Solvothermal Synthesis of Multiple Dihydropyrimidinones at a Time as Inhibitors of Eg5

Solvothermal synthesis of multiple dihydropyrimidinones at a time has been developed in inexpensive and green bio-based solvent lactic acid without any additional catalysts or additives. By this method, thirty new dihydropyrimidinone derivatives were synthesized in two batches and characterized. All of the compounds were screened by Eg5 motor protein ATPase assay, and the positive compounds were tested against the Caco-2 cell line, HeLa cell line, L929 cell line and T24 cell line in vitro. Among them, compound C9 exhibited the best inhibitory activity against motor protein ATPase with an IC₅₀ value of 30.25 μM and significant cytotoxic activity in the micromolar range against the cells above. The Lineweaver–Burk plot revealed that compound C9 was a mixed-type Eg5 inhibitor. A molecular modeling study using the Discovery Studio program was performed, where compound C9 exhibited good binding interaction with Eg5 motor protein ATPase, and this was consistent with the attained experimental results.     

Sartoryglabrins, analogs of ardeemins, from Neosartorya glabra

Chemical investigation of a collection of the fungus Neosartorya glabra from Thailand furnished sartoryglabins A-C (1a, 1b and 2) which are analogs of the reverse prenylated indole alkaloids known as (-) ardeemins. Structures of these compounds were established by NMR spectrometry and an X-ray analysis. Sartoryglabins A-C were evaluated for their in vitro growth inhibitory activity on three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma). All the compounds exhibited strong to moderate activity against the MCF-7 cell line but weak or no activity against the NCI-H460 and A375-C5 cell lines. Sartoryglabin B was found to exhibit selectivity towards the MCF-7 cell line.     

Novel bis(thiosemicarbazones) of the 3,5-diacetyl-1,2,4-triazol series and their platinum(II) complexes: chemistry, antiproliferative activity and preliminary nephrotoxicity studies

The preparation and characterization of three novel (4)N-monosubstituted bis(thiosemicarbazone) ligands of 3,5-diacetyl-1,2,4-triazol series and their dinuclear platinum complexes are described. The crystal and molecular structure of the [Pt(μ-H(3)L(3))](2) complex derived of 3,5-diacetyl-1,2,4-triazol bis((4)N-p-tolylthiosemicarbazone), H(5)L(3), has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumour properties since are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. The interactions of these compounds with calf thymus DNA was investigated by UV-vis absorption and a nephrotoxic study, in LLC-PK1 cells, has also been carried out.     

<em>Mesua beccariana </em>(Clusiaceae), A Source of Potential Anti-cancer Lead Compounds in Drug Discovery

An investigation on biologically active secondary metabolites from the stem bark of Mesua beccariana was carried out. A new cyclodione, mesuadione (1), along with several known constituents which are beccamarin (2), 2,5-dihydroxy-1,3,4-trimethoxy anthraquinone (3), 4-methoxy-1,3,5-trihydroxyanthraquinone (4), betulinic acid (5) and stigmasterol (6) were obtained from this ongoing research. Structures of these compounds were elucidated by extensive spectroscopic methods, including 1D and 2D-NMR, GC-MS, IR and UV techniques. Preliminary tests of the in vitro cytotoxic activities of all the isolated metabolites against a panel of human cancer cell lines Raji (lymphoma), SNU-1 (gastric carcinoma), K562 (erythroleukemia cells), LS-174T (colorectal adenocarcinoma), HeLa (cervical cells), SK-MEL-28 (malignant melanoma cells), NCI-H23 (lung adenocarcinoma), IMR-32 (neuroblastoma) and Hep-G2 (hepatocellular liver carcinoma) were carried out using an MTT assay. Mesuadione (1), beccamarin (2), betulinic acid (5) and stigmasterol (6) displayed strong inhibition of Raji cell proliferation, while the proliferation rate of SK-MEL-28 and HeLa were strongly inhibited by stigmasterol (6) and beccamarin (2), indicating these secondary metabolites could be anti-cancer lead compounds in drug discovery.     

Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity

The reaction of cyanoacetyl hydrazine (1) with 3-acetylpyridine (2) gave the hydrazide-hydrazone derivative 3. The latter compound undergoes a series of heterocyclization reactions to give new heterocyclic compounds. The antitumor evaluation of the newly synthesized products against three cancer cell lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) was performed. Most of the synthesized compounds showed high inhibitory effects.     

Synthesis,biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents

A series of dihydropyrimidine analogues were prepared via one-pot Biginelli three-component condensation reaction and characterized by NMR, FT-IR, MS spectra, and element analysis. Subsequently, they were screened for in vitro anticancer effect. These analogues revealed good cytotoxic activity against three human cancer cell lines including MCF-7, HepG-2, and A549. Among these analogues, compounds 4d and 4h were the most potent against three cell lines. Cell viability assays indicated 4a and 4c had lower cytotoxicity. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine contributed to the antiproliferative potency. Moreover, in silico molecular docking results stipulated a sign of good correlation between experimental activity and calculated binding affinity. It proved 4d and 4h as the strongest compounds. Binding modes of analogues proposed the involvement of hydrophobic interactions and hydrogen bonds with Eg5 active site. Structure activity relationship studies indicated that incorporating electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine are important for this biological activity.     

β-Lactam derivatives as potential anti-cancer compounds

A number of 1,4-diaryl-3-methylene substituted β-lactams, the addition products obtained from their reactions with N-, S-, and C-nucleophiles, and diverse related compounds were prepared, and a selection of 43 compounds was screened in preliminary tests as anti-tumor compounds by using 4 or 5 human cancer cell lines of diverse origins. Twelve compounds were highly active against all cell lines, 6 showed low activity, 12 no activity, and 13 exhibited a selective activity against a human small cell lung carcinoma cell line.     

Anti-lung Cancer Activity and Docking Study of Two Novel Isochroman Derivatives

Two new isochroman derivatives(1 and 2) were isolated from the fermentation products of mangrove endophytic fungus Phomopsis sp. 33#. Their structures were characterized by IR, ~1 H NMR, H RMS, and single-crystal X-ray crystallography. The anticancer activity of the two compounds was investigated against four human lung cancer cells(NCI-H292, NCI-H460, LTEP-A-2 and MSTO-211) by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide(MTT) assay. Furthermore, molecular docking studies supported the biological assay data, showing that compared with 1, compound 2 has stronger interaction with protein.     

Total synthesis and biological assessment of (-)-exiguolide and analogues

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.     

Novel synthesis and antitumor evaluation of polyfunctionally substituted heterocyclic compounds derived from 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide

The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with ethyl cyanoacetate gave 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide. The latter was used to synthesize different heterocyclic derivatives comprising thiophene, thiazole, pyrazole, pyridine, pyrimidine, and coumarin rings. The mechanistic and synthetic pathways depended on regioselective attack and/or cyclization by the cyanoacetamido moiety in the key precursor on various chemical reagents. The competition of the reaction pathways including dipolar cyclization, dinucleophilic-bielectrophilic attack, β-attack, Gewald-type attack, and condensation reactions led to the diversity of the synthesized products. The antitumor activities of the synthesized products were studied and evaluated. Most of the compounds revealed high inhibitory effects when screened in vitro for their antiproliferative activity. Three human cancer cell lines, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were used in the screening tests. The simplicity of the synthetic procedures which mainly involved one-pot reactions under mild reaction conditions, the convenience of yield production and the diversity of the reactive sites in the produced systems play a valuable role for further heterocyclic transformations and further biological investigations.     

Synthesis and cytotoxic activities of pyrrole[2,3-d]pyridazin-4-one derivatives

1-Methyl-2-phenyl (1) and 1,3-dimethyl-2-phenyl (2)-substituted pyrrole[2,3-d]pyridazinones, as well as their tetracyclic analogues 3-6, were synthesized and evaluated in vitro by the National Cancer Institute against 60 human tumor cell lines derived from nine cancer cell types. Biological results showed that the antitumor activities of these compounds were related to the planarity of their ring systems with potency increasing in the order 2<4 congruent with 5<6<3. Among them, the most potent compound 3 showed significant cell line cytotoxicity, particularly against the renal cancer subpanel [GI(50) (microM) 5.07] and displayed significant potency [GI(50) (microM) 3.04-4.32] against MOLT-4, SR (leukemia), NCI-H460 (non-small cell lung), HCT-116 (colon), and SF-295 (CNS) cancer cells, respectively.     

