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Two biotin-polyethylene glycol (PEG)4‑diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b, were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives (DAP-F and DAP-NO

Three ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes Ru1–Ru3 were designed and synthesized for evaluating antitumor activity. All the complexes exhibited high in vitro cytotoxicity against MGC-803, T24, HepG2, CNE2, MDA-MB-231, MCF-7, A549, and A549/DDP cell lines. Ru1, Ru2, and Ru3 were 11, 8 and 10 times, respectively, more active than cisplatin against A549/DDP. An in vivo study on MGC-803 xenograft mouse models demonstrated that representative Ru2 exhibited an effective inhibitory effect on tumor growth, showing stronger antitumor activity than cisplatin. Biological investigations suggested that Ru2 entered MGC-803 cells by a clathrin-mediated endocytic pathway, initially localizing in the lysosomes and subsequently escaping and localizing in the mitochondria. Mitochondrial swelling resulted in vacuolization, which induced vacuolation-associated cell death and necroptosis with the formation of necrosomes (RIP1–RIP3) and the uptake of propidium iodide. These results demonstrate that the potential of Ru2 as a chemotherapeutic agent to kill cancer cells via a dual mechanism represents an alternative way to eradicate apoptosis-resistant forms of cancer.

One new phenolic derivative, 1-(4',5'-dihydroxy-2'-methylphenyl)-pentane-1,4-dione (1), along with eighteen known compounds including eight sesquiterpenoids (2–9), one triterpenoid (10), one bisdpoxylignan (11), one coumarin (12), and seven flavonoids (13–19) were isolated from the dried inflorescence of Tibetan herbal medicine Pulicaria insignis. The structure of 1 was established by spectroscopic methods, including HRESIMS, IR, 1D, and 2D NMR. All isolates were assessed for the cytotoxic activities against MGC-803, T24, HepG2, and HeLa cell lines using the MTT assay. The results showed that compound 1 displayed moderate cytotoxicity against Hela and HepG2, and compounds 3, 4, 5, 6, and 13 exhibited potential cytotoxic activities against the four cell lines with IC50 values ranging from 3.05 to 14.37 μM. Notably, compound 5 exhibited significant anti-proliferative activities against HepG2 cell lines with the IC50 values of 3.05 ± 0.36 μM. Further bioactivity investigation showed that compound 5 could block HepG2 cells in the G1 phase of the cell cycle, thereby inhibiting the growth of HepG2 cells and inducing apoptosis in HepG2 cells.

A new labdane-type diterpenoid, ent-19-ol-13-epi-manoyl oxide,19-undecane ester, together with ten known diterpenes, were isolated from the ethanolic crude extract of the fresh tubers of Sagittaria trifolia L. The chemical structures of these compounds were determined by extensive 2-D NMR experiments and by comparison with the data reported in the literature. These compounds showed different inhibitory effects on various human cancer cells. Among these, compound 11 exhibited potential inhibition effects against human colon cancer cells. Moreover, flow cytometry demonstrated that compound 11 arrested the cell cycle at the G1 phase and induced cellular apoptosis, accompanied by mitochondrial membrane potential reduction. Mechanistic studies revealed that treatment with compound 11 inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Compound 11 also inhibited the expression of c-Myc, Cyclin D1, and Bcl-2, the downstream targets of NF-κB. Therefore, our findings provided insight into the anticancer components of Sagittaria trifolia L. tubers, which could facilitate their utilization as functional food ingredients.

Retinoic acid receptor related orphan receptor γt (RORγt), identified as the essential functional regulator of IL-17 producing Th17 cells, is an attractive drug target for treating autoimmune diseases. Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile. Efforts in reducing the lipophilicity and improving the LLE values led to the discovery of c9, which demonstrated potent RORγt inverse agonistic activity and consistent metabolic stability. During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases.

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ8-7,12-lactam moiety, glechomanamides A-C (1-3), and two pairs of 7,12-hemiketal sesquiterpenoid epimers (4a/b, 5a/b) were isolated from Salvia scapiformis. Their structures were elucidated by spectroscopic methods including HRESIMS, IR, UV, and 1D and 2D NMR and also confirmed by single-crystal X-ray diffraction analysis. The chemical transformation of compounds 1-5 in a solution environment was analyzed by 2D NMR spectroscopy. The aza acetallactams (1-3) were stable in organic solvent, while single crystals of the hemiacetal esters (4a/b, 5a/b) underwent a tautomeric equilibrium after being dissolved. Single crystals of 4a, 4b, and 5a were obtained for the first time as their naturally occurring forms. Glechomanamide B (2) exhibited antiangiogenic activity by suppression of vascular endothelial growth factor (VEGF)-induced tube formation through modulation of VEGF receptor 2 (VEGFR2)-mediated signaling pathways in human umbilical vascular endothelial cells (HUVECs). In addition, compound 2 also showed the significant suppression of mRNA expression associated with glycolysis and angiogenesis biomarkers in high glucose (30 mM)-induced HUVECs. These findings suggest that compound 2 might be a potential lead compound candidate for the management of diabetic retinopathy.

