Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

A new series of (E)‐3‐[(1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene]indolin‐2‐one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT‐15, HCT‐116, A549, NCI‐H460, and MCF‐7, including HFL. Among the tested compounds, (E)‐1‐benzyl‐5‐bromo‐3‐{[1‐(2,5‐dimethoxyphenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl]methylene}indolin‐2‐one ( 10 s ) showed potent cytotoxicity against HCT‐15 cancer cells with an IC₅₀ value of 1.43±0.26 μm and a GI₅₀ value of 0.89±0.06 μm . Notably, induction of apoptosis by 10 s on the HCT‐15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT‐15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, ‐8, and ‐9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10 s in a dose‐dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular‐docking studies showed that compound 10 s has typical intercalation with DNA.     

Bis‐arylidene Oxindoles as Anti‐Breast‐Cancer Agents Acting via the Estrogen Receptor

We report a new family of bis‐arylidene oxindole derivatives that show highly selective estrogen receptor (ER)‐mediated anticancer activity at low‐nanomolar concentrations in ER‐positive (ER+) breast cancer cells. In terms of cell growth inhibition, IC₅₀ values for these compounds in ER+ breast cancer cells are two to three orders of magnitude lower than in ER‐negative (ER?) breast cancer cells and non‐cancer cells. In comparison with known bis‐arylidene drugs, these compounds are at least three orders of magnitude more toxic than tamoxifen and 1.5–4‐fold more toxic than 4‐hydroxytamoxifen in ER+ MCF‐7 cancer cells. These oxindoles inhibit ER transactivation, and their anticancer activities are inhibited in ER‐depleted MCF‐7 cells. Some of these nonsteroidal molecules also exhibit essential properties of selective ER down‐regulation. From the development of two series of bis‐arylidene oxindole‐based compounds, we report a new series of anticancer agents for estrogen‐responsive breast cancer.     

Biocompatible polymers as a tool for the synthesis of silver nanoparticles: size tuning and in vitro cytotoxicity studies

Silver nanoparticles have attracted great attention in the biomedical research field, especially in cancer theranostics. In this study, we developed a synthesis method for silver nanoparticles in the solid state using high‐speed vibration milling, in which biocompatible polymers such as poly(vinylpyrrolidone), poly(ethylene glycol) and chitosan were used for the reduction of the silver salt. The synthesis of the size‐tunable silver nanoparticles was performed at room temperature and no surfactants to direct the anisotropic growth of the nanoparticles were required. The formation of the nanoparticles was studied using UV‐visible and Fourier transform infrared spectroscopy as well as transmission electron microscopy. The synthesized nanoparticles showed an average diameter ranging from 3.1 ± 1.4 to 22.8 ± 5.8 nm. In addition, the anticancer activity of these silver nanoparticles was assessed using cytotoxicity studies with human breast adenocarcinoma (MCF‐7), human lung adenocarcinoma (NCI‐H358) and mouse embryonic fibroblast (NIH‐3T3) cell lines. Accordingly, an effective suppression of the proliferation of cell growth was found. © 2016 Society of Chemical Industry     

Synthesis and in vitro biological evaluation as antitumour drug carriers of folate‐targeted N‐isopropylacrylamide‐based nanohydrogels

