ent-Herqueidiketal and epi-Peniciherqueinone Isolated from a Mushroom Derived Fungus Penicillium herquei YNJ-35

A new polyaromatic metabolite, ent-herqueidiketal ( 1 ), and a new phenalenone derivative, epi-peniciherqueinone ( 2 ), along with twelve known compounds 3 – 14 , were isolated from the fungus Penicillium herquei YNJ-35, a symbiotic fungus of Pulveroboletus brunneopunctatus collected from Nangunhe Nature Reserve, Yunnan Province, China. The structures of 1 – 14 and the absolute configurations of 1 and 2 were determined by their spectroscopic data or by their single-crystal X-ray diffraction analysis or optical rotation values. Compound 1 showed strong antibacterial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentration (MIC) of 8 μg/mL. In the cytotoxicity assays, compound 1 showed weak inhibitory activity against breast cancer MCF-7 and mice microglial BV2 cells with half maximal inhibitory concentration (IC₅₀) of 17.58 and 29.56 μM; compound 14 showed stronger cytotoxicity against BV2 and MCF-7 cells with IC₅₀ values of 6.57 and 10.26 μM.     

New Spirostane from a Fungus Neohelicomyces hyalosporus and Its Bioactivity

A new spirostane, namely neohelicomyine B ( 1 ), together with six known steroids ( 2 – 7 ) were isolated from the fermentation of fungus Neohelicomyces hyalosporus. The structures of these compounds were elucidated by extensive analyses of spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction. The bioactivities of compounds 1 – 7 were evaluated using cellular assays. Compound 1 displayed moderate cytotoxicity against HepG2 cells (hepatoma cells) with IC₅₀ value of 8.4±2.1 μM. Compound 7 also exhibited cytotoxic activity against HepG2 cells with the IC₅₀ value of 3.0±0.2 μM.     

Design,Synthesis and Cytotoxicity of New Coumarin-1,2,3-triazole Derivatives: Evaluation of Anticancer Activity and Molecular Docking Studies

A library of new coumarin-1,2,3-triazole hybrids 7a – l were synthesized from 4-(diethylamino)-2-hydroxybenzaldehyde precursor through a series of reactions including Vilsmeier-Haack reaction and condensation reaction to achieve key intermediate oxime and further performed click reaction by using different aromatic azides. We screened all molecules in silico against crystal structure of Serine/threonine-protein kinase 24 (MST3), based on these results all molecules were screened for their cytotoxicity against human breast cancer MCF-7 and lung cancer A-549 cell lines. Compound 7 b (p-bromo) showed best activity against both cell lines MCF-7 and A-549 with IC₅₀ value of 29.32 and 21.03 μM, respectively, in comparison to Doxorubicin corresponding IC₅₀ value of 28.76 and 20.82 μM. Another compound 7 f (o-methoxy) also indicated good activity against both cell lines with IC₅₀ value of 29.26 and 22.41 μM. The toxicity of all compounds tested against normal HEK-293 cell lines have not shown any adverse effects.     

Cytotoxic ent‐Kaurane Diterpenoids from Isodon nervosus

Four new ent‐kaurane diterpenoids, rabdonervosins G–J ( 1 – 4 , resp.), were isolated from the leaves and stems of Isodon nervosus. Their structures were elucidated by extensive spectroscopic analyses, including 1D‐, 2D‐NMR and HR mass spectra. Compound 2 showed potent cytotoxicity against the HepG2 and PC‐9/ZD cell lines with IC₅₀ values of 2.36 and 6.07 μM , respectively, and compound 3 exhibited cytotoxicity against the HepG2 and CNE2 cell lines with IC₅₀ values of 8.64 and 9.77 μM , respectively.     

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6-Methylpyridine Moiety

A series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles ( 15a – t and 16a – f ) were synthesized and their antibacterial activities were evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1–2 μg/mL) and 16d (MIC=0.5 μg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.     