A series of asiatic acid (AA) based 1,2,3-triazole derivatives were designed, synthesized and subjected to a cell-based NF-κB inhibition screening assay. Among the tested compounds, compound 6k displayed impressive NF-κB inhibitory activity with an IC(50) value in the low micromolar range. A molecular docking study was performed to reveal key interactions between 6k and NF-κB in which the 1,2,3-triazole moiety and the hydroxyl groups of the AA skeleton were important for improving the inhibitory activity. Subsequently, surface plasmon resonance analysis validated the high affinity between compound 6k and NF-κB protein with an equilibrium dissociation constant (KD) value of 0.36 μM. Further studies showed that compound 6k observably inhibited the NF-κB DNA binding, nuclear translocation and IκBα phosphorylation. Moreover, in vitro antitumor activity screening showed that compound 6k (IC(50) = 2.67 ± 0.06 μM) exhibited the best anticancer activity against A549 cells, at least partly, by inhibition of the activity of NF-κB. Additionally, the treatment of A549 cells with compound 6k resulted in apoptosis induction potency and in vitro cell migration inhibition. Thus, we conclude that AA based 1,2,3-triazole derivatives may be potential NF-κB inhibitors with the ability to induce apoptosis and suppress cell migration.

Novel NF-κB inhibitors based on Glycyrrhetinic acid (GA) derivatives containing aminophosphonate ester moieties were rationally designed and synthesized as well as evaluated their antitumor activities using MTT assay. Many target compounds showed potent antitumor activities against the tested human cancer cell lines including cisplatin-resistant cells, and exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 cells, respectively. Among them, compound 12e possessed excellent antitumor activities against the tested human cancer cell lines and showed low cytotoxicity toward to human normal liver cells. Moreover, 12e caused obvious loss of MMP and significantly induced ROS production, and displayed inhibition of cell migration against A549 cells in vitro. Importantly, 12e arrested the cell cycle at the S phases and ultimately induced cell apoptosis in A549 cells through blockage of NF-κB signaling pathway. Our research provided an efficient strategy for targeting NF-κB antitumor drug development.

A new labdane-type diterpenoid, ent-19-ol-13-epi-manoyl oxide,19-undecane ester, together with ten known diterpenes, were isolated from the ethanolic crude extract of the fresh tubers of Sagittaria trifolia L. The chemical structures of these compounds were determined by extensive 2-D NMR experiments and by comparison with the data reported in the literature. These compounds showed different inhibitory effects on various human cancer cells. Among these, compound 11 exhibited potential inhibition effects against human colon cancer cells. Moreover, flow cytometry demonstrated that compound 11 arrested the cell cycle at the G1 phase and induced cellular apoptosis, accompanied by mitochondrial membrane potential reduction. Mechanistic studies revealed that treatment with compound 11 inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Compound 11 also inhibited the expression of c-Myc, Cyclin D1, and Bcl-2, the downstream targets of NF-κB. Therefore, our findings provided insight into the anticancer components of Sagittaria trifolia L. tubers, which could facilitate their utilization as functional food ingredients.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) are important targets in the tumor microenvironment for cancer therapy. In the present study, a set of naphthoquinone aromatic amide-oxime derivatives were designed, which stimulated the immune response via IDO1 inhibition and simultaneously displayed powerful antitumor activity against three selected cancer cell lines through suppressing STAT3 signaling. The representative compound 8u bound effectively to IDO1, with greater inhibitory activity relative to the commercial IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear translocation of STAT3. Consistently, in vivo assays demonstrated a higher antiproliferative activity of compound 8u in both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound with dual immunotherapeutic and anticancer efficacy may represent a new generation of highly efficacious drug candidates for cancer therapy.

