Two new flavonols from Macaranga inermis pax & K.Hoffm.

Four isoprenylated flavonols, including two new compounds, macainermisins A-B (1-2), and two known compounds, sinoflavonoid P (3), broussoflavonol F (4), were isolated from the leaves of Macaranga inermis. A combination of HRESIMS, UV, 1D, and 2D NMR spectra elucidated the structures of 1-2. Flavonols (1-4) were evaluated against three cancer cells. Compound 1 showed high cytotoxicity against WiDR with an IC50 value of 0.93 µM, and compound 2 was active towards HeLa and WiDR (IC50 values of 0.90 and 0.94 µM), and compound 3 showed high activity towards 4T1 and HeLa (IC50 values of 0.83 and 0.98 µM).

Genoprotective potential of Macaranga species phytochemical compounds on HT-29 human colorectal adenocarcinoma cell line.

BACKGROUND: The species of genus Macaranga are widely found in Malaysian secondary forests and has been used as an alternative for treating varieties of illness. Studies have shown that the medicinal properties of this genus contain anti-inflammatory, antioxidant, and anti-cancer effects. This study aimed to determine the cytotoxicity of six isolated phytochemicals from Macaranga heynei (M. heynei), Macaranga lowii and Shorea leprosula on HT-29 human colorectal adenocarcinoma cell lines. RESULTS: One out of six isolated phytochemical compounds, identified as "Laevifolin A", showed a cytotoxicity with an IC50 value of 21.2 µM following 48 h treatment as detected using Sulforhodamine B (SRB) assay. Additionally, no induction of apoptosis and oxidative stress were observed on Laevifolin A treated HT-29 cells as determined using Annexin V-FITC/PI assay and dihydroethidine (HE) staining, respectively. Additionally, no damage to the DNA were observed as measured using the Alkaline Comet assay. Further investigation on menadione-induced oxidative DNA damage showed the genoprotective potential of Laevifolin A on HT-29 cells. CONCLUSIONS: In conclusion, this study indicated that only one compound (Laevifolin A) that extracted from M. heynei has the cytotoxicity potential to be developed as an anticancer agent in human colorectal adenocarcinoma. However, besides exhibiting cytotoxic effect, the compound also exhibits genoprotective capability that warrant further investigation.

Mutagenic Study of Benzimidazole Derivatives with (+S9) and without (-S9) Metabolic Activation.

Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential mutagenic activities of novel benzimidazole derivatives 1-4 using the Ames test and to study their structure-activity relationship (SAR). An Ames test was carried out on two strains of Salmonella typhimurium (TA98 and TA100) in the absence and presence of metabolic activation. Genetic analysis was performed prior to the Ames test to determine the genotypes of the bacterial tester strains. Both bacterial strains showed dependency on histidine with the presence of rfa mutation, uvrB deletion, and plasmid pKM101. Further, all derivatives tested showed no mutagenic activity in the absence of metabolic activation in both tester strains. However, in the presence of metabolic activation, compound 1 appeared to induce mutation at 2.5 µg/plate when tested against the TA98 strain. These results suggest that the absence of the -OH group at the ortho-position over the phenyl ring might be the cause of increased mutagenic activity in compound 1. Additionally, the presence of mutagenic activity in compound 1 when it was metabolically activated indicates that this compound is a promutagen.

Ampelopsin E Reduces the Invasiveness of the Triple Negative Breast Cancer Cell Line, MDA-MB-231.

Breast cancer is the most common and the second leading cause of cancer-related deaths in women. It has two distinctive hallmarks: rapid abnormal growth and the ability to invade and metastasize. During metastasis, cancer cells are thought to form actin-rich protrusions, called invadopodia, which degrade the extracellular matrix. Current breast cancer treatments, particularly chemotherapy, comes with adverse effects like immunosuppression, resistance development and secondary tumour formation. Hence, naturally-occurring molecules claimed to be less toxic are being studied as new drug candidates. Ampelopsin E, a natural oligostilbene extracted from Dryobalanops species, has exhibited various pharmacological properties, including anticancer and anti-inflammatory activities. However, there is yet no scientific evidence of the effects of ampelopsin E towards metastasis. Scratch assay, transwell migration and invasion assays, invadopodia and gelatin degradation assays, and ELISA were used to determine the effects of ampelopsin E towards the invasiveness of MDA-MB-231 cells. Strikingly in this study, ampelopsin E was able to halt migration, transmigration and invasion in MDA-MB-231 cells by reducing formation of invadopodia and its degradation capability through significant reduction (p < 0.05) in expression levels of PDGF, MMP2, MMP9 and MMP14. In conclusion, ampelopsin E reduced the invasiveness of MDA-MB-231 cells and was proven to be a potential alternative in treating TNBC.