Copolymeric nanohydrogels based on N‐isopropylacrylamide, N‐(pyridin‐4‐ylmethyl)acrylamide and tert‐butyl‐2‐acrylamidoethyl carbamate, synthesized by microemulsion polymerization, were characterized using Fourier transform infrared spectroscopy and their size (38–52 nm) determined using quasielastic light scattering. Folic acid was covalently attached to the nanohydrogels (1.40 ± 0.07 mmol g^?1). Tamoxifen (6.7 ± 0.2–7.3 ± 1.2 µg TMX mg^?1 nanohydrogel), a hydrophobic anticancer drug, and 5‐fluorouracil (7.7 ± 0.7–10.14 ± 1.75 µg 5‐FU mg^?1 nanohydrogel), a hydrophilic anticancer drug, were loaded into the nanohydrogels. Maximum in vitro TMX release (77–84% of loaded drug) depended on interactions of the drug with hydrophobic clusters of the nanogels; however, no nanogel/5‐FU interactions allowed total release of the loaded drug. The cytotoxicity of unloaded nanohydrogels in MCF7, T47D and HeLa cells was low. Cell uptake of nanogels without bound folic acid took place in the three cell types by unspecific internalization in a time‐dependent process. Cell uptake increased for folic acid‐targeted nanohydrogels in T47D and HeLa cells, which have folate receptors. The administration of 10 and 30 µmol L^?1 TMX by TMX‐loaded nanogels and 10 µmol L^?1 5‐FU by 5‐FU‐loaded nanogels was effective on the three cell types, and the best results were obtained for folic acid‐targeted nanohydrogels. Copyright © 2012 Society of Chemical Industry     

Encapsulation of docetaxel into PEGylated gold nanoparticles for vectorization to cancer cells

Encapsulation of docetaxel and its solubilization in water was carried out in PEGylated gold nanoparticles (AuNPs) as shown by ¹H NMR (600 MHz ) and UV/Vis spectroscopy and dynamic light scattering. Vectorization of PEGylated AuNP‐encapsulated docetaxel was probed in vitro toward human colon carcinoma (HCT15) and human breast cancer (MCF7) cells. AuNPs alone presented no cytotoxicity toward either MCF7 or HCT15 adenocarcinoma cells. AuNP–docetaxel was found to be 2.5‐fold more efficient than docetaxel alone against MCF7 cells, and the IC₅₀ value of AuNP–docetaxel against HCT15 cells was lower than that of free docetaxel; the increased efficiency brought about by AuNP drug encapsulation was ～1.5‐fold.     

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC₅₀ values ranging from 0.64 to 30.9 μM . Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC₅₀ values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein.     

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents

In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC₅₀=0.78±0.01 μM), HT29 (IC₅₀=0.92±0.15 μM) and K562 (IC₅₀=47.25±1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G₁/G₀ phase and decreased cell population in G₂/M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg⁻¹ dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5-dioes holds promise for the development of more potent and less toxic anticancer agents.     

PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery

Novel pH‐responsive PEGylated hollow nanocapsules (HNCaps) were fabricated through a combination of distillation–precipitation copolymerization and surface thiol–ene ‘click’ grafting reaction. For this purpose, SiO₂ nanoparticles were synthesized using the Stöber approach, and then modified using 3‐(trimethoxysilyl)propyl methacrylate (MPS). Afterward, a mixture of triethyleneglycol dimethacrylate (as crosslinker), acrylic acid (AA; as pH‐responsive monomer) and MPS‐modified SiO₂ nanoparticles (as sacrificial template) was copolymerized using the distillation–precipitation approach to afford SiO₂@PAA core–shell nanoparticles. The SiO₂ core was etched from SiO₂@PAA using HF solution, and the obtained PAA HNCaps were grafted with a thiol‐end‐capped poly(ethylene glycol) (PEG) through a thiol–ene ‘click’ reaction to produce PAA‐g‐PEG HNCaps. The fabricated HNCaps were loaded with doxorubicin hydrochloride (DOX) as a model anticancer drug, and their drug loading and encapsulation efficiencies as well as pH‐dependent drug release behavior were investigated. The anticancer activity of the drug‐loaded HNCaps was extensively evaluated using MTT assay against human breast cancer cells (MCF7). The cytotoxicity assay results as well as superior physicochemical and biological features of the fabricated HNCaps mean that the developed DOX‐loaded HNCaps have excellent potential for cancer chemotherapy. © 2020 Society of Chemical Industry     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Design,Synthesis, and Biological Evaluation of Pyrazoline‐Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors

Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein we describe the synthesis, biological evaluation, and structure–activity relationship study of two new series of pyrazoline analogues as APN inhibitors. Among these compounds, 5‐(2‐(2‐(hydroxyamino)‐2‐oxoethoxy)phenyl)‐3‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide (compound 13 e ) showed the best APN inhibition with an IC₅₀ value of 0.16±0.02 μm , which is more than one order of magnitude lower than that of bestatin (IC₅₀=9.4±0.5 μm ). Moreover, compound 13 e was found to inhibit the proliferation of diverse carcinoma cells and to show potent anti‐angiogenesis activity. At the same concentration, compound 13 e presents significantly higher anti‐angiogenesis activity than bestatin in human umbilical vein endothelial cells (HUVECs) capillary tube formation assays. The putative binding mode of 13 e in the active site of APN is also discussed.     

Sigma‐2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity

With the aim of contributing to the development of novel antitumor agents, high‐affinity σ₂ receptor agonists were developed, with 6,7‐dimethoxy‐2‐[4‐[1‐(4‐fluorophenyl)‐1H‐indol‐3‐yl]butyl]‐1,2,3,4‐tetrahydroisoquinoline ( 15 ) and 9‐[4‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl]‐9H‐carbazole ( 25 ) showing exceptional selectivity for the σ₂ subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin‐resistant MCF7adr cell line. Surprisingly, a few compounds, including 25 , displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug‐resistant tumors. All of the compounds showed interaction with P‐glycoprotein (P‐gp), and 15 and 25 , with the greatest activity, were able to revert P‐gp‐mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ₂ receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug‐ resistant cancers.     

Cell‐Selective,Apoptosis‐inducing Rhodium(III) Crown Thiaether Complexes

Half‐sandwich rhodium(III) polypyridyl (pp) complexes with the metal atom capped by the facial crown thiaether 1,4,7‐trithiacyclononane [9]aneS₃ represent a promising class of apoptosis‐inducing potent cytostatic agents. The necrotic damage caused by the complexes is negligible. In vitro cytotoxicity assays with the human cancer cell lines MCF‐7 and HT‐29 and immortalized HEK‐293 cells indicate that the dicationic κ²N(imino) complexes [([9]aneS₃)RhCl(pp)]²⁺ are much more active than monocationic complexes [([9]aneS₃)RhCl₂(L)]⁺ (L=imidazole, CH₃CN). Whereas the κ²N(amino) complex [([9]aneS₃)RhCl(piperazine)]²⁺ is inactive, replacing piperazine with the structurally analogous κ²S (thiaether) ligand 1,4‐dithiane restores cytotoxicity as evidenced by IC₅₀ values in the range 8.1‐11.6 μM . Spectroscopic (CD, UV/Vis, NOESY) and viscosity measurements indicate that the active dppz complex 8 (IC₅₀ values: 4.7–8.9 μM ) exhibits strong intercalative binding towards DNA whereas the even more potent bipyrimidine complex 9 (IC₅₀ values: 0.6–1.9 μM ) causes no alteration of the duplex B conformation. Weaker intercalative binding is observed for the dpq complex 7 . A comparative annexin V–propidium iodide binding assay with lymphoma (BJAB) cells and healthy leukocytes demonstrates that the cytotoxic activity of complex 8 and particularly complex 9 is highly selective towards the malignant cells.     

Switching the Mode of Cell Death between Apoptosis and Autophagy by Histone Deacetylase 6 Inhibition Levels

