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C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 exhibited almost the same tumor growth inhibition activity as cisplatin in the T24 xenograft model.

Twelve new complexes

Ruthenium(III) complex with pyrazolopyrimidine inhibited tumor cells proliferation, caused DNA damage by interacting with DNA and inhibition of the Topo I enzyme, induced cell cycle arrest in S phase and apoptosis via mitochondrial dysfunction.

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.

Nonplatinum metal complexes of [Pd(L1)Cl2] (C1), [Rh(L1)Cl3(DMSO)] (C2), [Pd(L2)Cl2] (C3), and [Rh(L3)Cl3(DMSO)] (C4) with isoquinoline derivatives have been prepared and characterized. C1–C4 exhib...

Background: Hepatocellular carcinoma (HCC) seriously affects human health, especially, it easily develops multi-drug resistance (MDR) which results in treatment failure. There is an urgent need to develop highly effective and low-toxicity therapeutic agents to treat HCC and to overcome its MDR. Targeted drug delivery systems (DDS) for cancer therapy, including nanoparticles, lipids, micelles and liposomes, have been studied for decades. Recently, more attention has been paid to multifunctional DDS containing various ligands such as polymer moieties, targeting moieties, and acid-labile linkages. The polymer moieties such as poly(ethylene glycol) (PEG), chitosan (CTS), hyaluronic acid, pullulan, poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO) protect DDS from degradation. Asialoglycoprotein receptor (ASGPR) and glycyrrhetinic acid receptor (GAR) are most often used as the targeting moieties, which are overexpressed on hepatocytes. Acid-labile linkage, catering for the pH difference between tumor cells and normal tissue, has been utilized to release drugs at tumor tissue. Objectives: This review provides a summary of the recent progress in ASGPR and GAR-mediated and/or pH-responsive HCC-targeted drug delivery. Conclusion: The multifunctional DDS may prolong systemic circulation, continuously release drugs, increase the accumulation of drugs at the targeted site, enhance the anticancer effect, and reduce side effects both in vitro and in vivo. But it is rarely used to investigate MDR of HCC; therefore, it needs to be further studied before going into clinical trials.

Metal complexes of [NiL2(NO3)2] (1), [CuL2(NO3)2] (2) and [ZnL2(NO3)2] (3) with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine (L) ligand were synthesized. We discovered that complexes 1–3 exhibited considerable anticancer activity in vitro via simultaneously targeting microtubules and mitochondria. Complexes 1–3 impaired mitochondrial bioenergetic function by causing ATP depletion and mitochondrial membrane depolarization. They also triggered excessive generation of intracellular ROS and Ca2+, activated caspase-3 and caspase-9, and triggered mitochondria-dependent apoptosis pathways. In addition, complexes 1–3 were shown by SPR and CETSA assays to have a good binding affinity for β-tubulin. Tubulin polymerization analysis suggested that complexes 1–3 promoted tubulin polymerization into microtubules, and disrupted the microtubule cytoskeleton network, which caused cell cycle arrest in the G2/M phase. Complexes 1–3 ultimately activated a strongly apoptotic response. Complexes 1 and 2 displayed high cancer growth inhibition efficacy in mice bearing T-24 xenografts, and had a good in vivo safety profile. Complexes 1–3 have the potential to become anticancer agents through targeting microtubule and mitochondria.

Enrofloxacin (EFX) was selected as the medicinal ligand to afford a new copper(ii)-based complex, EFX-Cu, which was structurally characterized by spectroscopic analyses including X-ray single crystal diffraction. It was also stable and could retain the coordination state in aqueous solution. The in vitro antibacterial activity of EFX-Cu against a panel of pathogenic bacteria was about the same as that of EFX, except that it was twice as active against E. coli. The in vivo test on mice gave a LD50 value of 8148 mg kg−1 for EFX-Cu, which was much lower than those for EFX (LD50, 5312 mg kg−1) and its clinically used sodium salt, EFX-Na (LD50, 1421 mg kg−1). In addition, no obvious lesions in the organs of the dead mice were found by histopathological examination. Pharmacokinetic studies on rats suggested similar pharmacokinetics between EFX-Cu and EFX. On the other hand, EFX-Cu showed higher acute toxicity than EFX-Na in zebrafish, which was inconsistent with that in mice. The ROS-related inflammation and anti-inflammatory assay of EFX-Cu, respectively, in normal cells and zebrafish could be ascribed to its ROS-related redox property. Unfortunately, the final in vivo therapeutic assay in the E. coli-infected mouse model indicated that the therapeutic effect of EFX-Cu, mainly in terms of mortality in mice, was found to be lower than that of EFX-Na at the same dosage (800 mg kg−1, continuous gavage), although the contradictory factors between toxicity and antibacterial activity could not be excluded in this trial.

