Synthesis and in vitro cytotoxic evaluation of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid

A series of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed and synthesized as potent antitumor agents. Structures of the target molecules were characterized using MS, IR, ¹H NMR, ¹³C NMR and elemental analyses. In the in vitro cytotoxic assay, most compounds showed significant cytotoxic activities against two hepatocarcinoma cells (SMMC-7721 and HepG2) and reduced cytotoxicity against noncancerous human hepatocyte (LO2). Among them, compound 7b exhibited the best cytotoxicity against SMMC-7721 cells (IC₅₀: 0.36 ± 0.13 μM), while 7e was most potent to HepG2 cells (IC₅₀: 0.12 ± 0.03 μM). The cell cycle analysis indicated that compound 7b caused cell cycle arrest of SMMC-7721 cells at G2/M phase. Further, compound 7b also induced the apoptosis of SMMC-7721 cells in Annexin V-APC/7-AAD binding assay.     

Cytotoxic clerodane diterpenoids from Croton crassifolius

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and treatment options for HCC are limited. In addition, the discovery of new natural compounds with anti-hepatocarcinoma activity is attracting increasing attention. For this reason, phytochemical investigation of Croton crassifolius led to the isolation of 17 diterpenoids, including three new clerodane diterpenoids, named crassifolius A-C (1–3), along with 14 known ones (4–17). Their structures were established by 1D, 2D NMR, HR-ESI-MS, detailed calculated electronic circular dichroism (ECD) spectra and the assistance of quantum chemical predictions (QCP) of ¹³C NMR chemical shifts. The cytotoxicities of all these compounds against human liver cancer lines (HepG2 and Hep3B) were determined. Among them, compound 1 exhibited good cytotoxicity with IC₅₀ value of 17.91 μM against human liver tumor cells Hep3B. Following further studies of the anti-tumor mechanism of compound 1-induced cell growth inhibition, we found that compound 1 caused apoptotic cell death in Hep3B cells by detecting morphologic changes and Western blotting analysis.     

Design and synthesis of 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase

Novel 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives 12a–n were designed and prepared through an intramolecular cyclization reaction and evaluated for in vitro anticancer activity. Among the synthesized compounds, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (12e) displayed potent cytotoxicity against several different tumor cell lines at a sub-micromolar level. Furthermore, results of fluorescence-activated cell sorting (FACS) analysis suggested that 12e induced cell cycle arrest in the G2/M phase accompanied by apoptosis in HL-60 and H460 cells. This action was confirmed by Hoechst staining and caspase-3 activation. Due to their easy synthesis and remarkable biological activities, 4-phenylquinolin-2(1H)-one analogs (4-PQs) are promising new anticancer leads based on the quinoline scaffold. Accordingly, compound 12e was identified as a new lead compound that merits further optimization and development as an anticancer candidate.     

Investigation of chemical constituents from Spiraea prunifolia var. simpliciflora and their biological activities

Quantum mechanics (QM)-based calculations for elucidating full structures of natural compounds are growing in importance and reliability. Two new phenolic glycosides (1 and 2) and 11 known compounds were isolated from the twigs of Spiraea prunifolia var. simpliciflora. The chemical structures of the new compounds (1 and 2) were initially established through different NMR techniques (¹H and ¹³C NMR, COSY, HSQC, and HMBC), HRMS data analysis, and chemical hydrolysis. These structure assignments were further verified by QM-based NMR chemical shift calculations. All of the purified compounds (1–13) were evaluated for their cytotoxicity against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and BT549). Those phytochemicals were also evaluated for both anti-inflammatory activity through the measurement of nitric oxide (NO) production levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cell lines and neuroprotective effects via induction of nerve growth factor (NGF) in C6 glioma cells.     

AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia

Pyrazole moiety represents an important category of heterocyclic compound in pharmaceutical and medicinal chemistry. The novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives were synthesized with complementary regioselectivity. The chemical structures were confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectral analysis. The chemical entities were screened in various cancer cell lines to assess their cell viability activity. Results showed that the compound 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl) pyridine (5d) possessed maximum cytotoxic effect against breast cancer and leukemic cells. The cytotoxicity was confirmed by live–dead cell assay and cell cycle analysis. Mitochondrial membrane potential, Annexin V-FITC staining, DNA fragmentation, Hoechst staining, and western blot assays revealed the ability of compound 5d to induce cell death by activating apoptosis in cancer cells. Thus, the present study demonstrates that compound 5d could be an attractive chemical entity for the development of small molecule inhibitors for treatment of leukemia and breast cancer.     

New tirucallane triterpenoids from Picrasma quassioides with their potential antiproliferative activities on hepatoma cells

Seven new tirucallane-type triterpenoids (1–7), kumuquassin A-G, along with 20 known analogues (8–27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ^{17, 20} double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Design,synthesis and evaluation of novel (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit as anticancer agents

A series of (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit were designed, synthesized and evaluated for their potential application as anticancer agents. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against HepG2, HeLa, CNE1 and A549 human cancer cell lines. Some of the synthesized compounds showed moderate to good anticancer activities against four selected cancer cell lines, among of which 6ag was found to be the most active analogue possessing IC₅₀ values 16.5–18.7?μM. Further mechanism studies revealed that compound 6ag could significantly induce HepG2 cell cycle arrest at G1 phase, promote cell apoptosis, and inhibit the colony formation as well.     

Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin

A series of novel coumarin-cyclic imide conjugates (1a–1j) were designed and synthesized to evaluate their glucose uptake activity by insulin resistant liver hepatocyte carcinoma (HepG2) cells through 2-NBDG uptake assay. Compounds (1a–1j) were characterised using various analytical methods such as ¹H NMR, ¹³C NMR, IR, GC–MS, elemental and single-crystal X-ray diffraction techniques. Compounds (1a–1j) exhibited 85.21 – 65.80% of glucose uptake and showed low level of cytotoxicity towards human embryonic kidney cells (HEK-293) indicating good selectivity and safety profile. Compound 1f was identified as a hit candidate exhibiting 85.21% of glucose uptake which was comparable with standard antidiabetic drug Metformin (93.25% glucose uptake). Solution stability study under physiological pH conditions ≈ (3.4 – 8.7), indicates that compound 1f is sufficiently stable at varied pH conditions and thereby compatible with bio-physiological environments. Interaction of 1f with human serum albumin (HSA) were also studied which quantifies that compound 1f binds with HSA efficiently through facile binding reaction in solution. Fluorescence, UV–vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1f with protein.     

New bis-thioglycosyl-1,1′-disulfides from Nasturtium officinale R. Br. and their anti-neuroinflammatory effect

As a part of our continuing search for bioactive constituents from Brassicaceae family, three new bis-thioglycosides (1–3) were isolated from the 80% MeOH extract of Nasturtium officinale, together with 13 known compounds (4–16). The chemical structures of three new bis-thioglycosides (1–3) were elucidated using NMR techniques (¹H and ¹³C NMR, ¹H–¹H COSY, HSQC, and HMBC), HRESIMS, and a chemical method. All the compounds were evaluated for their inhibitory effects on nitric oxide (NO) levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Among the isolates, compound 5 exhibited a strong inhibitory effect on NO production, and compounds 4 and 15 showed moderate inhibitory activities, suggesting the neuroprotective and anti-neuroinflammatory effects of bis-thioglycosides from N. officinale.     

Synthesis,crystal structure and biological evaluation of a main group seven-coordinated bismuth(III) complex with 2-acetylpyridine N4-phenylthiosemicarbazone

Up to now, bismuth(III) complexes with thiosemicarbazones have been comparatively rare. Here, a main group seven-coordinated bismuth(III) complex [Bi(L)(NO₃)₂(CH₃CH₂OH)] (1) (HL = 2-acetylpyridine N(4)-phenylthiosemicarbazone) has been synthesized and characterized by elemental analysis, IR, ¹H NMR and single-crystal X-ray diffraction studies. The cytotoxicity data suggest that 1 exhibits higher in vitro antiproliferative activity in four human cancer cells tested. Its possible apoptotic mechanism has been evaluated in HepG2 cells. Compound 1 promotes a dose-dependent apoptosis in HepG2 cells and the apoptosis is associated with an increase in intracellular reactive oxygen species (ROS) production and reduction of mitochondrial membrane potential (MMP).     