Inhibition of histone deacetylase (HDAC) has been demonstrated to be an effective strategy for cancer treatment. In this work, we have developed a new agent Ir-VPA , which exhibits the cell death mode switching between apoptosis and autophagy due to the distinct level of HDAC6 inhibition. Ir-VPA indicates the best anticancer activity to HeLa cells, and could be hydrolyzed due to the high expression of the esterase in HeLa cells. Ir-VPA could accumulate in nuclei, induce severe DNA damages and cell cycle arrest at G2/M phase. The anticancer mechanism of Ir-VPA to HeLa cells was dependent on the HDAC6 inhibitory performance, as the caspase dependent apoptosis at low concentration (IC₅₀) and autophagy with the autophagy flux blockage at high concentration (2×IC₅₀). This is resulted from the distinct inhibitory levels of HDAC6, as moderate/complete inhibition at the concentration of IC₅₀/2×IC₅₀.In the presence of autophagic inhibitor chloroquine, the apoptotic population elevated from 32.7 % to 61.7 %, indicating that Ir-VPA could activate apoptotic process through the autophagolysosome fusion inhibition. Ir-VPA also exhibits excellent antiproliferative behavior to 3D HeLa multicellular tumor spheroids (MCTSs). This work not only provided a new HDAC6 inhibitor and novel anticancer mechanism for the effective treatment of cervical cancer, but also demonstrated the strategy to conjugate the metal fragment with active organic drug to enhance the anticancer performance.     

Design and Synthesis of Aminostilbene–Arylpropenones as Tubulin Polymerization Inhibitors

A series of aminostilbene—arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI₅₀) values in the range from <0.01 to 19.9 μM . One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI₅₀ value of <0.01 μM . All of the synthesized compounds displayed cytotoxicity against A549 (non‐small‐cell lung cancer), HeLa (cervical carcinoma), MCF‐7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC₅₀) values ranging from 0.011 to 8.56 μM . A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC₅₀ values of 0.71 and 0.79 μM . Moreover, dot‐blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.     

Anticancer Activity and Mechanism of Action Evaluation of an Acylhydrazone Cu(II) Complex toward Breast Cancer Cells,Spheroids, and Mammospheres

The purpose of this work was to screen the anticancer activity and mechanisms of action of Cu(II)-acylhydrazone complex [Cu(HL)(H₂O)](NO₃)⋅H₂O, (CuHL), to find a potential novel agent for breast chemotherapies. Cytotoxicity studies on MCF7 cells demonstrated that CuHL has stronger anticancer properties than cisplatin over breast cancer cell models. Computational simulations showed that CuHL could interact in the minor groove of the DNA dodecamer, inducing a significant genotoxic effect on both cancer cells from 0.5 to 1 μM. In this sense, molecular docking and molecular dynamics simulations showed that the compound could interact with 20S proteasome subunits. Also, cell proteasome experiments using breast cancer cells revealed that the complex can inhibit proteasomal activity. Moreover, CuHL induced apoptosis in breast cancer cells at very low micromolar concentrations (0.5–2.5 μM) and displayed relevant anticancer activity over spheroids derived from MCF7 cells. Ultimately, CuHL diminished the number of mammospheres formed, disturbing their morphology and size.     

Cellular selectivity and biological impact of cytotoxic rhodium(III) and iridium(III) complexes containing methyl-substituted phenanthroline ligands

The antiproliferative properties and biological impact of octahedral iridium(III) complexes of the type fac‐[IrCl₃(DMSO)(pp)] containing pp=phenanthroline ( 1 ) and its 4‐ and 5‐methyl ( 2 , 3 ) and 4,7‐ and 5,6‐dimethyl derivatives ( 4 , 5 ) were investigated for both adherent and non‐adherent cells. A series of similar rhodium(III) complexes were studied for comparison purposes. The antiproliferative activity toward MCF‐7 cancer cells increases eightfold from IC₅₀=4.6 for 1 to IC₅₀=0.60 μM for 5 , and an even more pronounced 18‐fold improvement was established for the analogous rhodium complexes 6 and 8 , the respective IC₅₀ values for which are 1.1 and 0.06 μM . Annexin V/propidium iodide assays demonstrated that the 5,6‐dimethylphenanthroline complexes 5 and 8 both cause significant inhibition of Jurkat leukemia cell proliferation and invoke extensive apoptosis but negligible necrosis. The percentages of Jurkat cells exhibiting high levels of reactive oxygen species correlate with the percentages of cells undergoing apoptosis. The antiproliferative activity of 5 and 8 is strongly selective toward MCF‐7 and HT‐29 cancer cells over normal HFF‐1 and immortalized HEK‐293 cells. Complex 5 also exhibits high selectivity toward BJAB lymphoma cells relative to healthy leukocytes. Both 5 and 8 invoke permanent decreases in the adhesion and respiration of MCF‐7 cells.     