Myeloid cell leukemia 1 (Mcl-1), which belongs to the Bcl-2 family of prosurvival proteins, is a key regulator of cancer cell survival. To date, few drug-like Mcl-1 inhibitors have been reported. Herein, we report the preparation of 10 copper complexes with 9-substituted β-carboline ligands that act as metal-based Mcl-1 inhibitors. Complex 14 was identified as a potent and selective Mcl-1 inhibitor with strong in vitro antitumor activity. Mechanistic studies demonstrated that complex 14 disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex 14 significantly (P < 0.001) inhibited tumor growth in vivo, induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex 14 showed no apparent toxicity in mice. Together, these findings indicate that complex 14 is a copper-based Mcl-1 inhibitor with high efficacy and low toxicity that could be developed for the treatment of Mcl-1-related cancers.

Twenty new chebulic acid and brevifolincarboxylic acid derivatives, including eight optically pure or achiral compounds (1–7 and 14) and six pairs of enantiomers (8a/8b–13a/13b), along with nine kn...

Three new synthetic terpyridine copper(II) complexes were characterized. The copper(II) complexes induced apoptosis of three cancer cell lines and arrested T-24 cell cycle in G1 phase. The complexes were accumulated in mitochondria of T-24 cells and caused significant reduction of the mitochondrial membrane potential. The complexes increased both intracellular ROS and Ca

Four terpyridine copper(ii) complexes were prepared and they showed excellent cytotoxic activity, which induced mitochondrion-mediated apoptosis and cell cycle arrest in the G0/G1 phase. Complex 1 suppressed cell proliferation in vivo.

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC

Based on 1,2-dimethoxyphenyl (veratrole, open) and 1,2-methylenedioxyphenyl (pepper ring, close)-derived pyridine–triazole analogues, two groups of copper(II) complexes, namely, Group I(C1–C3) and Group II(C4–C6) were synthesized and fully characterized. All ligands and complexes were tested in vitro by MTT assays on seven tumour cell lines (T24, Hep-G2, Sk-Ov-3, MGC-803, HeLa, A549 and NCI-H460) and one normal liver cell line (HL-7702). Surprisingly, the pepper-ring-derived complexes (C4–C6) showed significantly enhanced cytotoxicity compared with the 1,2-bimethoxyphenyl ring-derived complexes (C1–C3) and the standard anticancer drug cisplatin. Cellular uptake assays indicated that the Cu accumulation was consistent with cytotoxicity. In addition, flow cytometry and western blot analysis showed that the apoptosis of the leading complex C4 may be induced by the Bcl-2 family-mediated proteins through the mitochondrial dysfunction pathway. Furthermore, UV-vis and fluorescence spectroscopy assays revealed that C4 has stronger insertion-binding interactions with CT-DNA than C1 and the fluorescence of C1 and C4 with BSA is mainly quenched by static quenching.