Two previous undescribed cyclic pentapeptide-type compounds (1–2), with two known ones (3–4), were first isolated and purified from Clerodendrum japonicum (Thunb.) Sweet. Their structures were elucidated by extensive spectroscopic data (1D and 2D NMR) analysis. The absolute configurations of the two compounds were assigned using a combination of Marfey’s method and HPLC-MS analysis. All four compounds showed weak cytotoxicity against four human cancer cells lines (T24, A549, HepG2, MGC-803), with IC50 values ranging from 23.8 to 39.6 μM.

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1−5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ

Potentilla discolor has been used as the Traditional Chinese Medicine ingredient in prescription for over 400 years, and scientific evidences have confirmed its effectiveness as an anticancer agent. The present study is undertaken to assess, for the first time, the chemical composition, potential in vitro anti-tumor activities and related mechanisms of the essential oil, which was extracted from Potentilla discolor fresh roots by supercritical CO2 fluid extraction technology. Twenty-nine compositions were identified by gas chromatography-mass spectrometry. The anti-tumor activity of the essential oil was screened against four cancer cell lines and the lowest IC50 value was 19.02 μg/mL on T24 cell line. Then, T24 was selected as a representative cell line for the related mechanism research. As a result, cell cycle assay confirmed that the cell growth was inhibited by Potentilla discolor essential oil and cell cycle was arrested in DNA synthesis phase. A series of apoptosis analysis indicated that Potentilla discolor essential oil induced apoptosis through mitochondrion-mediated intrinsic pathway. This study revealed that Potentilla discolor essential oil has significant anti-tumor activity. It should be useful in the search for new potential anti-tumor agents and pharmaceutical industries.

Six novel of Pt(IV) complexes comprising chalcone analogues were synthesized and evaluated for anti-proliferative activity using MTT assay. In vitro evaluation revealed that all Pt(IV) complexes showed better and more potent activity against three human cancer cells including CDDP resistant cells than that of their corresponding mother Pt(II) species. Among them, two representative complexes, 14 and 17, exhibited better cell selectivity between cancer cells and normal cells than CDDP. Molecular docking study indicated that complexes 14 and 17 could bind to the colchicine site of tubulin. Moreover, complexes 14 and 17 also remarkably displayed inhibition of cell migration against HUVEC cells in vitro. Molecular mechanism studies suggested that 14 and 17 induced production of reactive oxygen species (ROS), cell cycle arrest at the G2/M phase, and mitochondria-mediated apoptosis by regulating the expression of Bcl-2 family members.

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives (3a1−3d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a1 exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a1 may exert antitumor activity by the up-regulation of Bax, intracellular Ca2+ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.

A further phytochemical investigation of the aerial parts of Lysimachia foenum-graecum Hance led to the isolation of three new oleanane-type triterpenoid saponins, foegraecumosides L–N ( 1 – 3 ), along with one known saponin, 3- O - β - d -glucopyranosyl-(1 → 2)-α- l -arabinopyranosyl-cyclamiretin A ( 4 ). Their structures were elucidated by spectroscopic data analyses and chemical methods Compounds 1 − 4 were evaluated for their cytotoxicity against NCI-H460, MGC-803, HepG2, and T24 human cancer cell lines, and compound 4 showed moderate activity against all tested cell lines. Furthermore, the cytotoxicity of compound 4 was tested on drug-sensitive and drug-resistant lung cancer cell lines (A549 and A549/CDDP, respectively).

Series of novel alizarin and phosphoryl amino acid scaffold (4a–4d, 8a–8d) were synthesized and evaluated for the suppression of cancer cell proliferation in vitro against MGC-803, HepG2, T24, NCI-H460, and SK-OV-3 cell lines by standard 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay compared with commercial anticancer drug doxorubicin. Interestingly, all newly synthesized compounds exhibited relatively high cytotoxicity compared with alizarin and low cytotoxicity against human normal liver cell line HL-7702 cells. Especially, compound 8d showed the best cytotoxicity against SK-OV-3 cells with IC50 7.09 µM, which was slightly worse than that of drug doxorubicin. The cell apoptosis-inducing activity of representative compound 8d in SK-OV-3 cells revealed that the anticancer activity of this compound depended on apoptosis of cancer cells via regulation of Bcl-2 family members, activation of caspase-9 and caspase-3. Cell cycle analysis confirmed that compound 8d mainly arrested SK-OV-3 cells in G2 stage. In addition, molecular docking studies were performed to position compound 8d into the telomerase (5CQG) active site to determine the probable binding model.