Synthesis,biological evaluation and molecular docking studies of a new series of chalcones containing naphthalene moiety as anticancer agents

A series of chalcones containing naphthalene moiety 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro anticancer activity. The majority of the screened compounds displayed potent anticancer activity against both HCT116 and HepG2 human cancer cell lines. Among the series, compound 4h with a diethylamino group at the para position of the phenyl ring exhibited the most potent anticancer activity against HCT116 and HepG2 cell lines with IC₅₀ values of 1.20 ± 0.07 and 1.02 ± 0.04 μM, respectively. The preliminary structure–activity relationship has been summarized. Tubulin polymerization experiments indicated that 4h effectively inhibited tubulin polymerization and flow cytometric assay revealed that 4h arrests HepG2 cells at the G2/M phase in a dose-dependent manner. Furthermore, molecular docking studies suggested that 4h binds to the colchicine binding site of tubulin.     

Synthesis and an angiolytic role of novel piperazine–benzothiazole analogues on neovascularization,a chief tumoral parameter in neoplastic development

A novel series of benzoic acid N′-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a–j were synthesized and characterized by IR, ¹H, ¹³C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a–j were evaluated against Dalton’s lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis.     

Triterpenoids and triterpenoid saponins from the aerial parts of Fagonia indica Burm

As part of our search of new bioactive compounds from indigenous medicinal plants, phytochemical investigation of the aerial parts of Fagonia indica Burm led to the isolation of seven compounds including two new compounds, namely, indicacin (1) and fagonicin (2), and five known compounds (3–7) from the methanol extract. Compounds 6 and 7 are hitherto unreported from this plant. The structures of the new compounds were elucidated from their spectral data, mainly HREIMS, 1D NMR (¹H, ¹³C NMR, and DEPT) and 2D NMR (COSY, NOESY, HSQC and HMBC), and by comparison with the literature data. The new compounds 1 and 2 were assayed for their cytotoxicity against human colorectal cancer cell line H-29. Compound 1 exhibited 51.40% cytotoxicity at 6.25 μM/mL dose whereas compound 2 demonstrated 39.3% cytotoxicity at the same dose.     

Platachromone A–D: Cytotoxic 2-styrylchromones from the bark of Platanus × acerifolia (Aiton) Willd.

Four novel 2-styrylchromones, 4′,5,7-trihydroxy-6-isopentene-2-styrylchromone (1), 4′,5,7-trihydroxy-8-isopentene-2-styrylchromone (2), 4′,5,7-trihydroxy-6-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (3) and 4′,5,7-trihydroxy-8-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (4), were isolated from shed bark of Platanus × acerifolia (Aiton) Willd., as well as four known compounds, 4′,5,7-trihydroxy-2-styrylchromone (5), scutellarein (6), 4′,5,7-trihydroxy-6-prenylflavone (7), and 4′,5,7-trihydroxy-8-prenylflavone (8). The structures of compounds 1–4 were established by direct interpretation of their spectral data, mainly high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D NMR (¹H–¹H COSY, HSQC and HMBC). The cytotoxicity of the compounds 1–8 was evaluated in four human carcinoma cell lines, including HepG2, SMMC-7721, MDA-MB-231, and KB. Compounds 1–4 exhibited significantly cytotoxic activity toward HepG2 and KB cells, with IC₅₀ values ranging from 3.0 to 9.7 μM.     

