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Mycobacterial membrane protein Large 3 (MmpL3), an inner membrane protein, plays a crucial role in the transport of mycolic acids that are essential for the viability of M. tuberculosis and has been a promising therapeutic target for new anti-TB agents. Herein, we report the discovery of pyridine-2-methylamine antitubercular compounds using a structure-based drug design strategy. Compound 62 stands out as the most potent compound with high activity against M. tb strain H37Rv (MIC = 0.016 μg/mL) as well as the clinically isolated strains of MDR/XDR-TB (MIC = 0.0039–0.0625 μg/mL), low Vero cell toxicity (IC 50 ≥ 16 μ g /mL), and moderate liver microsomal stability (CL int = 28 μL/min/mg). Furthermore, the resistant mutant of S288T due to single nucleotide polymorphism in mmpL3 was resistant to pyridine-2-methylamine 62 , demonstrating compound 62 is likely target to MmpL3. [Display omitted] • Utilizing a structure-directed approach, a series of pyridine-2-methylamine compounds were designed and synthesized. • Compound 62 displayed potent antitubercular activity against the clinical isolates of MDR and XDR-TB (MIC = 0.004–0.063 μg/mL). • Compound 62 showed low Vero cytotoxicity and moderate metabolic stability. • Target verification demonstrated compound 62 is likely to target MmpL3. [ABSTRACT FROM AUTHOR]

Ten novel symmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs, 1–10 ) and fourteen dissymmetric BAPs ( 11–24 ) were synthesized and evaluated the cytotoxicity. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibitory effects on LPS-induced IL-6, TNF- α secretion. Among them, BAP 23 exhibits both the highest anti-inflammatory and anti-cancer properties. Western blot analysis showed that BAP 23 markedly reduced the levels of Bcl-2 but increased the levels of cleaved caspase-3and Bax. Moreover, BAP 23 prominently inhibited LPS-induced activation of NF- κ B in RAW264.7 cells as well as TNF- α -induced activation of NF- κ B in HepG2 cells by blocking phosphorylation of inhibitor I κ B α and p65. Consistent with these results, we found that BAP 23 prevented the nuclear translocation of NF- κ B induced by LPS or TNF- α . BAP 23 could reasonably bind to the active site of Bcl-2 protein and p65 which is proved by molecular docking modes. These data indicate that BAP 23 is a more potent inhibitor of NF- κ B activity which exhibites both anti-inflammatory and anticancer activities. [ABSTRACT FROM AUTHOR]

Thirty-five novel dissymmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs, 6a-h , 7a-h , 8a-g , 9a-g , 10a-e ) were synthesized and evaluated the cytotoxicity. BAPs 6d , 7h , 8g , 9g demonstrated the most potentially inhibitory activities against HepG2 and THP-1 but lower cytotoxicity toward LO2. In vitro , 6d , 7h , 8g , 9g can effectively up-regulate BAX expression, down-regulate Bcl-2 expression in HepG2 cell. They could reasonably bind to the active site of Bcl-2 protein proved by molecular docking modes. The most active BAP 6d induced HepG2 cells apoptosis in a dose-dependent manner by flow cytometrey. The cellular uptake of HepG2 cells showed 6d mainly accumulated into the nuclei by confocal laser scanning microscopy (CLSM). In vivo , 6d suppressed the growth of HepG2 xenografts in nude mice and relatively nontoxic to mice. These results suggest that 6d could be therapeutically beneficial as potential therapeutic agent for the early clinical treatment of liver cancers. [ABSTRACT FROM AUTHOR]

Intestinal commensal fungi are vital to human health, and their secondary metabolites play a key role in the reciprocal relationship. In the present study, the first example of 2,3- seco ergot alkaloids belonging to clavine-type were isolated from the fermentation of human intestinal fungus Aspergillus fumigatus CY018, including two pairs of diastereoisomers, secofumigaclavines A (3) and B (4) and secofumigaclavines C (5) and D (6), one analogue features a highly unsaturated skeleton, secofumigaclavine E (7), along with two known ones, fumigaclavines C (1) and D (2). Their structures were identified based on extensive spectroscopic data in a combination of quantum chemical calculations. Moreover, a single-step operation of semi-synthetic reaction based on riboflavin (RF)-dependent photocatalysis was performed to obtain the novel 2,3- seco ergot alkaloids 3 and 5 from their biosynthetic precursors 1 and 2. All the isolated compounds were evaluated for their anti-inflammatory activity. Among them, secofumigaclavine B (4) could bind to MD2 with a low micromole level of the equilibrium dissociation constant measured by surface plasmon resonance (SPR), and suppress TLR4-mediated NF-κB signaling pathway in RAW264.7 cells, resulting in its anti-inflammatory effect. Molecular dynamics revealed that amino acid residue Tyr131 played a key role in the interaction of secofumigaclavine B (4) with MD2. These findings suggested that secofumigaclavine B (4) could be considered as a potential candidate for the development of MD2 inhibitors. [Display omitted] • Novel 2,3- seco ergot alkaloids were obtained from human intestinal fungus. • Synthesis of 2,3- seco ergots from their biosynthetic precursors was established. • Compound 4 exhibited anti-inflammatory effect via the inactivation of NF-κB signaling pathway. • Compound 4 could bind to MD2 and suppress TLR4 signaling pathway in RAW264.7 cells. [ABSTRACT FROM AUTHOR]