Selagintamarlin A (1), a novel selaginellin analogue featuring the unique motif of 1H-2-benzopyran, a new selaginpulvilin E (2), together with eight known analogues were isolated from Selaginella tamariscina. Their structures were elucidated by extensive spectroscopic analyses. A plausible biosynthetic pathway of 1 was also postulated. Compound 1 showed remarkable inhibitory activity against phosphodiesterase-4 (PDE4D2), with an IC50 value of 40 nM, which is 20-fold higher than that of the positive control (rolipram). Furthermore, compound 1 significantly inhibited tubulin polymerization.

A series of novel chalcone derivatives were designed and synthesized as potential antitumor agents. Structures of target molecules were confirmed by 1 H NMR, 13 C NMR and HR-MS, and evaluated for their in vitro anti-proliferative activities using MTT assay. Among them, compound 12k displayed potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC 50 values ranged from 3.75 to 8.42 μM. In addition, compound 12k was found to induce apoptosis in NCI-H460 cells via the mitochondrial pathway, including an increase of the ROS level, loss of mitochondrial membrane potential, release of cytochrome c , down-regulation of Bcl-2, up-regulation of Bax, activation of caspase-9 and caspase-3, respectively. Moreover, the cell cycle analysis indicated that 12k effectively caused cell cycle arrest at G2/M phase. The results of tubulin polymerization assay displayed that 12k could inhibit tubulin polymerization in vitro . Furthermore, molecular docking study indicated that 12k can be binding to the colchicine site of tubulin.

A novel class of platinum(IV) complexes comprising a monoaminophosphonate ester moiety, which can not only act as a bone-targeting group but also inhibit matrix metalloproteinases (MMPs), were designed and synthesized. Biological assay of these compounds showed that they had potent antitumor activities against the tested cancer cell lines compared with cisplatin and oxaliplatin and indicated low cytotoxicity to human normal liver cells. Particularly, the platinum(IV) complexes were very sensitive to cisplatin resistant cancer cell lines. The corresponding structure-activity relationships were studied and discussed. Related mechanism study revealed that the typical complex 11 caused cell cycle arrest at S phase and induced apoptosis in Bel-7404 cells via a mitochondrial-dependent apoptosis pathway. Moreover, complex 11 had potent ability to inhibit the tumor growth in the NCI-H460 xenograft model comparable to cisplatin.

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amide side chains were synthesized and evaluated for inhibition of NF-κB as well as their antitumor effects. These compounds exhibited significant inhibition activity toward NF-κB with IC50 values at micromolar concentrations in the NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound 5Y8 revealed key interactions between 5Y8 and the active site of NF-κB in which the functionalized amide moiety at the C-28 position and an ester group at the C-3 position were important for improving the activity. In particular, compound 5Y8 appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and inducing apoptosis. Mechanistically, compound 5Y8 might trigger the apoptotic signaling pathway. Thus, the rational design of UA derivatives with functionalized aniline or amide side chains offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in the NCI-H460 lung adenocarcinoma cell line.

A series of antitumor agents based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for antiproliferative activity using a panel of cancer cell lines, and the effects and mechanism of apoptosis induction were determined. These compounds exhibited significant selectivity to different cancer cell lines with IC50 values at micromolar concentrations. In particular, compound I-11 appeared to be the most potent compound, with an IC50 = 4.85 ± 1.44 μM against the NCI-H460 cell line, at least partly, by the induction of apoptosis. Mechanistically, compound I-11 induced the activation of caspase-12 and CHOP, which triggered apoptotic signalling via the ROS-dependent endoplasmic reticulum pathway and arrested the cell cycle at the S phase. Thus, we concluded that dipeptide derivatives containing the thiourea moiety terminally functionalized by electron-withdrawing substituents may be potential antitumor agents for further investigation.

Cancer is one of the leading cause of unnatural death globally. There is still a great need for effective anticancer agents from plant sources. Corydalis saxicola Bunting is a medicinal plant that is traditionally used to treat various diseases in southwest China. Previous phytochemical investigations of C. saxicola have focused on isoquinoline alkaloids that have been isolated, which have activity against anti-hepatitis B virus and inhibit DNA topoisomerase I. However, the exploration of other classes of constituents and their bioactivities needs further study.The aim of this study was to investigate the antitumor activity of isolated lignanamides as well as their detailed cellular proliferation, suppression, and cytotoxic mechanisms.Herbs were extracted and constituents were purified by chromatographic separation, including silica gel, ODS, MCI, Sephadex LH-20 and Preparative HPLC. The compound structures were elucidated by the use of UV, IR, NMR and MS spectral data. The cytotoxicity effects of all compounds from the MGC-803, HepG2, T24, NCI-H460, Spca-2, and HL-7702 cell lines were studied by MTT assays. The induction of apoptosis by corydalisin C was investigated using acridine orange/ethidium bromide staining, Hoechst 33,258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry.Three new lignanamides, together with five known analogues, were isolated from the aerial parts of C. saxicola. Corydalisin C possessed the most potent inhibitory effects, with an IC50 value of 8.81 ± 2.05µM against MGC-803 cells. SAR analysis showed that the sterics and chirality of lignanamides play a crucial role in pharmacologically relevant events. The antitumor activity was possibly due to the induction of cell apoptosis. Western blot experiments demonstrated that corydalisin C may induce apoptosis through both intrinsic and extrinsic apoptosis pathways, accompanied by down-regulating the expression of Bcl-2 and FasL in a time-dependent manner.This study provides evidence that a lignanamide from the ethyl acetate extract of whole plants of C. saxicola showing potential in cancer treatment.