The Discovery of a Highly Selective 5,6,7,8‐Tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model

Sirtuins, NAD⁺‐dependent histone deacetylases (HDACs), have recently emerged as potential therapeutic targets for the treatment of a variety of diseases. The discovery of potent and isoform‐selective inhibitors of this enzyme family should provide chemical tools to help determine the roles of these targets and validate their therapeutic value. Herein, we report the discovery of a novel class of highly selective SIRT2 inhibitors, identified by pharmacophore screening. We report the identification and validation of 3‐((2‐methoxynaphthalen‐1‐yl)methyl)‐7‐((pyridin‐3‐ylmethyl)amino)‐5,6,7,8‐tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one (ICL‐SIRT078), a substrate‐competitive SIRT2 inhibitor with a K_i value of 0.62±0.15 μM and more than 50‐fold selectivity against SIRT1, 3 and 5. Treatment of MCF‐7 breast cancer cells with ICL‐SIRT078 results in hyperacetylation of α‐tubulin, an established SIRT2 biomarker, at doses comparable with the biochemical IC₅₀ data, while suppressing MCF‐7 proliferation at higher concentrations. In concordance with the recent reports that suggest SIRT2 inhibition is a potential strategy for the treatment of Parkinson’s disease, we find that compound ICL‐SIRT078 has a significant neuroprotective effect in a lactacystin‐induced model of Parkinsonian neuronal cell death in the N27 cell line. These results encourage further investigation into the effects of ICL‐SIRT078, or an optimised derivative thereof, as a candidate neuroprotective agent in in vivo models of Parkinson’s disease.     

Gold(I) N‐Heterocyclic Carbene Complexes with Naphthalimide Ligands as Combined Thioredoxin Reductase Inhibitors and DNA Intercalators

Organometallic conjugates consisting of a gold(I) N‐heterocyclic carbene (NHC) moiety and a naphthalimide were prepared and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF‐7 breast and HT‐29 colon adenocarcinoma cells. Strong effects on tumor cell metabolism were noted for the most cytotoxic complex, chlorido[1‐(3′‐(4′′‐ethylthio‐1′′,8′′‐naphthalimid‐N′′‐yl))‐propyl‐3‐methyl‐imidazol‐2‐ylidene]gold(I) ( 4 d ). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action.     

Synthesis and antitumor evaluation of nitrovinyl biphenyls: anticancer agents based on allocolchicines

A new class of nitrovinyl biphenyl compounds based on the structures of colchicines and allocolchicines were designed, synthesized, and shown to inhibit tubulin polymerization and cause mitotic arrest. A majority of these compounds were found to possess potent anticancer properties, with IC₅₀ values in the range of 0.05–7 μM , and are equally potent with colchicine in HeLa and MCF‐7 cells. Compounds 14 e and 14 f inhibited tubulin assembly by more than 60 %, and flow cytometry studies indicated growth arrest of cells in the G₂/M phase of the cell cycle in a concentration‐dependent manner. Treatment of cells with 14 f resulted in upregulation of cyclin B1 and aurora kinase B mRNA levels, corresponding to growth arrest in the G₂/M phase of the cell cycle as the mode of action.     

Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase I

Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine‐chain‐substituted compounds showed the most promising antiproliferative activity, with IC₅₀ values in the single‐digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single‐strand DNA damage by stabilizing the topo I–DNA cleavage complex. In particular, the most potent compound, 1‐(butylamino)‐3‐(3,6‐dichloro‐9H‐carbazol‐9‐yl)propan‐2‐ol ( 6 ), was shown to be able to induce G₂‐phase cell‐cycle arrest and apoptosis in HeLa cells.