Sesquiterpenoid oligomers, biogenetically assembled by at least two monomeric sesquiterpenoid units via diverse pathways, represent a unique class of natural products with distinct bioactivities. Herein, we provide a review covering the dimeric, trimeric, and tetrameric sesquiterpenoids categorized by reaction types in biosynthesis from a chemical perspective. Emphasis is focused on the biosynthetic oligomerization pathways of these interesting molecules and their related biological functions, which will supply inspiration for the total synthesis or biomimetic synthesis of more oligomeric sesquiterpenoids and further pharmacological investigations. Image 1 • Dimeric, trimeric, and tetrameric sesquiterpenoids are covered in the review. • Sesquiterpenoid oligomers are categorized by reaction types in biosynthetic pathways. • An attempt has been made to describe the mechanistic hypotheses in biosynthesis. • Natural sesquiterpenoid oligomers exhibit various bioactivities with potential. [ABSTRACT FROM AUTHOR]

Bufadienolides are a type of natural cardiac steroids and originally isolated from the Traditional Chinese Medicine Chan'Su, they have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy with potent anti-tumor activities. Due to their unique molecular structures with unsaturated six-membered lactones attached to the steroid core, bufadienolides have received great attention in the synthetic organic community. This review presents total synthetic efforts to some representative bufadienolides, chemical modification of bufadienolides will also be given to discuss their structure-activity relationship in anti-tumor. Image 1 • Bufadienolides, originally isolated from Chan'Su, are a type of natural heart-active steroids. • The bufadienolides are widely considered as effective agents for cardiac, diuretic, anti-tumor and local anesthesia. • The unique chemical structures and numerous biological activities of bufadienolides attracted the interest of scientists. • Total synthesis, chemical modification and structure-activity relationship of bufadienolides have been summarized. • This review provides references for future research on novel bufadienolides with better activities and reduced toxicity. [ABSTRACT FROM AUTHOR]

Abstract To get new anti-hepatoma agents with anti-inflammatory activity and hypotoxicity, a series of dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs, 25 – 82) were designed and synthesized. Many of them exhibited potential anti-hepatoma properties against human hepatocellular carcinoma cell lines (HepG2, QGY-7703, SMMC-7721) and hypotoxicity for human normal heptical cell line (HHL-5, LO2), and prominently inhibited lipopolysaccharides (LPS) induced IL-6, TNF-α secretion to exert its anti-inflammatory effect. Combining the data of cytotoxicity, cytocompatibility and anti-inflammatory activity, 3-pyridyl and -CF 3 substituted 67 may be the potential anti-hepatoma agent. 67 effectively promoted cell apoptosis through up-regulating cleaved caspase-3 and Bax expression and down-regulating Bcl-2 expression. Furthermore, 67 prominently inhibited NF-κB pathway activation by blocking the phosphorylation of IκBα, p65 and the nuclear translocation of NF-κB induced by TNF-α and LPS. In addition, 67 could reasonably bind to the active site of Bcl-2 and NF- κ B/p65 protein proved by Molecular docking analyses. Moreover, 67 significantly suppressed the growth and inflammatory response of HepG2 xenografts in nude mice and was relatively nontoxic to mice. These results suggest that 67 may be effective and hypotoxicity anti-hepatoma agent for the clinical treatment of liver cancers. Graphical abstract Fifty-eight dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) were synthesized and evaluated for their cytotoxicity and anti-inflammatory activity. 3-Pyridyl and -CF 3 substituted 67 could be the most potential anti-hepatoma agents by inhibiting NF-κB pathway activation. In vivo , 67 suppressed the growth and inflammatory response of HepG2 xenografts and was relatively nontoxic to mice. Image 1 Highlights • Fifty-eight dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) were synthesized. • 3-Pyridyl and -CF 3 substituted 67 could be the most potential anti-hepatoma agents by inhibiting NF-κB pathway activation. • 67 showed good anti-inflammatory activity by inhibiting nuclear translocation of NF-κB and phosphorylation of IκBα and p65. • 67 could reasonably bind to the active site of Bcl-2 and NF-κB/p65 protein proved by Molecular docking analyses. • In vivo , 67 suppressed the growth and inflammatory response of HepG2 xenografts and was relatively nontoxic to mice. [ABSTRACT FROM AUTHOR]

