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A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC 50 values among 0.003-0.024 μM and tubulin polymerization inhibitory activity (IC 50  = 3.06 μM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G 2 /M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC 50  = 0.49 ± 0.02 μM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC 50 value of 0.003 μM, but also effectively inhibited the growth of various solid tumor cell lines with IC 50 values ranging from 0.005 to 0.036 μM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Based on the multitarget strategy, a series of novel clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC 50  = 0.11 μM), appropriate metal chelating functions, modulation of AChE- and metal-induced Aβ aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 μM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD 50  = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Aβ 1-42 -induced) and suppressed inflammation induced by Aβ 1-42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A series of NQO1 selectively activated prodrugs were designed and synthesized by introducing indolequinone moiety to the C-3, C-23 or C-28 position of 23-hydroxybetulinic acid (23-HBA) and its analogues. Among them, the representative compound 32j exhibited significant antiproliferative activities against NQO1-overexpressing HT-29 cells and A549 cells, with IC 50 values of 1.87 and 2.36 μM, respectively, which were 20-30-fold more potent than those of parent compound 23-HBA. More importantly, it was demonstrated in the in vivo antitumor experiment that 32j effectively suppressed the tumor volume and largely reduced tumor weight by 72.69% with no apparent toxicity, which was more potent than the positive control 5-fluorouracil. This is the first breakthrough in the improvement of in vivo antitumor activities of 23-HBA derivatives. The further molecular mechanism study revealed that 32j blocked cell cycle arrest at G2/M phase, induced cell apoptosis, depolarized mitochondria and elevated the intracellular ROS levels in a dose-dependent manner. Western blot analysis indicated that 32j induced cell apoptosis by interfering with the expression of apoptosis-related proteins. These findings suggest that compound 32j could be considered as a potent antitumor prodrug candidate which deserves to be further investigated for personalized cancer therapy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A novel series of diphenylamine derivatives were designed and synthesized, and their biological activities were evaluated. The anti-proliferative activities of the derivatives were tested against five human cancer cell lines (MCF-7, MDA-MB-231, A549, HeLa and HT29). Among them, compound 5f exhibited the promising anti-proliferative activity against HT29 cell lines with the IC 50 value of 23 nM. Further biological studies depicted that compound 5f inhibited cancer cell migration, colony formation and angiogenesis. Besides, dynamics studies and molecular docking studies revealed that compound 5f inhibited tubulin polymerization which may be a result of the compound binding to the colchicine site of tubulin. Furthermore, compound 5f arrested HT29 cell cycle at G2/M phase, and induced HT29 cell apoptosis by upregulating cyclin B1, Bcl-2, Bax, Cleaved-caspase9, Cleaved-caspase3, PARP, Cleaved-PARP proteins, and downregulating p-cdc25c (S216), p-cdc2 (T15) proteins. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also determined to confirm the cell apoptosis process. Finally, compound 5f greatly inhibited the tumor growth in HT29 xenograft mice by 75.5% at 10 mg/kg. Meanwhile, compound 5f owned the good pharmacokinetic properties. All the results promised that 5f is of potential to act as an antitumor candidate and worthy of further investigation., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC 50  = 0.045 μM; eeBuChE IC 50  = 19.68 μM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The natural product oridonin has the potential to be a broad-spectrum antineoplastic agent. To develop oridonin analogues with high potency, a series of novel oridonin analogues were designed and synthesized by removing the multiple hydroxyl groups of parent compound. The representative analogues 14, 19, and 26 exhibited potent anticancer effects against K562, MDA-MB-231, SMMC-7721, and MCF-7 cells. Further structural modification on their 14-OH generated more potent derivatives 16n, 21d, and 28d respectively, in which the IC 50 value of compound 16n was 50-fold more potent than parent oridonin in K562 cells. Furthermore, compound 16n significantly induced the cell cycle arrest of K562 cells at the G2 phase and increased the fraction of apoptotic cells. Importantly, compounds 16n, 21d, and 28d exhibited good antitumor activities in H22 allograft mice in vivo. These results suggest that compounds 16n, 21d, and 28d deserve further development as promising candidates for the treatment of cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