Simple, rapid and selective methods for simultaneous determination of ultralow amount of multiple protein biomarkers in complicated biological samples are in great demand for early-stage diagnostics and biomedical research. Herein, we present a novel polydopamine nanoparticle (PDANP)-based multicolor fluorescent proximity immunoassay for ultrasensitive and multiplexed analysis of proteins in a single solu- tion using isothermal quadratic amplification (IQA). The assay system consists of DNA tethered-antibody pairs for different protein targets, different fluorophore-labeled DNA hairpin probes, DNA polymerase, T7 exonuclease and PDANPs. The DNA tethered- antibodies and fluorophore-labeled hairpin probes can coexist stably, and fluorophore- labeled DNA hairpin probes are adsorbed onto the PDANPs, leading to the significant quenching of the fluorescence of all fluorophores. When target proteins enter into the system, each pair of DNA tethered-antibodies simultaneously binds to a specific pro- tein target and forms the proximate complexes via proximity-dependent DNA hybridi- zation. The formed proximate complexes can then unfold the hairpin structures of the respective probes, leading to DNA polymerase/T7 exonuclease-catalyzed recycling of both proximate complexes and DNA strands to achieve IQA. This IQA results in the di- gestion of many fluorophore-labeled hairpin probes, causing a substantial increase in the fluorescence of corresponding fluorophores for detection of target proteins. As a proof of concept, we demonstrate that a three-color proximity immunoassay can si- multaneously detect prostate-specific antigen (PSA), carcinoembryonic antigen (CEA) and α-fetoprotein (AFP) with ultralow attomolar detection limits, high specificity and 6-log dynamic range. Furthermore, the application of this assay for direct and simulta- neous determination of multiple proteins in clinical sera has also been demonstrated. Our newly proposed assay can be expected to provide a generic method platform for multiplexed analysis of a variety of low-abundance proteins.

The real-time tracking of localization and dynamics of small molecules in organelles helps to understand their function and identification of their potential targets at subcellular resolution. To identify the mitochondrion-targeting effects of small molecules (NA-17 and NA-2a) in cancer cells, we used mass spectrometry to study their distribution and accumulation in mitochondria and in the surrounding cytoplasm thus enabling tracing of action processes of therapeutic compounds. Colocalization analysis with the aid of imaging agents suggests that both NA-17 and NA-2a display mitochondrion-targeting effects. However, MS analysis reveals that only NA-2a displays both a mitochondrion-targeting effect and an accumulation effect, whereas NA-17 only distributes in the surrounding cytoplasm. A combination of mitochondrion imaging, immunoblotting, and MS analysis in mitochondria indicated that NA-17 neither has the ability to enter mitochondria directly nor displays any mitochondrion-targeting effect. Further studies revealed that NA-17 could not enter into mitochondria even when the mitochondrial permeability in cells changed after NA-17 treatment, as was evident from reactive oxygen species (ROS) generation and cytochrome c release. In the process of cellular metabolism, NA-17 itself is firmly restricted to the cytoplasm during the metabolic process, but its metabolites containing fluorophores could accumulate in mitochondria for cell imaging. Our studies have furnished new insights into the drug metabolism processes.

Seven undescribed abietane-type diterpenoids, gauleucins A-G, and 11 known ones were isolated from an EtOH extract of the aerial parts of Gaultheria leucocarpa var. yunnanensis. These isolates could be classified into four subtypes: abietanes, 16-nor-abietanes, 16,18-di-nor-abietanes, and 3,4-seco-16-nor-abietane. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of an undescribed and two known diterpenoids were determined by single-crystal X-ray diffraction data. Four compounds showed moderate inhibitory effects against the LPS-induced production of nitric oxide in BV-2 microglial cells. In an α-glucosidase inhibitory assay, gauleucin E and margoclin displayed inhibitory activities with IC

A novel optically pure dinuclear copper(II) complex of a rosin derivative dehydroabietic acid (DHA, HL) was synthesized and fully characterized. The in vitro antitumor activities of the copper(II) complex Cu2(µ2-O)(L)4(DMF)2 (1) were explored and compared with those of a trinuclear iron(III) complex [Fe3(µ3-O)(L)6(CH3OH)2(CH3O)]·H2O (2). 1 was more cytotoxic than 2, and the in vitro cytotoxicity of 1 was comparable to that of cisplatin and oxaliplatin. The metal coordination improved the cytotoxicity of DHA. 1 could arrest cycle in G1 phase and induce apoptosis in MCF-7 cell. 1 increased reactive oxygen species level, GSSG/GSH ratio, and Ca2+ production, and caused the loss of mitochondrial membrane potential (Δψm) in MCF-7 cells. The up-regulated Bax and down-regulated Bcl-2 expression levels, caspase-9/caspase-3 activation, and the release of Cyt c demonstrate that 1 triggered mitochondria-mediated intrinsic apoptosis in MCF-7 cells. Caspase-8/caspase-4 activation and up-regulated Fas expression indicate that death receptor-mediated extrinsic apoptosis was included. Comet assay and up-regulated γ-H2AX and p53 expressions confirmed that 1 caused DNA damage in MCF-7 cells. Moreover, 1 led to enhancement of the biomarker of lipid peroxidation and the indicator of protein carbonylation in MCF-7 cells. All the results suggest that 1 could kill MCF-7 cells by generating oxidative stress, impairing DNA, promoting lipid peroxidation and protein carbonylation, and inducing apoptosis and autophagy. Furthermore, 1 also displayed antimetastatic activities with inhibition of cell invasion and migration, together with antiangiogenesis properties. On the whole, copper complex based on rosin derivatives is worth developing as metal-based antitumor drugs.

