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Abstract: Thirty-five S- and O-substituted 7-mercaptocoumarin (9–23) and 7-hydroxy- or 7-mercapto-chromone (24–43) analogs were designed, synthesized and evaluated in vitro against four human tumor cell lines [KB (nasopharyngeal), KB-vin (vincristine-resistant subline), A549 (lung) and DU145 (prostate)] with paclitaxel as the positive control. Many of the synthesized compounds exhibited potent cytotoxic activity. Among them, compounds 10 and 18 showed broad spectrum activity with GI50 values ranging from 0.92 to 2.11 μM and 2.06–14.07 μM, respectively. However, 33, a 3-brominated compound, displayed significant and selective inhibition against MDR KB-vin with a GI50 of 5.84 μM. Regardless of the size of the 7-alkoxy group, 2-α-bromoethyl-8-bromomethyl compounds (40–43) exhibited increased cytotoxicity compared with 2-ethyl-8-bromomethyl compounds (36–39). Moreover, in a preliminary pharmacological study, 10 not only remarkably increased cellular apoptosis in a concentration-dependent manner, but also clearly induced A549 cell cycle arrest at the G2/M phase. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism(s). [Copyright &y& Elsevier]

Abstract A novel series of 2-(phenoxyaryl)-3-urea derivatives were designed, synthesized, and biologically evaluated for their anti-thrombotic activity. Most of compounds exhibited good inhibition against P2Y 1 receptor. Among them, three compounds 11 , 12 , and 13 demonstrated good P2Y 1 receptor antagonistic potency in vitro (IC 50 = 0.62 μM, 0.82 μM, and 0.21 μM, respectively). In antiplatelet aggregation study, four compounds 2 , 3 , 9 , and 13 showed good antiplatelet activity. The possible binding modes of compounds with P2Y 1 receptor were also explored by molecular docking simulation. The docking studies demonstrated that compound 13 interacted well with Phe119 through hydrophobic interaction and modestly improved the P2Y 1 receptor antagonistic activity, making it justifiable for further investigation. Graphical abstract Image 1 Highlights • Novel 2-(phenoxyaryl)-3-urea derivatives were designed, synthesized, and biologically evaluated. • Three compounds 11 , 12 , and 13 demonstrated good P2Y 1 receptor antagonistic potency in vitro. • Four compounds 2 , 3 , 9 , and 13 showed good antiplatelet activity in antiplatelet aggregation study. • The docking studies showed compound 13 interacted well with Phe119. [ABSTRACT FROM AUTHOR]

A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5 H -thieno[3′,2’:3,4]pyrido[1,2- b ]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa , 4bq , and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60–85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db / db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC 50 > 10 μM). [ABSTRACT FROM AUTHOR]

The development of heterocyclic derivatives has progressed considerably over the past few decades, and many new agents of synthetic and natural origin have been produced. Among heterocyclic compounds, thiazole is a unique five-membered heterocyclic motif characterized by nitrogen and sulfur atoms, which is widely used as an important core skeleton in a variety of pharmaceutically important compounds due to their diverse biological activities, such as antibacterial, antivirus, and antifungal. To the best of our knowledge, more than 90 thiazole-containing derivatives have been currently under clinical investigation, and some thiazole analogs have been approved to treat various diseases. As the potentially privileged scaffolds, thiazole derivatives can be further extensively explored to search for new drugs characterized by improved therapeutic efficacy and similar biological targets. This review aims to outline the applications and synthetic routes of some representative thiazole-containing drugs approved in the clinic, which may guide medicinal researchers to rationally design more effective thiazole-containing drug candidates. [Display omitted] • Thiazole ring is widely used in many drugs to treat various diseases. • Recent advances in thiazole-containing drugs have been summarized. • The clinical applications and synthetic routes of 33 thiazole-containing drugs are highlighted. • Summary and prospect are briefly discussed to guide future design of thiazole-containing drugs. [ABSTRACT FROM AUTHOR]