In this study, eleven new 3- and 7-positions modified scopoletin derivatives (18a-k) were designed, synthesized, and biologically evaluated against human breast cancer cell lines. Most compounds showed improved antiproliferative activity against MCF-7 and MDA-MB-231 cells and weaker cytotoxicity on human breast epithelial cell line MCF-10A than lead compound 5. Among them, compound 18e exhibited the most potent antiproliferative activity against MCF-7 cells (IC 50  = 0.37 ± 0.05 μM). Particularly, 18e produced the highest levels of nitric oxide (NO) intracellularly, and its antiproliferation effect was attenuated by hemoglobin (an NO scavenger). Further pharmacological research showed that 18e blocked the cell cycle at the G 2 /M phase, downregulated the phosphorylation of PI3K and Akt in MCF-7 cells and regulated the expressions of the apoptosis proteins to induce apoptosis. Moreover, 18e inhibited the growth of MCF-7 in vivo. Overall, 18e is a novel anticancer agent with the abilities of high concentration of NO releasing and the inhibition of PI3K/Akt signaling pathway, and may be a promising agent against MCF-7 human breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC 50 values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD 50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC 50  = 18.2 μM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC 50  = 1.08 μM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of novel vinyl selenone derivatives were designed, synthesized and evaluated as the tubulin polymerization inhibitors using a bioisosteric strategy. Among them, the representative compound 11k exhibited satisfactory anti-proliferative activities with IC 50 values ranging from 0.287 to 0.621 μM against a panel of cancer cell lines. Importantly, 11k displayed more potent in vivo antitumor activity than the positive control paclitaxel, CA-4 and parent compound 4 without apparent toxicity, which was presumably ascribed to the antiangiogenic, antiproliferative and selective effects of selenium, along with the unique physiological activity of indole skeleton, which were both introduced into the structure of target compounds. Further mechanism study demonstrated that compound 11k showed potent activity in tubulin polymerization inhibition with IC 50 value of 1.82 μM. Moreover, cellular mechanism studies disclosed that 11k blocked cell cycle arrest at G2/M phase, induced cell apoptosis and depolarized mitochondria of K562 cells. Meanwhile, 11k reduced the cell migration and had potent vascular disrupting activity. In summary, 11k could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC 50  = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H 2 O 2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (K D ) value of 3.8 μM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Inhibition of transforming growth factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC 50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC 50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Crown Copyright © 2020. Published by Elsevier Masson SAS. All rights reserved.)

A novel series of shikonin-benzo[b]furan derivatives were designed and synthesized as tubulin polymerization inhibitors, and their biological activities were evaluated. Most compounds revealed the comparable anti-proliferation activities against the cancer cell lines to that of shikonin and simultaneously low cytotoxicity to non-cancer cells. Among them, compound 6c displayed powerful anti-cancer activity with the IC 50 value of 0.18 μM against HT29 cells, which was significantly better than that of the reference drugs shikonin and CA-4. What's more, 6c could inhibit tubulin polymerization and compete with [ 3 H] colchicine in binding to tubulin. Further biological studies depicted that 6c can induce cell apoptosis and cell mitochondria depolarize, regulate the expression of apoptosis related proteins in HT29 cells. Besides, 6c actuated the HT29 cell cycle arrest at G2/M phase, and influenced the expression of the cell-cycle related protein. Moreover, 6c displayed potent inhibition on cell migration and tube formation that contributes to the antiangiogenesis. These results prompt us to consider 6c as a potential tubulin polymerization inhibitor and is worthy for further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC 50 ranging from 0.03 to 0.09 μM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC 50  = 0.009 μM) over PI3Kβ, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα inhibitor., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of C-23 modified 23-hydroxybetulinic acid (HBA) derivatives were synthesized and evaluated for their antiproliferative activity against a panel of cancer cell lines (A2780, A375, B16, MCF-7 and HepG2). The biological screening results showed that most of the derivatives exhibited more potent antiproliferative activity than HBA, and compound 6e exhibited the most potent activity