To study the antitumor activity and action mechanism of Ru(II) polypyridyl plumbagin (PLN) complexes, four complexes [Ru(PLN)(DMSO)

Enrofloxacin (EFX) was selected as the medicinal ligand to afford a new copper(ii)-based complex, EFX-Cu, which was structurally characterized by spectroscopic analyses including X-ray single crystal diffraction. It was also stable and could retain the coordination state in aqueous solution. The in vitro antibacterial activity of EFX-Cu against a panel of pathogenic bacteria was about the same as that of EFX, except that it was twice as active against E. coli. The in vivo test on mice gave a LD50 value of 8148 mg kg-1 for EFX-Cu, which was much lower than those for EFX (LD50, 5312 mg kg-1) and its clinically used sodium salt, EFX-Na (LD50, 1421 mg kg-1). In addition, no obvious lesions in the organs of the dead mice were found by histopathological examination. Pharmacokinetic studies on rats suggested similar pharmacokinetics between EFX-Cu and EFX. On the other hand, EFX-Cu showed higher acute toxicity than EFX-Na in zebrafish, which was inconsistent with that in mice. The ROS-related inflammation and anti-inflammatory assay of EFX-Cu, respectively, in normal cells and zebrafish could be ascribed to its ROS-related redox property. Unfortunately, the final in vivo therapeutic assay in the E. coli-infected mouse model indicated that the therapeutic effect of EFX-Cu, mainly in terms of mortality in mice, was found to be lower than that of EFX-Na at the same dosage (800 mg kg-1, continuous gavage), although the contradictory factors between toxicity and antibacterial activity could not be excluded in this trial.

Two copper complexes, Cu1 (CuL1Cl2, L1 = 2-(6,7-dimethoxyisoquinolin-1-yl) aniline) and Cu2 (CuL2Cl2, L2 = 2-(6-methoxyisoquinolin-1-yl) aniline), were synthesized and characterized. These complexes exhibited high cytotoxic activity toward different cancer cell lines, including the A549 lung cancer cell line, and low cytotoxicity toward normal human cells. Mechanistic studies have shown that these complexes induce bimodal death of cancer cells through apoptosis and autophagy, including the activation of apoptotic and autophagic cell signaling pathways. In addition, Cu1 and Cu2 interacted with calf thymus DNA (ct-DNA) via an intercalative binding mode. The different biological behaviors of these copper complexes could be attributed to the presence of electron-donating methoxy groups on the ligands. Cu1 and Cu2 effectively inhibited tumor growth in a xenografted mouse model bearing A549 cells but exhibited lower in vivo toxicity than cisplatin. Thus, Cu1 and Cu2 can be developed as potential anticancer agents.

Two optically pure chiral binuclear copper(ii) complexes [Cu2(μ-Cl)2L2]·CH2Cl2 (1) and Cu2L4 (2) based on the natural product rosin derivative N-(5-dehydroabietyl-1,3,4-thiadiazole)-2-substituted pyridinecarboxamide (HL) were prepared, fully characterized and their biological activities were evaluated. The circular dichroism (CD), fluorescence spectroscopy, and DNA melting studies indicate that 1 and 2 interact with calf thymus DNA (CT DNA) via intercalation. It can be concluded that 1 and 2 have a strong affinity to bovine serum albumin (BSA) based on the fluorescence and CD spectral evidence. The MTT assay illustrates that the selective cytotoxic activity of 1 is better than that of HL, 2, cisplatin and oxaliplatin. The exposure of 1 to MCF-7 cells resulted in cell cycle arrest in the G1 phase, apoptosis, mitochondrial dysfunction and an elevated ROS level. The western blot analysis results indicate that 1 might induce apoptosis through intrinsic and extrinsic pathways, autophagy and DNA damage in MCF-7 cells. Furthermore, the down-regulated VEGFR2, MMP-2 and MMP-9 expression levels indicate that 1 should have the ability to resist metastasis and angiogenesis. Thus, based on the above described results 1 has high potential value for anticancer applications.