Four series of new 3-nitro naphthalimides derivatives, 4(4a‒4f), 5(5a‒5i), 6(6a‒6e) and 7 (7a‒7j), were designed and synthesized as antitumor agents. Methyl thiazolyl tetrazolium (MTT) screening assay results revealed that some compounds displayed effective in vitro antiproliferative activity on SMMC-7721, T24, SKOV-3, A549 and MGC-803 cancer cell lines in comparison with 5-fluorouracil (5-FU), mitonafide and amonafide. Nude mouse xenotransplantation model assay results indicated that compounds 6b and 7b exhibited good in vivo antiproliferative activity in MGC-803 xenografts in comparison with amonafide and cisplatin, suggesting that compounds 6b and 7b could be good candidates for antitumor agents. Gel electrophoresis assay indicated that DNA and Topo I were the potential targets of compounds 6b and 7b, and comet assay confirmed that compounds 6b and 7b could induce DNA damage, while the further study showed that the 6b- and 7b-induced DNA damage was accompanied by the upregulation of p-ATM, P-Chk2, Cdc25A and p-H2AX. Cell cycle arrest studies demonstrated that compounds 6b and 7b arrested the cell cycle at the S phase, accompanied by the upregulation of the expression levels of the antioncogene p21 and the down-regulation of the expression levels of cyclin E. Apoptosis assays indicated that compounds 6b and 7b caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-3, caspase-9 and PARP and the downregulation of Bcl-2. These mechanistic studies suggested that compounds 6b and 7b exerted their antitumor activity by targeting to DNA, thereby inducing DNA damage and Topo I inhibition, and consequently causing S stage arrest and the induction of apoptosis.

Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.

A new cytisine-type alkaloid, (-)-N-hexanoylcytisine (1), and a new isoflavan, (3S, 4R)-4-hydroxy-7,4'-dimethoxyisoflavan 3'-O-β-d-glucopyranoside (2), along with 10 known compounds, were isolated from the rhizomes of Sophora tonkinensis. Their structures were determined by spectroscopic methods, chemical evidence, and ECD data analysis. All of the isolates were evaluated for their cytotoxic activities against four human tumor cell lines.

A series of novel asiatic acid (AA) derivatives containing α-aminophosphonate were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against five cancer cell lines (A549, Hct-116, T24, Spca-2 and SK-OV-3 cell) and a normal cell line (HUVEC cell) were evaluated, employing standard MTT assay. Antitumor activities screening result indicated that many target compounds displayed moderate to high levels of antitumor activities compared with AA, 5-fluorouracil (5-FU) and cisplatin, and exhibited much lower cytotoxicity against normal cell than 5-FU and cisplatin. In addition, the mechanism of representative compound 3d was preliminarily investigated by AO/EB staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, flow cytometry and western blot. Compound 3d inducing apoptosis involved intracellular Ca2+ production, the loss of mitochondrial membrane potential and intracellular reactive oxygen species (ROS) production. Western blot analysis also demonstrated that compound 3d treatment triggered the mitochondrial apoptotic pathway, indicating by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation. Moreover, the cell cycle analysis showed that compound 3d may confine T24 cells in G1/S phase mainly through the p53-dependent pathway. Together, these results implied a critical role of ROS, caspase-9 and p53 in compound 3d-inducing G1/S arrest and apoptosis of T24 cells.