with IC 50 values of 2.14 μM, 2.89 μM, and 3.97 μM against A2780, B16, and MCF-7 cells, respectively. Further anticancer mechanism studies revealed that compound 6e induced the generation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential (MMP) of B16 cells in a dose-dependent manner. Moreover, western blot analysis indicated that compound 6e downregulated the expression of anti-apoptotic protein Bcl-2 and upregulated the expression of proapoptotic protein Bax, activation of caspase 3 to induce cell apoptosis. Meanwhile, compound 6e significantly inhibited the phosphorylation of MEK, ERK, and Akt without affecting the expression of MEK, ERK, and Akt. Furthermore, the in vivo anti-tumor activity of 6e was validated (tumor inhibitory ratio of 68.4% at the dose of 30 mg/kg) in mice with B16 melanoma., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC 50 values of 1.01, 0.88, 4.36 and 5.21 μM against above human cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is a multifactorial syndrome resulting in profound misery and poses a substantial burden on human health, economy, and society throughout the world. Based on the numerous AD-related targets in the disease network, multi-target design strategy is a crucial direction to seek for enhanced therapy, and multi-target drugs have the ability to regulate more targets than single-target drugs, affecting the disease network with more potency. Herein, we highlight nine major targets associated with AD, which are acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H 3 receptor), and phosphodiesterases (PDEs), and their respective relationship to the disease network. Furthermore, eleven multi-target design strategies classified by the involvement of AChE and related promising compounds for improved therapy of AD in recent years are described based on the nine major targets., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

On the basis of the hybridization strategy of natural products, a total of 32 novel celastrol hybrids were designed, synthesized and evaluated for their antitumor activities. Most of these derivatives exihibited significant antiproliferative activities compared to celastrol, among which compound 29 displayed the strongest inhibitory capability [IC 50  = 0.15 ± 0.03 μM (A549),0.17 ± 0.03 μM (MCF-7), 0.26 ± 0.02 μM (HepG2)], which exhibited equal or superior anti-cancer activities in comparison to 2-cyano-3,12-dioxoolean-1,9 (11)-dien-28-oic acid methyl ester (CDDO-Me). The mechanism of pharmacological research indicated that 29 possessed the ability to disrupt Hsp90-Cdc37 complex which was stronger than celastrol. Meanwhile, compound 29 could induce abnormal regulation of clients (p-Akt and Cdk4) of Hsp90 and cell cycle arrest at G 0 /G 1 phase in a concentration-dependent manner. In addition, compound 29 could also induce cell apoptosis through the death receptor pathway on A549 cells. Taken together, our results demonstrated that 29 might be a promising novel candidate for further druggability research., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC 50 values ranging from 0.023 to 0.045 μM against a panel of cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for cancer therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of enmein-type diterpenoid amino acid ester derivatives (14-22) were designed and synthesized according to l-alanine-(14-oridonin) ester trifluoroacetate (clinical candidate HAO472). Their antiproliferative activities were tested against SGC-7901, Bel-7402, HL-60, PC-3, A549 and K562 cancer cell lines and L-02 normal liver cells. The results showed that compound 19 possessed the most potent cytotoxicity with IC 50  s at sub-micromolar level against human hepatoma Bel-7402 and chronic myelogenous leukemia K562 cells and more potent than l-alanine-(14-oridonin) ester (23). More importantly, 19 displayed 70-fold less cytotoxicity than parent 3 (IC 50  = 25.47 μM) against L-02 cells, which exhibited certain selectivity. Further mechanism study in Bel-7402 cells revealed that 19 could induce apoptosis, G 1 phase cell cycle arrest and mitochondrial dysfunction. Western blot results of caspase-3, Bax and cytochrome c upregulation and pro-caspase-3, Bcl-2 and Bcl-xL downregulation confirmed the intrinsic pathways. Overall, these data collectively demonstrated the high efficiency and selectivity of 19, l-phenylalanine-enmein-type diterpenoid ester, which inspires further and effective application as a potential antitumor candidate., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)

Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC 50 via the inhibition of cell cycle and induction of apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for cancer chemotherapy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC 50 values ranging from 2 to 11 nM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