Hyposterolactone A,a 3α-Hydroxy Steroidal Lactone from the Deep-Sea-Derived Fungus Hypocrea sp. ZEN14

Chemical investigation of the deep-sea-derived fungus Hypocrea sp. ZEN14 afforded a new 3α-hydroxy steroidal lactone, hyposterolactone A ( 1 ) and 25 known secondary metabolites ( 2 – 26 ). The structure of the new compound was established by detailed spectroscopic analysis, electronic circular dichroism (ECD) calculation as well as a J-based configuration analysis. Compound 10 showed potent cytotoxicity against Huh7 and Jurkat cells with IC₅₀ values of 1.4 μM and 6.7 μM, respectively.     

Derivatives of Holomycin and Cyclopropaneacetic Acid from Streptomyces sp. DT‐A37

On the basis of the one strain–many compounds strategy, five compounds including two new holomycin derivatives 2 – 3 , two new cyclopropaneacetic acid derivatives 4 – 5 , together with one known compound holomycin ( 1 ) were isolated from a marine‐derived bacterium Streptomyces sp. DT‐A37. Their structures were elucidated using NMR and HR‐ESI‐MS analyses. All these compounds were evaluated for their antimicrobial activity, cytotoxic activity, and inhibitory activity against BRD4 protein. Compound 1 exhibited potent cytotoxicity against H1975 cells with IC₅₀ value of 1 μm , and its minimal inhibitory concentration values against Escherichia coli and Staphylococcus aureus were both 64 μm .     

Triterpenoid Alkaloids from Buxus microphylla

Two new triterpenoid alkaloids, buxmicrophyllines J and K ( 1 and 2 , resp.), together with four analogues, 3 – 6 , were isolated from the leaves and stems of Buxus microphylla. The structures of the new compounds were elucidated by NMR and MS spectroscopic analyses. The partial assignments of the NMR spectra of 3 were also revised. Compounds 1 and 3 – 6 were evaluated for their growth inhibitory activity against human cell lines HL‐60, SMMC‐7721, A‐549, SK‐BR‐3, and PANC‐1. Compound 6 showed significant cytotoxicity against HL‐60, SK‐BR‐3, and PANC‐1 cell lines, with IC₅₀ values of 6.46, 19.61, and 28.57 μM , respectively.     

New Pyran‐2‐ones from Alkalophilic Actinomycete,Nocardiopsis alkaliphila sp. Nov. YIM‐80379

Two new pyran‐2‐ones, nocardiopyrones A and B ( 1 and 2 , resp.), along with four known compounds, pyridinols 3 – 5 , and 1‐acetyl‐β‐carboline ( 6 ) were isolated from the alkalophilic actinomycete Nocardiopsis alkaliphila sp. nov. YIM‐80379. Their structures were established on the basis of spectroscopic analysis, CD spectra, and the quantum‐chemical ECD calculation. Pyridinols 3 – 5 were isolated from a natural source for the first time. Compounds 1 and 2 showed weak antibacterial activities against Pseudomonas aeruginosa, Enterobacter aerogenes, and Escherichia coli with MIC values of 20–48 μM . Compound 2 showed weak antimicrobial activities against Candida albicans and Staphylococcus aureus with MIC values of 24 and 48 μM , respectively.     

Cytotoxic Tetraprenylated Alkaloids from the South China Sea Gorgonian Euplexaura robusta

Nine achiral tetraprenylated alkaloids, including three new compounds, named malonganenones I–K ( 1 – 3 , resp.), together with six known analogs, 4 – 9 , were isolated from the gorgonian Euplexaura robusta collected from Weizhou Island of Guangxi Province, China. The structures of compounds 1 – 3 were elucidated by extensive spectral analyses, especially of their 1D‐ and 2D‐NMR data. Compounds 1, 4, 6 , and 7 showed moderate cytotoxicities against K562 and HeLa tumor cell lines with IC₅₀ values ranging from 0.35 to 10.82 μM . Compound 6 also showed moderate inhibitory activity against c‐Met kinase at a concentration of 10 μM .     