Scutellarin ( 1 ) could be hydrolyzed into scutellarein ( 2 ) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein ( 2 ) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H 2 O 2 -induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6- O -methylscutellarein ( 5 ) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin ( 1 ), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease. [ABSTRACT FROM AUTHOR]

The equilibrium between histone acetylation and deacetylation plays an important role in cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine ε -amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o , was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC 50 = 1.16 nM) and HDAC6 (IC 50 = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC 50 values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively. [Display omitted] • Novel indole-based HDAC inhibitors are designed and synthesized. • Compound 4o exhibited anti-tumor proliferation activity both in vitro and in vivo. • Compound 4k has a preference for the inhibition of HDAC6. [ABSTRACT FROM AUTHOR]

The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons. Hence, we developed an effective strategy to identify and design new inhibitors for protein-protein interaction targets. The hydroxyproline (Hyp564) of HIF-1α contributed the key interaction between HIF-1α and VHL. In this study, detailed information of the binding pocket were explored by alanine scanning, site-directed mutagenesis and molecular dynamics simulations. Interestingly, we found the interaction(s) between Y565 and H110 played a key role in the binding of VHL/HIF-1α. Based on the interactions, 8 derivates of VH032, 16a-h , were synthesized by introducing various groups bounded to H110. Further assay on protein and cellular level exhibited that 16a-h accessed higher binding affinity to VHL and markable or modest improvement in stabilization of HIF-1α or HIF-1α-OH in HeLa cells. Our work provides a new orientation for the modification or design of VHL/HIF-1α protein-protein interaction inhibitors. [Display omitted] • An extra sub-pocket Site4 between H110 and Y112 was determined by virtual mutation. • 8 derivates of VH032 were synthesized by introducing various groups bounded to Site4. • Inhibitory activities of all derivatives were evaluated against HIF-1α/VHL interaction. • 16h displayed more potential in binding affinity, negligible cytotoxicity and stabilization of HIF-1α. [ABSTRACT FROM AUTHOR]

NF- κ B is a key signaling pathway molecule linking hepatoma and chronic inflammation. Inhibition of NF- κ B activation can alleviate inflammation, and promote hepatoma cell apoptosis. In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3- d pyrimidines (PPMs, 31 – 57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4 – 30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF 3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF- κ B activation by suppressing LPS-induced phosphorylation levels of p65, I κ B α and Akt, and by indirectly suppressing MAPK signaling, and by inhibiting the nuclear translocation of NF-κB induced by TNF-α or LPS. Docking analysis verified simulated 43 could reasonably bind to the active site of Bcl-2, p65 and p38 proteins. This compound, as a novel NF-κB inhibitor, also demonstrated both anti-inflammatory and anti-hepatoma activities, warranting its further development as a potential multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases. Fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3- d pyrimidines (PPMs) were synthesized based on scaffold hopping. PPM 43 substituted by 3-F and 4-CF 3 groups could be the most potent NF- κ B inhibitor, because it induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF- κ B activation by suppressing LPS-induced phosphorylation and nuclear translocation of NF- κ B signaling. Image 1 • Fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3- d pyrimidines (PPMs) were synthesized based on scaffold hopping. • 3-F and 4-CF 3 -substituted 43 exhibited less toxicity and higher anti-inflammatory activity. • 43 induced dose-dependent cell apoptosis at cell and protein level. • 43 inhibited NF- κ B activation by suppressing LPS-induced phosphorylation of p65, IκBα and Akt and MAPK signaling. • 43 inhibited NF- κ B activation by inhibiting nuclear translocation of NF- κ B induced by TNF-α or LPS. [ABSTRACT FROM AUTHOR]

Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC 50 = 2.7 nM and IC 50 = 3.1 nM), HDAC2 (IC 50 = 4.2 nM and IC 50 = 3.6 nM) and HDAC8 (IC 50 = 3.6 nM and IC 50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs. Image 1 • Representative compounds 15k and 15m exhibited potent HDAC inhibitory activities against HDAC1, 2 and 8. • 15k and 15m exhibited higher antiproliferative activities than the positive drug SAHA toward HCT-116 and HeLa. • 15k and 15m arrested cell cycle in G2/M phase and promoted cell apoptosis, which was similar as SAHA. [ABSTRACT FROM AUTHOR]