A comparative study on foliage and peels of Hylocereus undatus (white dragon fruit) regarding their antioxidant activity and phenolic content.

Hylocereus undatus foliage is believed to contain antioxidants similar to its peel. Numerous studies have been conducted to determine the total phenolic content (TPC) and antioxidant activity on the Hylocereus undatus pulps and peels; however, similar studies on its foliage have yet to be investigated. In this study, Hylocereus undatus foliage and peels were extracted using two different solvents namely; chloroform and methanol through Folin-Ciocalteu method and Diphenyl-1-Ipicrylhydrazyl (DPPH) free radical scavenging assay for TPC and antioxidant activity, respectively. As for TPC, results revealed that the peels gave higher TPC in both methanol (48.15 mg GAE/100g extract) and chloroform (18.89 mg GAE/100g extract) extractions than foliage (30.3 mg GAE/100g extract and 5.92 mg GAE/100g extract, respectively). However, when a comparison was made between foliage and peels in terms of its scavenging effects in DPPH assay, the peels contained more antioxidants (18.71%) than foliage (38.3%) in the chloroform solvent extracts. This study shows that Hylocereus undatus foliage has a similar antioxidant activity as its peels and is potentially a natural antioxidant in food applications.

Synthesis of Bis-indolylmethane sulfonohydrazides derivatives as potent α-Glucosidase inhibitors.

In search of better α-glucosidase inhibitors, a series of bis-indolylmethane sulfonohydrazides derivatives (1-14) were synthesized and evaluated for their α-glucosidase inhibitory potential. All derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 0.10 ±â€¯0.05 to 5.1 ±â€¯0.05 µM when compared with standard drug acarbose having IC50 value 856.28 ±â€¯3.15 µM. Among the series, analog 7 (0.10 ±â€¯0.05 µM) with tri-chloro substitution on phenyl ring was identified as the most potent inhibitor of α-glucosidase (∼ 8500 times). The structure activity relationship has been also established. Molecular docking studies were also performed to help understand the binding interaction of the most active analogs with receptors. From the docking studies, it was observed that all the active bis-indolylmethane sulfonohydrazides derivatives showed considerable binding interactions within the active site (acarbose inhibition site) of α-glucosidase. We also evaluated toxicity of all derivatives and found none of them are toxic.

Synthesis: Small library of hybrid scaffolds of benzothiazole having hydrazone and evaluation of their ß-glucuronidase activity.

Due to the great biological importance of ß-glucuronidase inhibitors, here in this study, we have synthesized a library of novel benzothiazole derivatives (1-30), characterized by different spectroscopic methods and evaluated for ß-glucuronidase inhibitory potential. Among the series sixteen compounds i.e.1-6, 8, 9, 11, 14, 15, 20-23 and 26 showed outstanding inhibitory potential with IC50 value ranging in between 16.50 ±â€¯0.26 and 59.45 ±â€¯1.12 when compared with standard d-Saccharic acid 1,4-lactone (48.4 ±â€¯1.25 µM). Except compound 8 and 23 all active analogs showed better potential than the standard. Structure activity relationship has been established.

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies.

Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ±â€¯0.01 to 18.50 ±â€¯0.90 µM when compared with the standard inhibitor thiourea having IC50 value 21.25 ±â€¯0.90 µM. Among the series, analog 9 (0.14 ±â€¯0.01 µM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.

Synthesis of bis-indolylmethanes as new potential inhibitors of ß-glucuronidase and their molecular docking studies.

Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1-32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for ß-glucuronidase inhibitory potential. All analogs showed varying degree of ß-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 µM when compared with the standard drug d-saccharic acid-1,4-lactone (IC50 value 48.30 ± 1.20 µM). Derivatives 1-32 showed the highest ß-glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of ß-glucuronidase enzyme. This study has culminated in the identification of a new class of potent ß-glucuronidase inhibitors.

Synthesis, molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor.

Thiourea derivatives having benzimidazole 1-17 have been synthesized, characterized by 1H NMR, 13C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker's yeast α-glucosidase enzyme. Compounds 1-17 exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 35.83±0.66 and 297.99±1.20µM which are more better than the standard acarbose (IC50=774.5±1.94µM). Compound 10 and 14 showed significant inhibitory effects with IC50 value 50.57±0.81 and 35.83±0.66µM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.