Based on the characteristic anthrahydrazone pharmacophore, two new anthrahydrazone derivatives (9-PMAH and APMAH) were synthesized, which further afforded two corresponding cisplatin-like Pt(II) complexes (9-PMAH-Pt and APMAH-Pt). Their chemical structures were characterized by IR, ESI-MS, elemental analysis and X-ray single crystal diffraction method. Their in vitro cytotoxicity towards a series of human tumor cell lines and the normal liver cell line HL-7702 were screened and shown in IC50 values and compared with that of cisplatin. 9-PMAH-Pt showed higher cytotoxicity against MGC-803 and HepG-2 than the other tested compounds including cisplatin, while it showed lower toxicity on HL-7702 than cisplatin. The structure–activity relationship from the in vitro cytotoxicity study indicated that the substitution of –CHO on the opposite C10 of anthrahydrazone was unfavorable to higher cytotoxicity, which might be due to its steric hindrance considering the planar aromatic anthracene. Further studies demonstrated that 9-PMAH-Pt induced cell apoptosis in both MGC-803 and T-24 cells by arresting the cell cycle at the G2/M phase, which was totally different for cisplatin, suggesting the different antitumor efficacies of this platinum complex and cisplatin. On the molecular level, it was suggested that 9-PMAH-Pt could bind with DNA via an intercalative mode, likely competing with GelRed in similar intercalative binding sites. 9-PMAH-Pt also effectively inhibited the activity of TOPO I, acting as a TOPO I suppressor. The results of this work suggest a new type of platinum complex bearing anthrahydrazone ligands to form a new bifunctional antitumor candidate in comparison with the classic platinum drugs.

Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins with anti-apoptotic activity. It plays a key role in the regulation of the intrinsic pathway of apoptosis. Moreover, Mcl-1 is correlated with the progression and drug-resistance of various cancers. The development of inhibitors of Mcl-1 may provide effective cancer therapies. While the inhibitors of other Bcl-2 anti-apoptotic proteins have been well explored, the discovery of Mcl-1inhibitors with high selectivity has been challenging. In this review, we summarize the recent literature on small molecule and peptide inhibitors of Mcl-1, which are divided into different types including peptide inhibitors, gossypol derivatives, marinopyrrole derivatives, S1 derivatives, indole derivatives, quinoline derivatives, S63845, AZD5991, AMG176, etc. Their biological activities are also summarized. Mcl-1 is a valid drug target and inhibition of Mcl-1 with a small molecule inhibitor is a promising strategy for cancer therapy.

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1-6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate.

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.

Six previously undescribed oleanane-type triterpenoid saponins, fortunosides A–F, together with six known ones, were isolated from the aerial parts of Lysimachia fortunei Maxim. Their structures were established by spectroscopic data analyses (1D, 2D-NMR and HRESIMS) and chemical methods. All isolated triterpenoid saponins were evaluated for their cytotoxicity against four human liver cancer cell lines (SMMC-7721, Hep3B, HuH7, and SK-Hep-1). Three saponins with the aglycone protoprimulagenin A exhibited moderate cytotoxicity against all of the tested human cancer cell lines, with IC50 values ranging from 4.76 to 15.12 μM.

Three Cu(II) complexes of quinoline derivatives as cancer chemodynamic therapy agents were synthesized and characterized. These complexes were heavily taken up by cells and reacted with cellular glutathione (GSH) to reduce Cu2+ to Fenton-like Cu+, which catalyzed endogenous H2O2 to produce the highly toxic hydroxyl radicals (•OH) to kill cancer cells. Cu1 and Cu2 initiated CAT activity declines, mitochondrial membrane potential and ATP concentration decrease, mitochondrial Ca2+ overload and ER stress response, leading to cell cycle arrest in sub-G1 and cancer cell caspase-dependent apoptosis. On account of the high GSH and H2O2 specific properties of the tumor microenvironment, Cu1 and Cu2 exhibited higher in vitro anticancer activity and lower toxicity to normal cells. Cu1 and Cu2 efficiently inhibited tumor growth in the SK-OV-3 xenograft mouse model without obvious systemic toxicity.

