Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives.

Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket.

Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity.

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects.

Albusamides A-G: Hydroxylated Fatty Amine Derivatives from the Deep-Sea-Derived Actinomycete 228DD-066 and Their Cytotoxic Activity.

A series of new hydroxylated fatty amine derivatives, albusamides A-G (-), along with four known compounds (-), which are reported for the first time from a natural source, were isolated from the culture broth of 228DD-066 derived from a deep-sea sediment sample gathered off the coast of Dokdo Island, Republic of Korea. Their structures were elucidated through the comprehensive analysis of 1D and 2D NMR spectra and HRESIMS, and absolute configurations were determined using the modified Mosher's method. Biological evaluations against solid and blood cancer cell lines revealed that these new metabolites have moderate to strong cytotoxic activity.

A small molecule compound 759 inhibits the wnt/beta-catenin signaling pathway via increasing the Axin protein stability.

Wnt/β-catenin signaling plays important role in cancers. Compound 759 is one of the compounds previously screened to identify inhibitors of the Wnt/β-catenin pathway in A549 cells [Lee et al. in Bioorg Med Chem Lett 20:5900-5904, 2010].

Labdane-Type Diterpenoids from and Their Antimicrobial and Cytotoxic Activities.

Chemical investigation of the ethyl acetate (EtOAc) extract from a marine-derived actinomycete, , resulted in the discovery of five new labdane-type diterpenoids: chlorolabdans A-C (-), epoxylabdans A and B ( and ), along with one known analog (). The structures of the new compounds were determined by spectroscopic analysis (HR-ESIMS, 1D, and 2D NMR) and by comparing their experimental data with those in the literature. The new compounds were evaluated for their antimicrobial activity, and displayed significant activity against Gram-positive bacteria, with minimum inhibitory concentration (MIC) values ranging from 4 to 8 µg/mL.

Meirols A-C: Bioactive Catecholic Compounds from the Marine-Derived Fungus sp. 1210CH-42.

Three new catecholic compounds, named meirols A-C (-), and one known analog, argovin (), were isolated from the marine-derived fungus sp. 1210CH-42. Their structures were determined by extensive analysis of 1D, 2D NMR, and HR-ESIMS spectroscopic data.

Rifamycin-Related Polyketides from a Marine-Derived Bacterium and Their Cytotoxic Activity.

Eight rifamycin-related polyketides were isolated from the culture broth of a marine-derived bacterium , including five known (- and ) and three new derivatives (, , and ). The structures of the new compounds were determined by means of spectroscopic methods (HRESIMS and 1D, 2D NMR) and a comparison of their experimental data with those previously reported in the literature. The isolated compounds were evaluated for their cytotoxicity against one normal, six solid, and seven blood cancer cell lines and showed moderate activity against all the tested cell lines with GI values ranging from 2.

VDUP1 Deficiency Promotes the Severity of DSS-Induced Colitis in Mice by Inducing Macrophage Infiltration.

The loss of vitamin D upregulated protein 1 (VDUP1) has been implicated in the pathogenesis of various inflammation-related diseases. Notably, reduced expression of VDUP1 has been observed in clinical specimens of ulcerative colitis (UC). However, the role of VDUP1 deficiency in colitis remains unclear.

Sesquiterpenes from and Their Cytotoxic Activity.

Nine sesquiterpenes, including eight pentalenenes (-) and one bolinane derivative (), were isolated from the culture broth of a marine-derived actinobacterium 213DD-006. Among them, , , , and were new compounds. Their planar structures were determined by spectroscopic methods (HRMS, 1D, and 2D NMR), and the absolute configuration was established by biosynthesis consideration and electronic-circular-dichroism (ECD) calculations.

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.

Pyrrole-Containing Alkaloids from a Marine-Derived Actinobacterium and Their Antimicrobial and Cytotoxic Activities.

Two new alkaloids, streptopyrroles B and C ( and ), were discovered through a chemical investigation of the ethyl acetate (EtOAc) extract from a marine-derived actinomycete, , along with four known analogs (-). The structures of the new compounds were elucidated by spectroscopic analysis (HR-ESIMS, 1D, and 2D NMR) and a comparison of their experimental data with literature values. The new compounds were evaluated for their antimicrobial activity by standard broth dilution assay, and the tested compounds showed significant activity against Gram-positive bacteria with minimum inhibitory concentration (MIC) values ranging from 0.

New Angucycline Glycosides from a Marine-Derived Bacterium .

Chemical investigation of the ethyl acetate extract from the culture broth of the marine-derived actinobacterium 156VN-095 led to the isolation of three hitherto undescribed angucycline glycosides, including urdamycins W and X ( and ) and grincamycin U (), as well as their seven known congeners. The structures of the new compounds were elucidated by means of spectroscopic methods (HRESIMS, 1D and 2 D NMR) and comparison of their experimental data with literature values. Compounds - and were evaluated for their anti-Gram-positive bacterial effect and cytotoxicity against six cancer cell lines.