Medicinal uses, chemistry and pharmacology of Dillenia species (Dilleniaceae).

The genus Dillenia is comprised of about 100 species of evergreen and deciduous trees or shrubs of disjunct distribution in the seasonal tropics of Madagascar through South and South East Asia, Malaysia, North Australia, and Fiji. Species from this genus have been widely used in medicinal folklore to treat cancers, wounds, jaundice, fever, cough, diabetes mellitus, and diarrhea as well as hair tonics. The plants of the genus also produce edible fruits and are cultivated as ornamental plants. Flavonoids, triterpenoids, and miscellaneous compounds have been identified in the genus. Their extracts and pure compounds have been reported for their antimicrobial, anti-inflammatory, cytotoxic, antidiabetes, antioxidant, antidiarrheal, and antiprotozoal activities. Mucilage from their fruits is used in drug formulations.

Induction of apoptosis and G2/M arrest by ampelopsin E from Dryobalanops towards triple negative breast cancer cells, MDA-MB-231.

BACKGROUND: Several compounds isolated from Dryobalanops have been reported to exhibit cytotoxic effects to several cancer cell lines. This study investigated the cytotoxic effects, cell cycle arrest and mode of cell death in ampelopsin E-treated triple negative cells, MDA-MB-231. METHODS: Cytotoxicity of ampelopsin E, ampelopsin F, flexuosol A, laevifonol, Malaysianol A, Malaysianol D and nepalensinol E isolated from Dryobalanops towards human colon cancer HT-29, breast cancer MDA-MB-231 and MCF-7, alveolar carcinoma HeLa and mouse embryonic fibroblast NIH/3 T3 cells were determined by MTT assay. The cells were treated with the compounds (0.94-30 µM) for 72 h. The mode of cell death was evaluated by using an inverted light microscope and annexin V/PI analysis. Cell cycle analysis was performed by using a flow cytometer. RESULTS: Data showed that ampelopsin E was most cytotoxic toward MDA-MB-231 with the IC50 (50 % inhibition of cell viability compared to control) of 14.5 ± 0.71 µM at 72 h. Cell shrinkage, membrane blebbing and formation apoptotic bodies characteristic of apoptosis were observed following treatment with ampelopsin E. The annexin V/PI flow cytometric analysis further confirmed that ampelopsin E induced apoptosis in MDA-MB-231 cells. Cell cycle analysis revealed that ampelopsin E induced G2/M phase cell cycle arrest in the cells. CONCLUSION: Ampelopsin E induced apoptosis and cell cycle arrest in MDA-MB-231 cells. Therefore, ampelopsin E has the potential to be developed into an anticancer agent for treatment of triple negative breast cancer.

Synthesis of novel disulfide and sulfone hybrid scaffolds as potent ß-glucuronidase inhibitor.

Novel series of disulfide and sulfone hybrid analogs (1-20) were synthesized and characterized through EI-MS and (1)H NMR and evaluated for ß-glucuronidase inhibitory potential. All synthesized analogs except 13 and 15 showed excellent ß-glucuronidase inhibitory potential with IC50 value ranging in between 2.20-88.16µM as compared to standard d-saccharic acid 1,4 lactone (48.4±1.25µM). Analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2, 11, 14 and 5 showed many fold potent activity against ß-glucuronidase inhibitor. Structure activity relationship showed that substitution of electron withdrawing groups at ortho as well as para position on phenyl ring increase potency. Electron withdrawing groups at meta position on phenyl ring showed slightly low potency as compared to ortho and para position. The binding interactions were confirmed through molecular docking studies.

Benzimidazole derivatives as new α-glucosidase inhibitors and in silico studies.

Newly synthesized benzimidazole hydrazone derivatives 1-26 were evaluated for their α-glucosidase inhibitory activity. Compounds 1-26 exhibited varying degrees of yeast α-glucosidase inhibitory activity with IC50 values between 8.40 ± 0.76 and 179.71 ± 1.11 µM when compared with standard acarbose. In this assay, seven compounds that showed highest inhibitory effects than the rest of benzimidazole series were identified. All the synthesized compounds were characterized by different spectroscopic methods adequately. We further evaluated the interaction of the active compounds with enzyme with the help of docking studies.