To develop multifunctional drugs, a series of celastrol/NO donor hybrids were designed, synthesized and evaluated. The detection of NO release amounts showed that the more NO of these hybrids released, the more tumor cells were inhibited. 11b, which released the highest level of NO in vitro, exhibited superior potency (IC 50  = 0.48 ± 0.06 μM) compared to the other compounds. Further pharmacological studies showed that 11b induced dysregulations of the Hsp90 clients (Akt and Cdk4), apoptosis, and cell cycle arrested at G 0 /G 1 phase against A549 cells. These results suggested that inhibition of Hsp90 and release of NO was synergistic in cancer cells. Overall, the NO-releasing capacity and the inhibition of Hsp90 pathway signaling might explain the potent anti-proliferative activities of these compounds., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Antioxidant therapy is considered as promising strategy for treating oxidative stress-induced cardiovascular disease. Bis (β-elemene-13-yl) glutarate (BEG) is a novel β-elemene derivative. Herein, we examined the antioxidant activity of BEG on human umbilical vein endothelial cells (HUVECs) after injury with hydrogen peroxide (H 2 O 2 ) and investigated the mechanism involved. HUVECs were divided into the following groups: control group (untreated cells); treated groups (cells treated with 0.1, 1, 10 μmol/L of BEG); positive control group (cells treated with 0.1 mM Vitamin E); model group (cells treated with 0.5 mM H 2 O 2 alone). Cells were pre-incubated with or without BEG for 24 h and then incubated for a further 2 h with 0.5 mM H 2 O 2 . Our results showed that BEG significantly reduced H 2 O 2 induced loss in endothelial cell viability, reactive oxygen species (ROS) production, reduced lactate dehydrogenase (LDH) release, and malonyldialdehyde (MDA) level in a concentration-dependent manner. Also, BEG increased the cellular the superoxide dismutase (SOD) activity. Moreover, we found that H 2 O 2 decreased Akt and eNOS phosphorylation, which perhaps, indirectly reduced nitric oxide (NO) production. These effects induced by H 2 O 2 , however, were reduced by pre-treatment with BEG. BEG effects were inhibited by a PI3K inhibitor (wortmannin) and eNOS inhibitor (L-NAME). In conclusion, the present study demonstrated that BEG has antioxidant activity. Furthermore, BEG reduced H 2 O 2 -induced endothelial cells injury by the involvement of antioxidation and PI3K/Akt/eNOS/NO signaling pathways., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Vinyl sulfone or sulfoxide moieties were firstly introduced to the structure of chalcone compound by replacing the carbonyl group to afford a series of novel compounds as potential anti-tubulin agents. All of the target compounds were evaluated for their anti-proliferative activity. Among them, compound 12m showed the most potent activity against a panel of cancer cell lines with IC 50 values ranging from 0.128 to 0.606 μM. Further mechanism studies demonstrated that compound 12m caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Moreover, compound 12m reduced the cell migration and disrupted the capillary-like tube formation in human umbilical vein endothelial cell (HUVEC) assays. Importantly, compound 12m significantly and dose dependently inhibited tumor growth in H22 liver cancer allograft mouse model, which is more potent than control compound CA-4, suggesting that 12m deserves further research as a potential anti-tubulin agent targeting colchicine binding site on tubulin., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC 50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The diterpenoids present highly varied oxidation patterns subjected to fascinating skeletal rearrangements, and possess antitumor, antibacterial, antihyperglycemic, anti-inflammatory activities and so on. While total synthesis is a possible solution to obtain required diterpenoid derivatives, the need for multisteps to build complex "privileged structures" is always prohibitive by semi-synthesis from naturally abundant related molecules. From this perspective, stevioside and its hydrolysis products steviol and isosteviol are good leads in the field of medicinal chemistry for diterpenoid drug discovery. Stevioside has a complex diterpenoid glycoside molecule comprised of an aglycone, steviol with the ent-kaurane skeleton and three molecules of glucose. Hydrolyzed under alkaline or acidic condition, stevioside generates ent-kaurane diterpenoid steviol or ent-beyerane diterpenoid isosteviol, respectively. Except for direct applications, they are widely used to provide ent-kaurane or ent-beyerane core structures for further medicinal chemistry study. Besides, these molecules also serve as model molecules, starting materials or catalysts in the field of synthetic chemistry. In this review, their biological activities and medicinal chemistry work are comprehensively summarized which are very helpful for diterpenoid drug exploration., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