Diterpenoids from Euphorbia neriifolia and Their Related Anti‐HIV and Cytotoxic Activity

Fifteen diterpenoids ( 1 – 15 ), including three undescribed ones with ent‐atisane skeleton, eupnerias G–I ( 1 – 3 ), were obtained from Euphorbia neriifolia. Compounds 1 – 3 were established through comprehensive spectroscopic analysis. Compounds 4 and 5 exhibited obvious anti‐HIV‐1 effect, and their EC₅₀ were 6.6±3.2 and 6.4±2.5 μg mL^?1, respectively. Compound 6 exhibited moderate cytotoxicity on HepG2 and HepG2/Adr cells with IC₅₀ at 13.70 and 15.57 μm , respectively. In addition, compound 15 exhibited significant cytotoxicity on HepG2 cell lines (IC₅₀=0.01 μm ), while it did not show any cytotoxicity against HepG2/Adr cell lines.     

Bioactive Diphenyl Ether Derivatives from a Gorgonian‐Derived Fungus Talaromyces sp.

Three new diphenyl ether derivatives, talaromycins A–C ( 1 – 3 , resp.), together with six known analogs, 4 – 9 , were isolated from a gorgonian‐derived fungus, Talaromyces sp. The structures of the new compounds were determined by analysis of extensive NMR spectroscopic data. All of the isolated metabolites, 1 – 9 , were evaluated for their cytotoxic and antifouling activities. Compound 4 exhibited pronounced cytotoxicity against the tested human cell lines with the IC₅₀ values ranging from 4.3 to 9.8 μM . Compounds 3, 5, 8 , and 9 showed potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC₅₀ values ranging from 2.2 to 4.8 μg/ml.     

New Glycerolipids from the Traditional Chinese Medicine of Syngnathus acus (Hai-Long)

Two new glycerolipids, syngaculipids A and B ( 1 and 2 ), one first naturally occurring metabolite ( 8 ), together with five known compounds ( 3 – 7 ) were isolated from the AcOEt fraction of Syngnathus acus L. (Hai-Long). Their structures were elucidated by comprehensive spectral analyses involving UV, IR, MS, 1D and 2D NMR spectra and ECD calculations. All the isolated compounds were evaluated for their cytotoxicity against A549 and HCT-116 cell lines. Compound 8 exhibited moderate cytotoxicity with IC₅₀ values of 34.5 and 38.9 μM on the A549 and HCT-116 cell lines, respectively.     

Simple Synthesis and Anti-Hiv Activity of Novel 3′-Vinyl Branched Apiosyl Pyrimidine Nucleosides

Novel vinyl branched apiosyl nucleosides were synthesized in this study. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The bases (uracil and thymine) were efficiently coupled by glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2, and HCMV. Compound 10β displayed moderate anti-HIV activity (EC₅₀ = 17.3 μg/mL) without exhibiting any cytotoxicity up to 100 μM.     

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity-guided fractionation to afford two chemically related dibenzylbutyrolactone lignans – hinokinin ( 1 ) and hibalactone ( 2 ). Compounds 1 and 2 showed activity against trypomastigote with EC₅₀ values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC₅₀ value of 34.4 μM. The structure-activity relationship (SAR) indicated that the absence of the double bond at C-7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent-based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds – 3,4-methylenedioxydihydrocinnamic acid ( 3 ), 3,4-methylenedioxydihydrocinnamic alcohol ( 4 ) and 3,4-methylenedioxycinnamic acid ( 5 ) – were prepared and tested against T. cruzi. These derivatives displayed EC₅₀ values of 37.2 ( 3 ), 25.8 ( 4 ) and 73.5 ( 5 ) μM against trypomastigotes, and 41.3 ( 3 ) and 48.2 ( 4 ) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2 , which resulted in a CC₅₀ value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug-likeness profile for compounds 1 – 5 . Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease.     

Synthesis of Lanostane‐Type Triterpenoid N‐Glycosides and Their Cytotoxicity against Human Cancer Cell Lines

Seventeen lanostane‐type triterpenoid derivatives ( 2 – 18 ), including 11N‐glycosides ( 8 – 18 ), were synthesized from the natural triterpenoid, lanosterol ( 1 ), and were evaluated for their cytotoxicity against the human cancer cell lines, HL‐60, A549, and MKN45, as well as the normal human lung cells, WI‐38. Among them, N‐β‐d ‐2‐acetamido‐2‐deoxyglucoside ( 10 ) showed cytotoxicity against HL‐60, A549, MKN45, and WI‐38 cells (IC₅₀ 0.0078 – 2.8 μm ). However, N‐β‐d ‐galactoside ( 12 ) showed cytotoxicity against HL‐60 and MKN45 cells (IC₅₀ 0.0021 – 4.0 μm ), but not the normal WI‐38 cells. Furthermore, Western blot analysis suggested that 12 induces apoptosis by activation of caspases‐3, 8, and 9. These results will be useful for the synthesis of other tetracyclic triterpenoids or steroid N‐glycosides to increase their cytotoxicity and apoptosis‐inducing activities.     