New thienopyrimidine hydroxamic acid derivatives as HDACs inhibitors were designed, synthesized and evaluated. All compounds were evaluated for their ability to inhibit recombinant human HDAC1, HDAC3, and HDAC6 isoforms and in vitro anti-proliferative activity on tumor cell lines RMPI 8226 and HCT 116. Most of these compounds displayed good to excellent inhibitory activities against HDACs. The IC 50 values of compound 9m against HDAC1, HDAC3, and HDAC6 was 29.81 ± 0.52 nM, 24.71 ± 1.16 nM, and 21.29 ± 0.32 nM. Most of these compounds showed strong anti-proliferative activity against human cancer cell lines including RMPI 8226 and HCT 116. The IC 50 values of compound 9m against RPMI 8226 and HCT 116 proliferation were 0.97 ± 0.072 μ M and 1.01 ± 0.033 μ M, respectively. In addition, compound 9m noticeably up-regulated the level of histone H3 acetylation at the low concentration of 0.3 μ M. [ABSTRACT FROM AUTHOR]

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert -butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4 H -chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate ( 8i ) showed the best inhibitory activity against PC-3 cells (IC 50 = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells. [ABSTRACT FROM AUTHOR]

Inhibition of lysine-specific demethylase 1 (LSD1) has recently emerged as an attractive therapeutic target for treating cancer and other diseases. As a continuity of our ongoing effort to identify novel small-molecule LSD1-inhibitors, we designed and synthesized a series of resveratrol derivatives, which were shown to be potent inhibitors of LSD1. Among them, compounds 4e and 4m displayed the most potent LSD1-inhibitory activities in enzyme assays, with IC 50 values of 121 nM and 123 nM, respectively. Biochemistry study and docking analysis indicated that compounds 4e and 4m were reversible LSD1 inhibitors. High content analysis showed that 4e and 4m induced a dose-dependent increase of dimethylated Lys4 of histone H3 and had no impact on the expression of LSD1 in MGC-803 cells. Furthermore, 4e or 4m could remarkably increase the mRNA level of CD86, a surrogate cellular biomarker for LSD1 activity, in MGC-803 cells, suggesting that they are likely to exhibit LSD1-inhibitory activities intracellularly. These findings should encourage further modification of these compounds to produce more potent LSD1 inhibitors with potential anticancer activity. [ABSTRACT FROM AUTHOR]

A new series of [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 inhibitors were designed, synthesized, and further evaluated for their cytotoxicity against MGC-803, EC109, A549 and PC-9 cells as well as the ability of inhibiting LSD1. Some of these compounds showed potent inhibition toward LSD1 and selectively inhibited growth of A549 and PC-9 cells. Compound 6l potently inhibited growth of PC-9 cells (IC 50 = 0.59 μM), about 4-fold more potent than 5-FU. Further SARs studies led to the identification of compounds 6l-m , which had good growth inhibition against all the tested cancer cell lines and were much more potent than 5-FU and GSK2879552 . Besides, compounds 5p , 5q and 6i inhibited LSD1 potently (IC 50 = 0.154, 1.19 and 0.557 μM, respectively). Docking studies revealed that compound 5p formed arene-H interactions with Val333 and hydrogen bonds with surrounding Ala331, Met332, and Ala539 residues. Compound 5p significantly inhibited migration of A549 and PC-9 cells in a concentration-dependent manner, but had different effect on the expression of E-cadherin and N-cadherin. The [1,2,4]triazolo[1,5-a]pyrimidine scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy. [ABSTRACT FROM AUTHOR]

A series of new isatin/triazole conjugates were designed based on the hypothesis that the ester-linked compounds could be enzymatically hydrolyzed by cellular esterases inside the cells. These compounds showed moderate to good growth inhibition toward the tested cancer cells, exerted selective inhibition toward MGC-803 cells and were less toxic to normal cells HL-7702 and GES-1. Of these compounds, compound 5a showed the best inhibitory activity against MGC-803 cells (IC 50 = 9.78 μM), induced apoptosis through multiple mechanisms, as well as inhibited migration of MGC-803 cells. [ABSTRACT FROM AUTHOR]

A series of [1,2,3]triazolo[4,5- d ]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 0.85 μM against MGC-803 and 56.17 μM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 μM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1. [ABSTRACT FROM AUTHOR]

Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo . Compound 8l had moderate DPP4 inhibitory activity (IC 50 = 0.05 μM) and good oral bioavailability ( F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC 50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles ( F = 22.8%, t 1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9. [ABSTRACT FROM AUTHOR]

A series of novel 1,2,3-triazole-pyrimidine hybrids were designed, synthesized and evaluated for their anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Compound 17 showed the most excellent anticancer activity with single-digit micromolar IC 50 values ranging from 1.42 to 6.52 μM. Further mechanism studies revealed that compound 17 could obviously inhibit the proliferation of EC-109 cancer cells by inducing apoptosis and arresting the cell cycle at G2/M phase. [ABSTRACT FROM AUTHOR]

Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC 50 values ranging from 2.0 to 4.5 μM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706. [ABSTRACT FROM AUTHOR]

Abstract: A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer was designed, synthesized and evaluated for its cytotoxic activity against five human cancer cell lines and the cytotoxicity against human normal liver cell L-02. Compound 3 showed excellent cytotoxic activity and good selectivity between cancer and normal cells. Further mechanistic studies revealed that treatment of EC109 cells with compound 3 caused an obvious G2/M arrest in a concentration- and time-dependent manner and induced apoptosis probably through the mitochondrial pathway accompanied with the decrease of mitochondrial membrane potential, activations of caspase-9/-3, cleavage of MDM2 as well as up-regulation of the expressions of p53 and Bax. [Copyright &y& Elsevier]

Abstract: Two series of novel isosteviol-fused pyrazoline and pyrazole derivatives were facilely synthesized via intramolecular 1,3-dipolar cycloaddition and condensation reaction, respectively. All compounds were characterized by NMR, IR and HRMS spectra. The stereochemistry of compounds 9b, 10, 11a and 11v were further confirmed by X-ray crystallographic analysis. The antiproliferative activities of the structurally related pyrazoline and pyrazole derivatives were tested in vitro on four human malignant cell lines (SGC 7901, A549, Raji and HeLa): Our results revealed that isosteviol-fused pyrazole derivatives exhibited noteworthy cytotoxic activities. Among them, 2,4-di-Cl-phenylpyrazole derivative 11t displayed better cytotoxities with IC50 values: 2.71, 3.18, 1.09 and 13.52 μM against SGC 7901, A549, Raji and HeLa, respectively, compared to cisplatin (IC50 values: 7.56, 17.78, 17.32 and 14.31 μM, respectively). [Copyright &y& Elsevier]

Abstract: A series of novel 1,2,3-triazole–dithiocarbamate–urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 μM and 0.76 to 13.55 μM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 μM and 70 μM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques. [Copyright &y& Elsevier]

Abstract: A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC50 values ranging from 0.73 to 11.61 μM and 0.49–12.45 μM, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h. [Copyright &y& Elsevier]

Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis. Image 1 • 51 tetrahydroisoquinolines derivatives as novel PDE4 inhibitors were designed, synthesized and evaluated. • The optimum compound 36 exhibited high safety, potency, permeability and selectivity in vitro. • The crystal structure of PDE4D in complex with compound 36 was solved. • Compound 36 exhibited superior therapeutic efficacy than calcipotriol against the IMQ-induced murine psoriasis-like skin inflammation. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23 , 25 and 26 showed significant inhibitory activity against hIDO1 (IC 50 = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC 50 = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t 1/2 = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation. Image 1 • Novel 1,2,5-oxadiazole-3-carboximidamide derivatives as IDO1 inhibitors were designed, synthesized, and evaluated. • The structure-activity relationship (SAR) of this novel series of 27 compounds was demonstrated. • Compound 23 , 25 and 26 demonstrated potent in vitro inhibitory activity against hIDO1 (IC 50 = 108.7, 178.1 and 139.1 nM respectively) and compound 25 showed improved PK profiles (t 1/2 = 3.81 h, F = 33.6%) compared with epacadostat. • Compound 25 exhibited the similar anti-tumor efficacy with epacadostat without inducing significant change in body weight compared to the control group. [ABSTRACT FROM AUTHOR]