Synthesis, in vitro evaluation and molecular docking studies of biscoumarin thiourea as a new inhibitor of α-glucosidases.

Biscoumarin analogs 1-18 have been synthesized, characterized by EI-MS and (1)H NMR and evaluated for α-glucosidase inhibitory potential. All compounds showed variety of α-glucosidase inhibitory potential ranging in between 13.5±0.39 and 104.62±0.3µM when compared with standard acarbose having IC50 value 774.5±1.94µM. The binding interactions of the most active analogs were confirmed through molecular docking. The compounds showed very good interactions with enzyme. All synthesized compounds 1-18 are new. Our synthesized compounds can further be studied to developed lead compounds.

Benzimidazole derivatives protect against cytokine-induced apoptosis in pancreatic ß-Cells.

Apoptotic cell death is the cause of the loss of insulin-producing ß-cells in all forms of diabetes mellitus. The identification of small molecules capable of protecting cytokine-induced apoptosis could form the basis of useful therapeutic interventions. Here in, we present the discovery and synthesis of new benzimidazole derivatives, capable of rescuing pancreatic ß-cells from cytokine-induced apoptosis. Three hydrazone derivatives of benzimidazole significantly increased the cellular ATP levels, reduced caspase-3 activity, reduced nitrite production and increased glucose-stimulated insulin secretion in the presence of proinflammatory cytokines. These findings suggest that these compounds may protect ß-cells from the harmful effects of cytokines and may serve as candidates for therapeutic intervention for diabetes.

Novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone: a new class of ß-glucuronidase inhibitors and in silico studies.

A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as ß-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4±1.25µM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies.

Inhibitory effect of triterpenoids from Dillenia serrata (Dilleniaceae) on prostaglandin E2 production and quantitative HPLC analysis of its koetjapic acid and betulinic acid contents.

The crude methanol extracts and fractions of the root and stem barks of Dillenia serrata Thunb. showed 64% to 73% inhibition on the production of prostaglandin E2 (PGE2) in lipopolysaccharide-induced human whole blood using a radioimmunoassay technique. Three triterpenoids isolated from the root bark of the plant, koetjapic (1), 3-oxoolean-12-en-30-oic (2), and betulinic (3) acids, exhibited significant concentration-dependent inhibitory effects on PGE2 production with IC50 values of 1.05, 1.54, and 2.59 µM, respectively, as compared with the positive control, indomethacin (IC50 = 0.45 µM). Quantification of compounds 1 and 3 in the methanol extracts and fractions were carried out by using a validated reversed-phase high performance liquid chromatography (RP-HPLC) method. The ethyl acetate fraction of the stem bark showed the highest content of both compound 1 (15.1%) and compound 3 (52.8%). The strong inhibition of the extracts and fractions on cyclooxygenase-2 (COX-2) enzymatic activity was due to the presence of their major constituents, especially koetjapic and betulinic acids.

A new symmetrical tetramer oligostilbenoid containing tetrahydrofuran ring from the stem bark of Dryobalanops lanceolata.

A new tetramer oligostilbenoid possessing tetrahydrofuran ring, malaysianol C (1), was isolated from the acetone extract of the stem bark of Dryobalanops lanceolata, together with four known oligostilbenoids nepalensinol E (2), ϵ-viniferin (3), laevifonol (4), and ampelopsin F (5). The structures of isolated compounds were elucidated on the basis of spectral evidence. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay, whereas the cytotoxic activity was tested using MTT assay. The plausible biogenetic routes of the isolated compounds are also discussed.

Synthesis, crystal structure, DFT studies and evaluation of the antioxidant activity of 3,4-dimethoxybenzenamine schiff bases.

Schiff bases of 3,4-dimethoxybenzenamine 1-25 were synthesized and evaluated for their antioxidant activity. All the synthesized compounds were characterized by various spectroscopic techniques. In addition, the characterizations of compounds 13, 15 and 16 were supported by crystal X-ray determinations and their geometrical parameters were compared with theoretical DFT calculations at the B3LYP level of theory. Furthermore, the X-ray crystal data of two non-crystalline compounds 8 and 18 were theoretically calculated and compared with the practical values of compounds 13, 15, 16 and found a good agreement. The compounds showed good DPPH scavenging activity ranging from 10.12 to 84.34 µM where compounds 1-4 and 6 showed stronger activity than the standard n-propyl gallate. For the superoxide anion radical assay, compounds 1-3 showed better activity than the standard.