buxifoliadine E suppressed cancer cell proliferation by inhibiting the Erk pathway.

Structural modification of olibergin A, an isoflavonoid, from Dalbergia stipulacea Roxb. and its cytotoxicity.

Fifteen derivatives were synthesized from olibergin A, a major isoflavonoid isolated from the stems of Dalbergia stipulacea Roxb. All compounds were evaluated for cytotoxicity against HCT-116, HT-29, MCF-7 and vero cell lines using MTT assay. Cytotoxicity results showed 5-hydroxy-7,2',4',5'-tetramethoxyisoflavone (5) was the most active with IC50 values of 19.03 ± 0.70, 10.83 ± 1.65, 12.53 ± 0.70 and 13.53 ± 0.84 µM against HCT-116, HT-29, MCF-7 and vero cell lines, respectively. It should be noted that 5-hydroxy-7,2',4',5'-tetramethoxyisoflavone (5) showed two times less toxicity against vero cells than the cisplatin standard (IC50 = 6.55 ± 0.81 µM) while 5 and cisplatin exhibited nearly equal cytotoxicity against the MCF-7 cell line. 5,7,2',4',5'-Pentamethoxyisoflavanone (10) showed an IC50 value of 30.34 ± 1.15 µM against the HCT-116 cell line and exhibited weak cytotoxicity against normal cells, the vero cell line. In addition, 5,7,4'-trihydroxy-2',5'-dimethoxyisoflavan oxime (13) demonstrated cytotoxicity against HT-29 cells with an IC50 value of 31.41 ± 1.38 µM and displayed weak activity toward the vero cell line. The information revealed that these compounds were suitable for development to anticancer agents against HCT-116, HT-29 and MCF-7 cell lines.

Histone Deacetylase Inhibitory Activity and Antiproliferative Potential of New [6]-Shogaol Derivatives.

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, 5j and 5k, and the Michael adduct with pyridine 4c and benzothiazole 4d, with IC50 values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound 4d showed the best selectivity towards HDAC3, whereas compound 5k showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor 5j exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC50 values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.

A new sesquiterpenoid juvenile hormone III from the stems of Cananga latifolia.

A new juvenile hormone III, canangalia I (1), along with six known juvenile hormone III analogues (2-7), was isolated from the methanolic extract of Cananga latifolia stems. All structures were elucidated using spectroscopic data and compared with data from previous literature. Canangalia I (1) was found to be cytotoxic against human cervical adenocarcinoma (HeLa) cells with an IC50 value of 35.00 ± 2.15 µg/ml after 72 h, but was not toxic to Vero cells.

Brandisianones F and G from Millettia brandisiana Kurz and their cytotoxicity.

A new flavanone and a new chalcone, brandisianones F and G, were purified from the roots of Millettia brandisiana Kurz, moreover, sixteen known compounds were found. The chemical structures of all isolated compounds were identified using spectroscopic methods including 1D-NMR, 2D-NMR, MS, IR and CD data. Chalcone 15 exhibited the most cytotoxic activity against liver cancer, HepG2, and cholangiocarcinoma, KKU-M156, cell lines with IC50 values of 1.74 ± 0.91 and 1.95 ± 0.95 µg/mL, respectively. Chalcones 2, 14, 16 and 18 as well as flavones 5, 6 and 12 showed moderate cytotoxicity with IC50 values ranging from 5.39 to 14.00 µg/mL.[Formula: see text].

A new diarylhexane and two new diarylpropanols from the roots of Knema globularia.

A new diarylhexane, kneglobularone B (1) and two new diarylpropanols, kneglobularols A - B (2 - 3) along with seven known compounds (4 - 10) were isolated and characterized from the roots of Knema globularia. It is the first time to find arylpropyl quinone (4) and isoflavone (8) in Myristicaceae family. In addition, 5 was found for the first time in Knema genus. Their structures were elucidated by UV, IR, MS, 1 D and 2 D NMR techniques. Compound 4 exhibited strong cytotoxicity against the NCI - H187 and MCF - 7 cell lines with IC50 values of 3.08 and 6.68 µg/mL, respectively.

Derrischalcone suppresses cholangiocarcinoma cells through targeting ROS-mediated mitochondrial cell death, Akt/mTOR, and FAK pathways.

Chemotherapy is a palliative treatment for unresectable patients with cholangiocarcinoma (CCA). However, drug resistance is a major cause of the failure of this treatment. Derrischalcone (DC), a novel chalcone isolated from Derris indica fruit, has been shown pharmacologically active; though, the effect of DC on CCA is unknown. The present study investigated the cytotoxic, antiproliferative, anti-migration, and anti-invasion effects and underlying mechanisms of DC on CCA KKU-M156 and KKU-100 cells. Cytotoxicity and apoptosis were evaluated by acridine orange and ethidium bromide fluorescent staining. Reactive oxygen species (ROS) was measured by dihydroethidium assay. Cell proliferation and reproductive cell death were assessed by sulforhodamine B staining and colony-forming assay. Migration and invasion were determined by wound healing and transwell chamber assays. Protein expressions associated with cell death, proliferation, migration, and invasion were analyzed by western immunoblotting. We found that DC induced cytotoxicity and apoptosis in association with ROS formation and oxidative stress. Treatment with N-acetylcysteine suppressed ROS formation and attenuated DC-induced cytotoxic and apoptotic effects. DC increased the expression of p53, p21, Bax, and cytochrome c proteins in association with cell death. DC-induced antiproliferation, colony formation, anti-migration, and anti-invasion were associated with the suppression of Akt/mTOR/cyclin D1 and FAK signaling pathways. These findings suggest that the multi-targeting strategies with DC may be a novel treatment for cancer therapy.