An efficient electrochemical transformation of structurally diverse sulfonyl hydrazides and thiols into thiosulfonates in the presence of ammonium iodide as redox catalyst and electrolyte in acetonitrile at ambient temperature is reported. Transition metal- and oxidant-free conditions are the striking features of this protocol. The in vitro cytotoxicity of all compounds is evaluated by MTT assay against four human cancer cell lines. The results reveal that 3ac and 3ag exhibit potential inhibitory activity against tumor cells. Furthermore, 3ag inhibits cell migration ability and tubulin polymerization in T-24 cells, leading to cell cycle arrest and apoptosis.

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.

// Qi-Pin Qin 1 , Jiao-Lan Qin 1 , Ming Chen 1 , Yu-Lan Li 1 , Ting Meng 1 , Jie Zhou 1 , Hong Liang 1 and Zhen-Feng Chen 1 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, P. R. China Correspondence to: Hong Liang, email: hliang@gxnu.edu.cn Zhen-Feng Chen, email: chenzf@gxnu.edu.cn Keywords: chiral platinum(II) complex, oxoaporphine, G-quadruplex DNA, telomerase, antitumor activity Received: March 01, 2017 Accepted: May 06, 2017 Published: June 28, 2017 ABSTRACT Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(–)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells. Moreover, our in vivo studies showed that complex 6 can effectively inhibit tumor growth in the BEL-7404 and BEL-7402 xenograft mouse models and is less toxic than 5-fluorouracil and cisplatin. The effective inhibition of tumor growth is attributed to its interactions with 53BP1, TRF1, c-myc, TRF2, and hTERT. Thus, complex 6 can serve as a novel lead compound and a potential drug candidate for anticancer chemotherapy.

Four μ2-Cl bridged dinuclear metal complexes with isoquinoline ligands, (MPDQ)2Zn2Cl4 (1) (MPDQ = 4.5-methylenedioxy-1-pyridinedihydroisoquinoline), (PYP)2Zn2Cl4 (2) (PYP = 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline), (MPDQ)2Mn2Cl4 (3),and (PYP)2Mn2Cl4 (4) were synthesized and characterized. All complexes exhibited strong proliferation inhibition activity against various cancer cells. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. Induction of apoptosis in MGC-803 cells by complex 2 was evidenced by annexin V+/PI− detection and DiD/DAPI staining assay. Further investigation revealed that complex 2 was able to induce intrinsic pathway-dependent apoptosis in cancer cells by triggering DNA damage which was caused by the overproduction of reactive oxygen species. Based on these studies, we suggest that Zn(II) complexes containing isoquinoline ligands can be developed as candidates for anti-cancer chemotherapeutics.

[Zn(L)2(H2O)] (1), [Mn(L)2(CH3OH)2] (2) and [Fe(L)2(CH3OH)Cl] (3) with 6-hydroxyloxoisoaporphine (H-L) were synthesized and characterized. Complex 1 was a five-coordinated distorted tetragonal pyramid, whereas complexes 2 and 3 were six-coordinated distorted octahedral structure. Complexes 1-3 exhibited selective cytotoxicity against MGC80-3, Hep-G2, BEL-7404, and T-24 cells with IC50 values in range of 8.19-15.98 μM, and low cytotoxicity to HL-7702 cells. T-24 was the most sensitive tumour cells towards complexes 1-3. Complexes 1-3 induced T-24 cells arrest in G1 phase and G2/M phase, which led to the up-regulation of p27, CDK2, p53, and p21 and down-regulation of cyclin E, chk1, cdc25 A, and chk2. Complexes 1-3 triggered T-24 cells apoptosis via a mitochondrial dysfunction pathway. The interaction of complexes 1-3 with DNA was most likely via an intercalation and cleavage mode.