High levels of both nitric oxide (NO) and reactive oxygen species (ROS) could act as pro-apoptotic signals in cancerous cells. In this study, we conjugated diazeniumdiolates (NONOates), an important class of NO donors, with a natural occurring plumbagin (PL) which is primarily an excellent ROS inducer. Herein, a total of 12 novel plumbagin/NONOate hybrids have been synthesized and evaluated for their inhibitory effects on a panel of human cancer cell lines (MDA-MB-231, A549, HepG2 and HCT-116 cells) and two normal human cells (HK-2 and WRL-68 cells). Among them, compounds 10a and 10b demonstrated superior potencies compared to their parent compound (IC 50 values of 3.48-6.68 μM) against the above cancer cell lines but weak inhibitory effects on normal cells. In concordance with their selective cytotoxicities, 10a and 10b released higher level of NO in cancer cells than normal cells. Besides, the potent compound 10a induced apoptosis of A549 cells in a concentration-dependent manner and resulted in more ROS generation compared with the parent compound plumbagin., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Persistent activated STAT3 has a striking correlation with cancer development and inhibition of STAT3 signaling pathway is a novel therapeutic way for human cancers. Among STAT family, STAT1 and STAT3 play opposite roles in tumorigenesis. However, the discovery of selective STAT3 inhibitors is still challenging to date. In this study, a series of small-molecular (MW < 500) benzensulfanilamide derivatives were designed to selectively suppress STAT3 activation for anti-cancer treatment. The most potent compound 11 inhibited both overexpressed and IL-6 induced STAT3 phosphorylation, whereas 11 displayed little effect on the phosphorylation of other STAT isoforms STAT1, STAT5, demonstrating 11 was a selective STAT3 inhibitor. Meanwhile, 11 dismissed STAT3 DNA binding activity and colony formation. In addition, 11 elevated the ROS level and induced apoptosis of cancer cells. Furthermore, 11 effectively suppressed tumor growth in an in vivo mouse-xenograft model., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A series of O 2 -(2,4-dinitrophenyl)diazeniumdiolates derivatives were designed, synthesized and antiproliferative activities evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferases π (GSTπ). Most of these derivatives exhibited significant antiproliferative activities compared to the reported NO-donor prodrug JS-K, among which compounds 27 and 36 had superior potency with IC 50 below 1 μM. NO released amounts detection of all derivatives indicated that the antiproliferative activities were positively correlated with the levels of intracellular NO release in HCT116 cells. The most potent compound 36 exhibited improved uncatalyzed stability of GSTπ. Additionally, 36 showed remarkably multidrug resistance reversal activity which reversed multidrug resistance of adriamycin (ADR) in MCF-7/ADR cells with IC 50 from 84.94 μM to 1.13 μM., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Because it is highly contagious, the influenza A virus (IAV) has the potential to cause pandemics in humans. The emergence of drug-resistant strains requires the development of new chemical therapeutics. Oroxylin A (OA) is a flavonoid which has been shown to have antioxidant and antitumor effects. However, intensive studies in which OA fights against different influenza virus strains and the underlying antiviral mechanisms have not been reported. In our study, the antiviral activities in cells and in mice, the preliminary mechanisms of OA were investigated. Our data show that it can inhibit A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant A/FM/1/47-H275Y (H1N1-H275Y) viruses in MDCK cells in a dose-dependent manner with inhibitory rates of 70.9%, 59.5% and 23.2%, respectively, at 50μM doses. Orally administered OA effectively protected mice from H1N1 virus-induced death, body weight loss and lung injury, with a survival rate of 60.0% at 100mg/kg/d dose. In addition, the H1N1 M1 gene transcription and protein synthesis were suppressed by 43.7% and 33.2%, respectively, in the late biosynthesis stage. This resulted in inhibition of viral replication. Furthermore, we found that OA has a neuraminidase (NA) inhibitory effect with IC 50 values for H1N1-H275Y and A/Anhui/1/2013-R294K (H7N9-R294K) of 241.4μM and 203.6μM, respectively. Interferons (IFNs) produced by the virally infected cells play important roles in antiviral defense, therefore, IFN levels in the blood were also tested in mice. We found that IFN-β and IFN-γ in the OA 100mg/kg/d group were markedly increased by 24.5pg/mL and 859.9pg/mL, respectively, compared with those in the model group. This indicated that OA could induce the secretion of IFNs. The potent inhibition of virus replication and NA inhibitory activity, as well as the promotion of IFN production suggest that OA could be a drug candidate to fight against IAVs including oseltamivir-resistant strains., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation., (Copyright © 2017. Published by Elsevier Masson SAS.)