Matrix metalloproteinase 9 (MMP-9) is one of the structurally related zinc-dependent endopeptidases families and provides a new target for cancer therapy owing to its pivotal role in metastatic tumors. In this paper, fourteen lignans, including three novel lignans, named selamoellenin B-D (1-3), and eleven known lignan derivatives (4-14) were isolated from the plant of Selaginella moellendorffii. Among them, compound 3 is optically active, which was enantiomerically seperated to afford a pair of enantiomers, (-)-3 and (+)-3. Their structures were elucidated by extensive spectroscopic analyses. Their cytotoxic activities were evaluated against four human cancer cell lines. Among them, five compounds (4, 5, 6, 11 and 13) exhibited great potent cytotoxicity and their structure-activity relationships were also discussed. All compounds except for 3 lignan analogues with low cytotoxicity were selected for further in vitro enzyme inhibition, surface plasmon resonance (SPR), and molecular docking assays based on the MMPs target. The results shown that, compound 11 have the best inhibitory effect and can be considered as a potential drug candidate targeting at MMP-9 for cancer therapy.

A series of novel 2-chloro-3-(1

Pentacyclic triterpene derivatives possessing polyhydroxyl ring A exhibit many important pharmacological activities. (1β, 2α, 3β, 19β, 23)-1,2,3,19,23-pentahydroxyolean-12-en-28-oic acid (5), a new bioactive phytochemical with tetra-hydroxyl ring A isolated from Euphorbia sieboldiana in our laboratory, showed potential inhibition effects against several cancer cells previously. This study was performed to investigate the underlying mechanisms of action for its antitumor activity. The results showed that compound 5 inhibited dose-/time-dependently cell growth with low toxicity to normal cells and induced apoptosis in cervical cancer cells. Also, compound 5 inhibited the growth and proliferation of HeLa cells and resulted in G1 phase arrest. Furthermore, exposure of cells to compound 5 caused inactivation of the TNF-α-TAK1-IKK-NF-κB axis and inhibition of TNF-α-stimulated NF-κB activity, followed by down-regulation of NF-κB target genes involved in cell apoptosis (Bcl-2) and in the cell cycle and growth (Cyclin D, c-Myc). Additionally, compound 5 significantly suppressed the migration of HeLa cells. In addition, exposure of HeLa cells to compound 5 decreased the activity of NF-κB through the generation of reactive oxygen species (ROS). Collectively, these results suggested that compound 5 exerted potent anticancer effects on HeLa cells in vitro through targeting the ROS-dependent NF-κB signaling cascade and this compound may be a promising anticancer agent for cancer treatment.

A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant.

A series of novel ursolic acid (UA) derivatives modified at the C-3 and the C-28 positions were designed and synthesized in an attempt to develop potential antitumor agents. The in vitro cytotoxicity were evaluated against five cancer cell lines (MGC-803, HCT-116, T24, HepG2 and A549 cell lines) and a normal cell (HL-7702) by MTT assay. The screening results indicated that some of these target compounds displayed moderate to high levels of antiproliferative activities compared with ursolic acid and 5-fluorouracil (5-FU), and exhibited much lower cytotoxicity than 5-FU, indicating that the targeted compounds had selective and significant effect on the cell lines. The induction of apoptosis and affects on the cell cycle distribution of compound 6r were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which revealed that the antitumor activity of 6r was possibly achieved through the induction of cell apoptosis by G1 cell-cycle arrest. Western blot and qRT-PCR (quantitative real-time PCR) experiments demonstrated that compound 6r may induce apoptosis through both of intrinsic and extrinsic apoptosis pathway.

In an effort to develop potent anti-cancer chemopreventive agents, a novel series of bisindole derivatives bearing oxime moiety were synthesized. Structures of all compounds were characterized by NMR and HRMS. Anti-proliferative activities for all of these compounds were investigated by the method of MTT assay on 7 human cancer lines and the normal cell lines (HUVEC). Most of them showed a noteworthy anti-cancer activity in vitro, the half maximal inhibitory concentration (IC50) value is 4.31 μM of 4e against T24. The results from Hoechst 33258 and acridine orange/propidium iodide staining as well as annexinV-FITC assays provided evidence for an apoptotic cell death. The further mechanisms of compound 4e-induced apoptosis in T24 cells demonstrated that compound 4e induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis and western-blot analysis indicated that compound 4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins particularly cyclin D1.