Bioactive triterpenoids from twigs of Betula schmidtii

Investigation of the MeOH extract of Betula schmidtii twigs resulted in the isolation and identification of three new triterpenoids (1–3), along with ten known ones (4–13). The structures of new compounds (1–3) were elucidated by spectroscopic methods, including 1D, 2D NMR (¹H and ¹³C NMR, COSY, HSQC, HMBC, and NOESY), HR-MS, and chemical methods. All the isolated compounds were evaluated for their cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines. Compound 11 exhibited potent cytotoxic activities against four cell lines, and compounds 5 and 13 significantly induced nerve growth factor secretion in a C6 rat glioma cell line. Their anti-inflammatory effects were also assessed by measuring nitric oxide production in lipopolysaccharide–activated BV-2 cells. Compounds 7 and 12 displayed potent inhibition of nitric oxide production, without significant cell toxicity.     

Synthesis of novel isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives and their insecticidal/acaricidal activities

In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives were prepared, and their structures were well characterized by ¹H NMR, IR, optical rotation, HRMS and mp. Especially the structure of compound Ia was further confirmed by ¹H–¹H COSY and NOESY spectrum. Among them, two compounds showed good insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure–activity relationships were also observed.     

Synthesis,spectral and antimicrobial evaluation of some novel 1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates

Synthesis of some novel biologically active piperidin-4-one oxime carbonates from 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes and substituted chloroformates was carried out in the presence of potassium carbonate as base and tetrabutylammonium bromide (TBAB) as catalyst. The newly synthesized compounds were characterized by IR, ¹H, ¹³C NMR and LC–mass spectra. Based on the ¹H NMR analysis, all the compounds were found to adopt normal chair conformation with equatorial orientation of all the substituents. For all the synthesized compounds (5a–5l) antimicrobial activity has been tested against bacterial and fungal strains using Streptomycin and Amphotericin B as standards.     

Enantiomeric neolignans from Picrasma quassioides exhibit distinctive cytotoxicity on hepatic carcinoma cells through ROS generation and apoptosis induction

Three pairs of enantiomeric neolignans 1a/1b–3a/3b were isolated from the stems of Picrasma quassioides, and separated successfully by chiral-phase HPLC. Their structures were established by comprehensive spectroscopic analyses as well as ECD spectroscopy. The in vitro cytotoxicity of the isolates was evaluated against human hepatocellular carcinoma HepG2 and Hep3B cells. Among them, 1 and its enantiomers 1a/1b, 3 and 3a/3b displayed similar cytotoxicity in pair-wise comparison against HepG2 and Hep3B cells, and the similar effects of 2 and 2a/2b were found in Hep3B cells. Interestingly, 2a and 2b had different cytotoxic activities on HepG2 cells with IC₅₀ values of 35.6?μM and 104.4?μM, respectively. In addition, 2 exerted middle cytotoxicity against HepG2 cells with an IC₅₀ value of 78.6?μM. The different cytotoxicity between enantiomers 2a and 2b attracted our interest. To investigate the underlying mechanisms responsible for the distinct cytotoxicity, we further assessed the effects of 2a and 2b on cell cycle distribution, cell apoptosis and reactive oxygen species (ROS) generation. The results indicated that 2a had more significant effect than 2b on apoptosis induction and ROS generation, but both had no obvious effect on cell cycle of HepG2 cells. It is concluded that the different configurations of 2a/2b determined the enantioselective cytotoxicity on HepG2 cells through apoptosis induction and ROS generation.     

Cytotoxic metabolites from the leaves of the mangrove Rhizophora apiculata

One new 8,4’-oxyneolignan (1) and one new 7,8-dihydrobenzofuranone (2), together with twenty-one known compounds (3‒23) were isolated from the methanol extract of Rhizophora apiculata leaves. The structures of new compounds, as well as their absolute configuration, were determined by a combination of spectroscopic methods and quantum chemical calculations of NMR and ECD data. All isolated compounds were evaluated for their cytotoxicity, and only 2,6-dimethoxy-1,4-benzoquinone (8) exhibited inhibitory effects against SK-LU-1, HepG2, and MCF7 cells with IC₅₀ values in the range of 8.33–14.82 μM.