Two New Limonoids from the Fruits of Melia azedarach (Meliaceae)

Two new limonoids, trichilinin M ( 1 ) and ohchinin benzoate ( 2 ), along with two known limonoids, 12-hydroxyamoorastatone ( 3 ) and mesendanin H ( 4 ), were isolated from the fruits of Melia azedarach Linn. The structures of new limonoids were determined by analyses of HR-ESI-MS, 1D and 2D NMR (HSQC, HMBC and NOESY) data. All compounds were evaluated against human pancreatic cancer PANC1 cells and the results showed that compounds 3 – 4 exhibited substantial cytotoxic activity ( 3 : IC₅₀=4.55 μM; 4 : IC₅₀=7.54 μM), and compounds 1 – 2 exhibited moderate cytotoxicity ( 1 : IC₅₀=27.06 μM; 2 : IC₅₀=21.17 μM).     

Synthesis of 9‐(Heteroarylmethylidene)amino Derivatives of Homocamptothecin with Biological Activities

Six 9‐(heteroarylmethylidene)amino derivatives, 2a – 2f , of homocamptothecin were synthesized for the first time by total synthesis in 22 steps and biologically evaluated as inhibitors of topoisomerase I. Moreover, the antitumor activities of 2a – 2f against three human tumor cell lines, i.e., A‐549, MDA‐MB‐435, and HCT‐116, were determined and the results showed that compound 2c was the most active homocamptothecin derivative against the A‐549 (IC₅₀=0.046 μM ) and HTC‐116 tumor cells (IC₅₀=3.67 μM ), with a ca. 50 times higher activity than the reference drug topotecan (TPT) against the lung cancer cell line A‐549.     

Cytotoxicity and Antibacterial Evaluation of O-Alkylated/Acylated Quinazolin-4-one Schiff Bases

A series of quinazolin-4-one Schiff bases were synthesized and tested in vitro for their cytotoxicity against two cancerous cell lines (MCF-7, Caco-2) and a human embryonic cell line (HEK-293) including their antibacterial evaluation against two Gram-positive and four Gram-negative bacterial strains. Most of the quinazoline-Schiff bases exhibited potent cytotoxicity against Caco-2. 3-[(Z)-({4-[(But-2-yn-1-yl)oxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one ( 6f ) with the O-butyne functional group displayed three-fold higher cytotoxic activity (IC₅₀=376.8 μM) as compared to 5-fluorouracil (5-FU; IC₅₀=1086.1 μM). However, all compounds were found to be toxic to HEK-293, except for 3-[(Z)-({4-[(2,4-difluorophenyl)methoxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one ( 6h ) that showed ∼three-fold lower toxicity and higher selectivity index than 5-FU. Structure–activity relationship (SAR) analysis revealed that O-alkylation generally increased the anticancer activity and selectivity of quinazoline-4-one Schiff bases toward Caco-2 cells. The fluorinated Schiff-base generally exhibited even more significant cytotoxic activity compared to their chlorine analogs. Surprisingly, none of the quinazoline-4-one Schiff bases displayed encouraging antibacterial activity against the bacterial strains investigated. Most of the compounds were predicted to show compliance with the Lipinski parameters and ADMET profiles, indicating their drug-like properties.     

Novel (E)-3-(3-Oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides as Histone Deacetylase Inhibitors: Design,Synthesis and Bioevaluation

Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides ( 4 a – i , 7 a – g ) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a – i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a – g in all biological assays. Compounds 7 e – f were found to be the most active HDAC inhibitors with IC₅₀ of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC₅₀ values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.