It is well-known that cisplatin exhibited a broad spectrum of anticancer activities against many solid tumors, but its severe toxicity and drug resistance have largely limited wider clinical applications. Various strategies have been tried to discover new Pt (II) drugs with at least equal activity as well as low toxicity compared to cisplatin, but the inherent problem remains unsolved. Here we report that Pt (IV) complexes comprising a CA-4 analogue, as dual-targeting Pt (IV) prodrug, were synthesized and evaluated for anti-proliferative activity using MTT assay. Among them, complex 19 displayed most potent activity against the tested cancer cell lines, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than that of cisplatin. Mechanism studies revealed that complex 19 effectively induced cell cycle arrest at the G2/M phase and dramatically disrupted the microtubule organization. Moreover, complex 19 significantly induced cell apoptosis and decreased MMP. Importantly, complex 19 significantly inhibited tumor growth in SK-OV-3 xenograft model in vivo without apparent toxicity.

Background Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and novel chemotherapeutic drugs for treating HCC are urgently needed. 16-O-caffeoyl-16-hydroxylhexadecanoic acid (CHHA) is a new phenylpropanoid isolated by our group from Euphorbia nematocypha which is commonly used to treat solid tumors. However, the underlying mechanisms responsible for the CHHA-induced apoptosis in cancer cells, particularly in HCC, remain unknown. Purpose In the present work, we evaluated the growth inhibitory effect of CHHA on HCC cells and explored the underlying molecular mechanisms. Methods/Study designs The anti-proliferative activity of CHHA was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. ER localization was performed by ER-tracker red staining. The effect of CHHA on the expression of mRNA in HCC cells was detected by RT-PCR. The potential mechanisms for proteins level in ER pathway and apoptosis were analyzed by Western blot. Results Our results showed that CHHA exerted strong anti-proliferative activity against both HepG2 and Bel-7402 cells in a concentration- and time-dependent manner. Mechanistic studies demonstrated that CHHA induced apoptosis through mitochondrial apoptotic pathway, and arrested the cell cycle at G1 phase. CHHA was also found to induce endoplasmic reticulum (ER) stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of GRP78, CHOP, caspase-12 and p-PERK. Inhibition of endoplasmic reticulum stress by salubrinal pretreatment could suppress both apoptosis and ER stress, indicating that ER stress induction contributes to apoptosis and is required for the latter. Besides, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by CHHA and reversed CHHA-stimulated the expression of ER markers. Conclusion In conclusion, CHHA inhibited HCC cell growth and induced apoptosis through mitochondria-mediated pathway and ROS-mediated endoplasmic reticulum stress. This provides molecular bases for developing CHHA into a drug candidate for the treatment of HCC.

A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration.

Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model.

Series of novel hybrids of alizarin and diamide scaffold (3a–3h, 7a–7h) were designed and synthesized. In vitro antitumor activities of all compounds against HepG-2, CNE, Spca-2, Hct-116, and MGC-803 cell lines were evaluated, and employing standard MTT assay compared with commercial anticancer drug 5-fluorouracil (5-FU). Compounds 7b, 7c, 7d, and 7e showed relatively high cytotoxicity. Especially, compound 7c exhibited the best cytotoxicity against CNE cells with IC50 9.08 µM, which was even stronger than that of 5-FU. All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The action mechanism of representative compound 7c was preliminarily investigated by flow cytometry, which indicated that the compound can induce cell apoptosis in CNE cells. Cell cycle analysis showed that compound 7c mainly arrested CNE cells in G1 stage. In addition, the binding properties of a model analog 7c to DNA were investigated by different methods (fluorescence, CD spectroscopy), and the results indicated that 7c showed a moderate preference for binding ct-DNA.

Several rhein α-aminophosphonates conjugates (5a-5q) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially, compound 5i exhibited the strongest cytotoxicity against Hct-116 cells (IC50 was 5.32 μM). All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The mechanism of compound 5i was preliminarily investigated by Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound 5i induced apoptosis in Hct-116 cancer cells. Cell cycle analysis showed that these compound 5i mainly arrested Hct-116 cells in G1 stage. The effects of 5i on the activation of caspases expression indicated that 5i might induce apoptosis via the membrane death receptor pathways. In addition, the binding properties of a model analog 5i to DNA were investigated by methods (UV-vis, fluorescence, CD spectroscopy and FRET-melting) in compare with that of rhein. Results indicated that 5i showed moderate ability to interact ct-DNA.