Protection against Lipopolysaccharide-Induced Endotoxemia by Terrein Is Mediated by Blocking Interleukin-1β and Interleukin-6 Production.

Terrein is a fungal metabolite and has been known to exert anti-melanogenesis, anti-cancer, and anti-bacterial activities. However, its role in endotoxemia has never been investigated until now. In the present study, we examined the effect of terrein on lipopolysaccharide (LPS)-induced endotoxemia in mice and characterized the potential mechanisms of action.

Aspersterols A-D, Ergostane-Type Sterols with an Unusual Unsaturated Side Chain from the Deep-Sea-Derived Fungus .

Four previously undescribed ergostane-type sterols, aspersterols A-D (-), were isolated from a deep-sea-derived fungus, IV17-109. The structures of the new compounds were determined by extensive analyses of their spectroscopic data, pyridine-induced deshielding effect, Mosher's method, and electronic circular dichroism calculations. The key feature of these sterols is the presence of a rare unsaturated side chain with conjugated double bonds at Δ and Δ.

Targeted Induction of Endogenous VDUP1 by Small Activating RNA Inhibits the Growth of Lung Cancer Cells.

Recent studies have reported that small double-strand RNAs (dsRNAs) can activate endogenous genes via an RNA-based promoter targeting mechanism termed RNA activation (RNAa). In the present study, we showed that dsVDUP1-834, a novel small activating RNA (saRNA) targeting promoter of vitamin D up-regulated protein 1 (VDUP1) gene, up-regulated expression of VDUP1 at both mRNA and protein levels in A549 lung cancer cells. We also demonstrated that dsVDUP1-834 inhibited cell proliferation in A549 lung cancer cells.

New Glycosylated Secondary Metabolites from Marine-Derived Bacteria.

Three new glycosylated secondary metabolites, including a new indole alkaloid, pityriacitrin D (), and two new trehalose lipids ( and ), together with three known compounds (-) were isolated from two marine-derived bacterial strains, 168CLC-66.1 and IV19-045. The structures of - were determined by extensive analysis and comparison of their spectroscopic data with literature values.

Design, Synthesis, and Cytotoxicity and Topoisomerase I/IIα Inhibition Activity of Pyrazolo[4,3-]quinoline Derivatives.

With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly designed pyrazolo[4,3-]quinoline derivatives were synthesized via inverse imino Diels-Alder reaction.

Isolation, Structure Determination, and Semisynthesis of Diphenazine Compounds from a Deep-Sea-Derived Strain of the Fungus and Their Biological Activities.

Phenazostatins E-J (-), six new diphenazine derivatives, were isolated from the EtOAc extract of the culture broth of a strain of derived from deep-sea sediments of the Indian Ocean Ridge. The structures of - were elucidated based on the HRESIMS and 1D and 2D NMR spectra. The absolute configurations of -, except for and , were determined by modified Mosher's method, ECD data analysis, and calculations of optical rotation values.

Antibacterial and Cytotoxic Phenolic Polyketides from Two Marine-Derived Fungal Strains of .

A chemical investigation on the EtOAc extracts from two marine-derived fungal strains of resulted in the isolation of three previously undescribed phenolic polyketides including unguidepside C (), aspersidone B (), and agonodepside C (), and their 14 known congeners. The structures of the new compounds were determined based on detailed analysis and comparison of their spectroscopic data with literature values, as well as Snatzke's method. The new compounds (, , and ) displayed a significant anti-Gram-positive bacterial activity, with MIC values ranging from 5.

Design, Synthesis and Evaluation of Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as Antitumor Agents.

Background: Herein, we have designed and synthesized a series of the novel (E)-N'-((1-(4-chlorobenzyl)- 1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5) as potent small molecules activating procaspase- 3. The compounds were designed by the amalgamation of structural features of PAC-1 (the first procaspase-3 activator) and oncrasin-1, one potential anticancer agent.

Methods: The target acetohydrazides (5a-m) were prepared via the Niementowski condensation of anthranilic acid (1a) or 5-substituted-2-aminobenzoic acid (1b-m) and formamide.

Design, synthesis, and biological evaluation of potent 1,2,3,4-tetrahydroisoquinoline derivatives as anticancer agents targeting NF-κB signaling pathway.

The multifunctional transcription factor, nuclear factor-κB (NF-κB), is broadly involved in multiple human diseases, such as cancer and chronic inflammation, through abnormal modulations of the NF-κB signaling cascades. In patients with several types of cancer diseases, NF-κB is excessively activated, which could result in the stimulation of proliferation and/or suppression of apoptosis. Herein, we present a new series of 1,2,3,4-tetrahydroisoquinoline derivatives with good anticancer activities against various human cancer cell lines, which are rationally designed based on our novel NF-κB inhibitors.