A series of plumbagin/NO donor hybrids were designed, synthesized and evaluated in vitro against triple negative breast cancer (MDA-MB-231), hepatocellular (HepG2) and lung (A549) carcinoma cells. Most furoxan-based plumbagin derivatives exhibited significantly superior potency compared to their parent compound. Noticeably, MDA-MB-231 cells are the most sensitive to these furoxan-based plumbagin derivatives as evidenced by IC 50 values ranging from 1.24 to 5.20 μM. Besides, NO released amounts detection of all hybrids suggested that in most cases, the antiproliferative activities were positively correlated with the levels of intracellular NO release in MDA-MB-231 cells. The most active compound (11a) also possessed higher chemical stability at different pHs (6.0, 7.4 and 8.0) than plumbagin. Together, the above promising results warrant the future potential of plumbagin/NO hybrids as the lead compounds against triple negative breast cancer deserving further research., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A series of novel furoxan-based NO-donating β-elemene hybrids were designed and synthesized to improve the anticancer efficacy of natural β-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound β-elemene. Interestingly, these compounds displayed excellent sensitivity to U87 cells with IC 50 values ranging from 173 to 2 nM. Moreover, most compounds produced high levels of NO in vitro, and the antitumor activity of 11a in U87 cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced apoptosis of U87 cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which was superior to that of β-elemene (TIR, 49.6%) at the same dose of 60 mg/kg. Together, the remarkable biological profiles of these novel NO-donating β-elemene derivatives may make them promising candidates for the intervention of human cancers., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC 50  = 0.263-2.904 μM), while NQO1-defficient lung adenosquamous carcinoma cells (H596) were less sensitive to these compounds, among which, compound 29h exhibited the most potent antiproliferative activity against both A549 and HT-29 cells, with IC 50 values of 0.386 and 0.263 μM, respectively. Further HPLC and docking studies demonstrated that 29h is a good substrate of NQO1. Moreover, the investigation of anticancer mechanism showed that the representative compound 29h affected cell cycle and induced NQO1 dependent apoptosis through an oxidative stress triggered mitochondria-related pathway in A549 cells. Besides, the antitumor activity of 29h was also verified in a liver cancer xenograft mouse model. Biological evaluation of these compounds concludes that there is a strong correlation between NQO1 enzyme and induction of cancer cell death. Thus, this suggests that some of the target compounds activated by NQO1 are novel prodrug candidates potential for selective anticancer therapy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A novel class of NO-donating protoberberine derivatives were synthesized and initially evaluated for their anti-hepatocellular carcinoma activities. Most of the compounds exhibited more potent activity against HepG2 cells than parent compounds berberine and palmatine. In particular, compound 15a exerted the strongest activity with an IC 50 value of 1.36 μM. Moreover, most compounds released moderate levels of NO in vitro, and the antitumor activity of 15a in HepG2 cells was remarkably diminished by an NO scavenger. Interestingly, compound 15a displayed a broad-spectrum antitumor efficacy and possessed good selectivity between tumor cells (HepG2, SMMC-7721, HCT-116, HL-60) and normal liver LO-2 cells. The mechanism studies revealed that 15a blocked the G2 phase of the cell cycle and induced apoptosis of HepG2 cells by mitochondrial depolarization. Furthermore, 15a inhibited tumor growth in H22 liver cancer xenograft mouse model by 62.5% (w/w), which was significantly superior to parent compound palmatine (41.6%, w/w). Overall, the current study may provide a new approach for the discovery of novel antitumor agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC 50 range in 0.33-0.75 μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15in vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)