2,5-Bis(2,2,2-trifluoroethoxy)phenyl-tethered 1,3,4-Oxadiazoles Derivatives: Synthesis,In Silico Studies,and Biological Assessment as Potential Candidates for Anti-Cancer and Anti-Diabetic Agent

In the present work, a series of new 1-{5-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-3-acetyl-2-aryl-2H/methyl derivatives were synthesized through a multistep reaction sequence. The compounds were synthesized by the condensation of various aldehydes and acetophenones with the laboratory-synthesized acid hydrazide, which afforded the Schiff’s bases. Cyclization of the Schiff bases yielded 1,3,4-oxadiazole derivatives. By spectral analysis, the structures of the newly synthesized compounds were elucidated, and further, their anti-cancer and anti-diabetic properties were investigated. To examine the dynamic behavior of the candidates at the binding site of the protein, molecular docking experiments on the synthesized compounds were performed, followed by a molecular dynamic simulation. ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) prediction revealed that most of the synthesized compounds follow Lipinski’s rule of 5. The results were further correlated with biological studies. Using a cytotoxic assay, the newly synthesized 1,3,4-Oxadiazoles were screened for their in vitro cytotoxic efficacy against the LN229 Glioblastoma cell line. From the cytotoxic assay, the compounds 5b, 5d, and 5m were taken for colony formation assay and tunnel assay have shown significant cell apoptosis by damaging the DNA of cancer cells. The in vivo studies using a genetically modified diabetic model, Drosophila melanogaster, indicated that compounds 5d and 5f have better anti-diabetic activity among the different synthesized compounds. These compounds lowered the glucose levels significantly in the tested model.     

Cytotoxic Potential of Bioactive Compounds from Aspergillus flavus,an Endophytic Fungus Isolated from Cynodon dactylon,against Breast Cancer: Experimental and Computational Approach

Endophytic fungi are a diverse group of microorganisms that colonize the inter- or intracellular spaces of plants and exhibit mutual benefits. Their interactions with the host plant and other microbiomes are multidimensional and play a crucial role in the production of secondary metabolites. We screened bioactive compounds present in the extracts of Aspergillus flavus, an endophytic fungus isolated from the roots of the medicinal grass Cynodon dactylon, for its anticancer potential. An in vitro analysis of the Ethyl acetate extract from A. flavus showed significant cytostatic effects (IC₅₀: 16.25 μg/mL) against breast cancer cells (MCF-7). A morphological analysis of the cells and a flow cytometry of the cells with annexin V/Propidium Iodide suggested that the extract induced apoptosis in the MCF-7 cells. The extract of A. flavus increased reactive oxygen species (ROS) generation and caused a loss of mitochondrial membrane potential in MCF-7 cells. To identify the metabolites that might be responsible for the anticancer effect, the extract was subjected to a gas chromatography-mass spectrometry (GC-MS) analysis. Interestingly, nine phytochemicals that induced cytotoxicity in the breast cancer cell line were found in the extract. The in silico molecular docking and molecular dynamics simulation studies revealed that two compounds, 2,4,7-trinitrofluorenone and 3α, 5 α-cyclo-ergosta-7,9(11), 22t-triene-6beta-ol exhibited significant binding affinities (−9.20, and −9.50 Kcal/mol, respectively) against Bcl-2, along with binding stability and intermolecular interactions of its ligand-Bcl-2 complexes. Overall, the study found that the endophytic A. flavus from C. dactylon contains plant-like bioactive compounds that have a promising effect in breast cancer.     