Candidone Inhibits Migration and Invasion, and Induces Apoptosis in HepG2 Cells.

The aim of the study was to investigate the inhibitory activity of candidone, the active constituent of Derris (D.) indica, on the proliferation, migration, and invasiveness of human hepatoblastoma (HepG2) cells. Cancer cell death was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis-associated morphological changes were observed by phase contrast microscopy. Additionally, Western blotting was used to study protein expression following treatment with candidone, and transwell migration and invasion assays were used for observing cancer cell migration and invasiveness, respectively. The results suggest that candidone possesses potent inhibitory activity against HepG2 cells (concentration, 100 µM; 24 h treatment). Cancer cells treated with candidone exhibited apoptosis-associated changes, including detachment, cell shrinkage and death. Furthermore, candidone was shown to promote cell death by activating caspase-3 and -9, and decreasing the expression of antiapoptotic proteins, including p65, induced myeloid leukemia cell differentiation protein Mcl-1, B-cell lymphoma 2 (Bcl2), Bcl2-associated agonist of cell death and survivin. Moreover, candidone inhibited the migration and invasion abilities of HepG2 cells and decreased the levels of proteins associated with these processes, including phospho-p38 and active matrix metallopeptidase 9. Collectively, the results of the present study indicate that candidone is able to inhibit the proliferation, migration and invasive potential of HepG2 cells.

Cytotoxicity of acylphloroglucinol derivatives from the fruits of Horsfieldia irya.

Four new acylphloroglucinol derivatives 1, 3, 5 and 13 were isolated from the fruits of Horsfieldia irya, and in addition, thirteen known compounds were also discovered. All compounds were evaluated for cytotoxicity against HeLa and HCT116 cell lines, as well as normal cells (Vero cells). Compound 13 showed cytotoxicity against HeLa and HCT116 cell lines with IC50 values of 4.53 ± 0.05 and 4.53 ± 0.16 µg/mL, respectively, and showed less activity against normal cells (IC50 = 13.38 ± 0.75 µg/mL). Compound 13 may be useful for the development of anticancer agents. It was found that decanoyl side chain may be necessary for the cytotoxicity. The chemical structures of all isolated compounds were elucidated using spectroscopic methods including 1 D-NMR, 2 D-NMR, MS and IR data.

Structure-Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer's Disease.

Coumarins, naturally occurring phytochemicals, display a wide spectrum of biological activities by acting on multiple targets. Herein, nine coumarins from the root of Toddalia asiatica were evaluated for activities related to pathogenesis of Alzheimer's disease (AD). They were examined for acetylcholinesterase (AChE) and AChE- or self-induced amyloid beta (Aß) aggregation inhibitory activities, as well as neuroprotection against H2O2- and Aß1-42-induced human neuroblastoma SH-SY5Y cell damage. Moreover, in order to understand the mechanism, the binding interactions between coumarins and their targets: (i) AChE and (ii) Aß1-42 peptide were investigated in silico. All coumarins exhibited mild to moderate AChE and self-induced Aß aggregation inhibitory actions. In addition, the coumarins substituted with the long alkyl chain at position 6 or 8 illustrated ability to inhibit AChE-induced Aß aggregation, resulting from their dual binding site at catalytic anionic site and peripheral active site in AChE. Moreover, the most potent multifunctional coumarin, phellopterin, could attenuate neuronal cell damage induced by H2O2 and Aß1-42 toxicity. Conclusively, seven out of nine coumarins were identified as multifunctional agents inhibiting the pathogenesis of AD. The structure-activity relationship information obtained might be applied for further optimization of coumarins into a useful drug which may combat AD.

Influence of side-chain changes on histone deacetylase inhibitory and cytotoxicity activities of curcuminoid derivatives.

Using curcuminoids as lead compounds, fifty-nine curcuminoid derivatives with different side chains at the phenolic moiety were synthesized. All compounds were investigated for their histone deacetylase (HDAC) inhibitory activities. The potent pan-HDAC inhibitors were further tested against three human cancer cell lines including Hela, HCT116 and MCF-7 with MTT-based assay. The bisethylamide 4z and the mono-sec-butyl derivative 5j manifested good antiproliferative activities against HCT116 cancer cells with the IC50 values as 14.60 ± 1.19 µg/mL and 7.33 ± 0.98 µg/mL, respectively. Molecular docking study of both compounds with Class I HDACs revealed that the compounds might bind tightly to the binding pocket of HDAC2. These findings suggested that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.

Atalantums H-K from the peels of Atalantia monophylla and their cytotoxicity.

Four new benzoyltyramines, atalantums H-K (1-4) and seven known compounds were isolated from the peels of Atalantia monophylla. All compounds were tested for cytotoxicity against HeLa, HCT116 and MCF-7 cell lines, as well as normal cells (Vero cells). Compound 5 showed cytotoxicity against HeLa, HCT116 and MCF-7 cell lines with IC50 values ranging from 16-25 µg/mL but was inactive against Vero cells. Compound 6 also showed interesting results as compound 5 with IC50 values ranging from 15-18 µg/mL and an IC50 value of 80.20 µg/mL against Vero cells. This means compounds 5 and 6 can be used as lead compounds for anticancer agents.