Background Non-Small-Cell Lung Cancer (NSCLC) is the most-frequent cause of cancer death, and novel chemotherapeutic drugs for treating NSCLC are urgently needed. 2α, 3α, 23-trihydroxy-13α, 27-cyclours-11-en-28-oic acid (euscaphic acid G) is a new hexacyclic triterpene acid isolated by our group from Glechoma longituba (Nakai) Kupr. However, the underlying mechanisms responsible for the anticancer effects of hexacyclic triterpene acid have not been elucidated. Purpose In the present work, we evaluated growth inhibitory effect of the new isolated hexacyclic triterpene acid and explored the underlying molecular mechanisms. Methods/study designs Herbs were extracted and constituents were purified by chromatographic separation, including silica gel, ODS, MCI, Sephadex LH-20 and preparative HPLC. The compound structures were elucidated by the use of UV, NMR and MS spectral data. The anticancer activity of euscaphic acid G was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. To display the possible mechanism of euscaphic acid G on NCI-H460 cells, RT-PCR, immunofluorescence and Western blot analysis were carried out. Results A new hexacyclic triterpene acid, euscaphic acid G, together with fifteen known triterpenoids, was isolated from the aerial parts of G. longituba. Our results showed that euscaphic acid G exerted strong anti-proliferative activity against NCI-H460 cells in a concentration- and time-dependent manner. Flow cytometry demonstrated euscaphic acid G arrested the cell cycle at G1 phase, induced cellular apoptosis, accompanied by ROS generation and mitochondrial membrane potential reduction. Mechanistic studies revealed that euscaphic acid G treatment inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Conclusion In conclusion, these results suggested that euscaphic acid G from G. longituba showed potential anticancer effects against lung cancer cells via inducing cell cycle arrest and apoptosis, at least partly, through NF-κB signaling pathways.

A series of novel coumarin-containing α-aminophosphonates with two chiral centers were synthesized and a single-crystal structure of compound 8g (8g′, (R)-diethyl ((S)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)propanamido)(2-bromophenyl)methylphosphonate) was obtained. The in vitro antitumor activities of compound 8a–8g′ against human pulmonary carcinoma cell line (A549), human nasopharyngeal carcinoma (human KB), and human lung adenocarcinoma (MGC-803) cell lines were evaluated. Some compounds showed relatively high cytotoxicity. Compared with 8g, 8g′ exhibited an improved activity against three tumor cells, which was evidenced by the IC50 that was four- to five-fold lower than those for 8g. The influence of chirality was also observed in DNA-binding assay of 8g and 8g′. 8g′ exhibited higher binding constant (1.96 × 103 M−1) as compared to 8g (1.69 × 103 M−1).

Maleopimaric acid N-aryl imides (2) and methyl maleopimaric acid N-aryl imides (3) were designed and synthesized. Their atropisomers (A and B) were separated into their enantiomeric pure forms and the anti-proliferative activity was tested against NCI, A549, Hep G-2, MGC-803 and Hct-116 cell lines, respectively. A significant difference in the level of cytotoxicity was observed between R and S conformers. Atropisomers A with an R configuration exhibited significant toxicity (the IC50 values ranging from 7.51 to 32.1 μM). Further experiments proved that antitumor activity of 2A was achieved through the induction of cell apoptosis by G1 cell-cycle arrest.

Eleven oleanane-type triterpenoid saponins, foegraecumosides A–K, and eight known ones, were isolated from the aerial parts of Lysimachia foenum-graecum. Their structures were elucidated by spectroscopic data analyses and chemical methods. All isolated saponins were evaluated for their cytotoxicity against four human cancer cell lines (NCI-H460, MGC-803, HepG2, and T24). Seven saponins containing the aglycone cyclamiretin A exhibited moderate cytotoxicity against all tested human cancer cell lines, with IC50 values of 9.3–24.5 μM. Simultaneously, the cytotoxic activities of foegraecumosides A and B, lysichriside A, ardisiacrispins A and B, cyclaminorin, and 3-O-α-L-rhamnopyranosyl-(1 → 2)-β- d -glucopyranosyl-(1 → 4)-α- l -arabinopyranosyl-cyclamiretin A were tested on drug-resistant lung cancer cell lines (A549 and A549/CDDP, respectively). Ardisiacrispin B displayed moderate cytotoxicity against A549/CDDP, with an IC50 value of 8.7 μM and a resistant factor (RF) of 0.9.

A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the β5-subunit of the human 20S proteasome with IC50 values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity. In particular, compound 6i appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by inhibition of the activity of 20S proteasome and induce apoptosis. In addition, 6i-induced apoptosis was significantly facilitated in NCI-H460/DOX cells that had been pretreated with inhibitors of P-gp. Mechanistically, compound 6i might trigger apoptotic signalling pathway. Thus, we conclude that dipeptide derivatives containing the thiourea moiety may be the potential inhibitors of proteasome with the ability to reverse multidrug resistance.

Background: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties. Objective: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs. Method: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR. Results: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1. Conclusion: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.