Biologically active constituents of Aglaia erythrosperma

From the fruits and leaves of Aglaia erythrosperma (Meliaceae), 10 chemical constituents were isolated and identified, i.e. the dammarane triterpenoids cabraleadiol (1), cabraleahydroxylactone (2), ethyl eichlerianoate (3), eichlerialactone (4), aglinin A (5), cabralealactone (6), the aglaialactone 5,6-desmethylenedioxy-5-methoxy-aglalactone (7), the flavagline 4'-demethoxy-3',4'-methylenedioxy-methyl rocaglate (8) and two coumarins: scoparone and scopoletin. Flavagline 8 exhibited antimalarial activity with an IC(50) value of 7.30 μg mL(-1) and was strongly cytotoxic against small cell lung cancer (NCI-H187), epidermoid carcinoma (KB) and breast cancer (BC) cell lines, with IC(50) values of 2.17, 2.10 and 0.11 μg mL(-1), respectively. Aglinin A (5) displayed moderate cytotoxicity against all the three cancer cell lines, whereas ethyl eichlerianoate (3), cabralealactone (6) and the aglaialactone 7 were exclusively cytotoxic to NCI-H187 cell line. Cabraleahydroxylactone (2) showed antiviral activity against herpes simplex virus type-1 with an IC(50) value of 3.20 μg mL(-1), in comparison with the standard acyclovir (IC(50)?= 1.90 μg mL(-1)). When tested for antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra, compounds 1-4 and 6-8 displayed minimum inhibitory concentration in the range of 25-50 μg mL(-1).     

Cytotoxicity,tyrosine kinase inhibition of novel pyran,pyridine, thiophene,and imidazole derivatives

In this work, we are interested to use multicomponent reactions of cyclohexan-1,3-dione with different reagents for synthesizing new derivatives of pyran, pyridine, thiophene, and imidazole with antitumor activities. Twenty-two newly synthesized derivatives were selected and tested for their anticancer potency. Several of these compounds exhibited quite interesting potencies toward three human tumor cell lines, namely NCI-H460 (non-small cell lung cancer), SF-268 (CNS cancer), and MCF-7 (breast adenocarcinoma), especially when compared to that of reference drugs, doxorubicin and 5-Fu.Compounds 5b , 5c , 7b , 9b , 14a , 16c , 18a , 19c , 20b , and 22b , were found to be the most cytotoxic compounds toward the selected cell lines. On the other hand, 7b , 14a , 16c , 19c , and 22b revealed high inhibitions toward the tyrosine kinases. Active compounds against VEGFR-2, 14a , 16c , and 19c, were docked inside VEGFR-2enzyme to show the interaction between the tested compounds and the amino acids of the active site.     

Supported silver nanoparticles over alginate-modified magnetic nanoparticles: Synthesis,characterization and treat the human lung carcinoma

This article displays synthesis of Silver nanoparticles (Ag NPs) decorated on sodium alginate covered magnetite (Fe₃O₄/Alg-Ag NPs) nanocomposite. Sodium alginate shell as a natural anionic polysaccharide on Fe₃O₄ microparticles core acted as a stabilizing agent for the reduction of Ag(I) ions into Ag NPs. The structural features of the synthesized nanocomposite were investigated by fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field emission scanning electron microscopes (FE-SEM), transmission electron microscopes (TEM), energy-dispersive X-ray spectroscopy (EDX) and vibrating-sample magnetometer (VSM) studies and inductively coupled plasma-optical emission spectroscopy (ICP-OES). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used on common lung cancer cell lines i.e., NCI-H1975, NCI-H1563, and NCI-H1299 to survey the cytotoxicity and anti-lung cancer effects of the synthesized nanocomposite. The synthesized nanocomposite had very low cell viability and high anti-lung cancer activities dose-dependently against NCI-H1975, NCI-H1563, and NCI-H1299 cell lines without any cytotoxicity on the normal cell line (Human umbilical vein endothelial cells (HUVECs)). To determine the antioxidant properties of the synthesized nanocomposite, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test was used in the presence of butylated hydroxytoluene as the positive control. The synthesized nanocomposite inhibited half of the DPPH molecules in the concentration of 194 µg/mL. Maybe significant anti-human lung cancer potentials of the synthesized nanocomposite against common human lung cancer cell lines are linked to their antioxidant activities.     

Phytochemicals from Vanda bensonii and Their Bioactivities to Inhibit Growth and Metastasis of Non-Small Cell Lung Cancer Cells

The most prevalent lung cancer is non-small cell lung cancer (NSCLC). This lung cancer type often develops other organ-specific metastases that are critical burdens in the treatment process. Orchid species in the genus Vanda have shown their potential in folkloric medication of diverse diseases but not all its species have been investigated, and little is known about their anticancer activities against NSCLC. Here, we firstly profiled the specialized metabolites of Vanda bensonii and examined their capability to inhibit growth and metastasis of NSCLC using NCI-H460 cells as a study model. Four phytochemicals, including phloretic acid methyl ester (1), cymbinodin-A (2), ephemeranthoquinone B (3), and protocatechuic acid (4), were isolated from the whole plant methanolic extract of V. bensonii. The most distinguished cytotoxic effect on NCI-H460 cells was observed in the treatments with crude methanolic extract and compound 2 with the half maximal inhibitory concentrations of 40.39 μg mL⁻¹ and 50.82 μM, respectively. At non-cytotoxic doses (10 μg mL⁻¹ or 10 μM), only compound 1 could significantly limit NCI-H460 cell proliferation when treated for 48 h, while others excluding compound 4 showed significant reduction in cell proliferation after treating for 72 h. Compound 1 also significantly decreased the migration rate of NCI-H460 cells examined through a wound-healing assay. Additionally, the crude extract and compound 1 strongly affected survival and growth of NCI-H460 cells under anchorage-independent conditions. Our findings proved that natural products from V. bensonii could be promising candidates for the future pharmacotherapy of NSCLC.     

Uses of cyanoacetylhydrazine in heterocyclic synthesis: novel synthesis of pyrazole derivatives with anti-tumor activities

The reaction of cyanoacetylhydrazine with chloroacetyl chloride gave N'-(2-chloroacetyl)-2-cyanoacetohydrazide. The latter underwent cyclization to afford 1-(5 amino-3-hydroxy-1H-pyrazol-1-yl)-2-chloroethanone, which underwent nucleophilic substitution to give 3-(5-amino-3-hydroxy-1H-pyrazol-1-yl)-3-oxopropanenitrile. The latter two compounds were used as key synthons to synthesize new thiophene, pyran, thiazole and some fused heterocyclic derivatives. The antitumor activity of the newly synthesized compounds was evaluated against three human tumor cells lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) and some of these compounds were found to exhibit much higher inhibitory effects towards the three tumor cell lines than the Gram positive control doxorubicin.     

β-Lactam derivatives as potential anti-cancer compounds

A number of 1,4-diaryl-3-methylene substituted β-lactams, the addition products obtained from their reactions with N-, S-, and C-nucleophiles, and diverse related compounds were prepared, and a selection of 43 compounds was screened in preliminary tests as anti-tumor compounds by using 4 or 5 human cancer cell lines of diverse origins. Twelve compounds were highly active against all cell lines, 6 showed low activity, 12 no activity, and 13 exhibited a selective activity against a human small cell lung carcinoma cell line. Correspondence: Hans-Hartwig Otto, Department of Pharmaceutical/Medicinal Chemistry (PMC), Institute of Pharmacy, Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany.     

Cytotoxic and antimalarial prenylated xanthones from Cratoxylum cochinchinense

A new prenylated xanthone, 5-O-methylcelebixanthone (1), together with six known compounds; celebixanthone (2), 1,3,7-trihydroxy-2,4-di(3-methylbut-2-enyl)xanthone (3), cochinchinone A (4), alpha-mangostin (5), beta-mangostin (6) and cochinchinone C (7) were isolated from roots of Cratoxylum cochinchinense. Their structures were elucidated by spectroscopic methods. Compounds 2 and 4-7 showed cytotoxic activity against the human lung cancer cell line (NCI-H187) with IC(50) values ranging from 0.65 to 5.2 microg/ml. Compounds 1, 2, 6 and 7 also showed antimalarial activity against Plasmodium falciparum with IC(50) values of 3.2, 4.9, 7.2 and 2.6 microg/ml, respectively.