Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Biological properties of aqueous extract and pyranocoumarins obtained from the bark of Brosimum alicastrum tree.

ETHNOPHARMACOLOGICAL RELEVANCE: Brosimum alicastrum is a tree used in Mexican traditional medicine for the treatment of several diseases, including uterine cancer. AIM OF THE STUDY: In this study, the cytotoxic activity of aqueous extract of B. alicastrum bark and isolated compounds xanthyletin (1), luvangetin (2), and 8-hydroxyxanthyletin (3) on three human cancer cell lines was determined. Moreover, the biological effects of 8-hydroxyxanthyletin (3) were investigated. MATERIALS AND METHODS: The aqueous extract was prepared according to the ethnomedical information reported from the bark. The compounds were purified using chromatographic methods and their structures were elucidated by spectroscopic techniques. The antiproliferative effect of aqueous extract and isolates was determined in three human tumor cell lines: HeLa, A2780, and MSTO-211H, and evaluated by trypan blue exclusion assay. The cell cycle and the mitochondrial transmembrane potential (ΔΨ) were measured by flow cytometry, while Reactive Oxygen Species (ROS) levels were determined using 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. The effect on the relaxation activity, mediated by topoisomerase I and II, was evaluated by electrophoresis, and docking studies were performed using Autodock 4.2 to analyze the interactions. RESULTS: Aqueous extract of B. alicastrum bark showed significant antiproliferative effect on the evaluated cancer cell lines (IC50 = 1.6, 8.5, and 21.4 µg/ml). Four coumarins were identified in the extract and three of them were also evaluated. A2780 cell line exhibited higher sensitivity against pyranocoumarins with IC50 values ranging from 32 to 47 µmol/l. 8-hydroxyxanthyletin (3) exerts an interesting effect on human topoisomerases I and II, by inhibiting the enzymes at concentrations comparable to those obtained in antiproliferative assay. Moreover, 8-hydroxyxanthyletin (3) arrests the cell cycle at G0/G1 phase and induces in A2780 cells a concentration-dependent increase in ROS levels. The results of molecular docking suggest the participation of the hydroxyl group in the interaction between 8-hydroxyxanthyletin (3) and topoisomerase I and II. CONCLUSION: This is the first report that demonstrates the cytotoxic activity of the aqueous extract of B. alicastrum bark, and determines the main metabolites.

Design, physico-chemical characterization and in vitro biological activity of organogold(III) glycoconjugates.

To develop new metal-based glycoconjugates as potential anticancer agents, four organometallic gold(iii)-dithiocarbamato glycoconjugates of the type [AuIII(2-Bnpy)(SSC-Inp-GlcN)](PF6) (2-Bnpy: 2-benzylpyridine; Inp: isonipecotic moiety; GlcN: amino-glucose scaffold; Au3-Au6) and the corresponding model non-glycosylated counterparts [AuIII(2-Bnpy)(SSC-Inp-R)](PF6) (R: OEt (Au1), NH2 (Au2)) have been generated and characterized by means of several analytical techniques (elemental analysis, FT-IR, 1H-/13C-NMR, ESI-MS, UV-Vis, X-ray crystallography). Their stability under physiologically-relevant conditions (PBS solution) and n-octanol/PBS distribution coefficient (D7.4) have also been evaluated. Gold(iii) glycoconjugates showed an antiproliferative effect against ovarian carcinoma A2780 cells, with GI50 values in the low micromolar range. Remarkably, their cell growth inhibitory effect increases upon the addition of a glucose transporter 1 (GLUT1) inhibitor, thus ruling out the involvement of GLUT1 in their transport inside the cell. Additional mechanistic studies have been carried out in A2780 cells, supporting the hypothesis of a facilitated diffusion mechanism (possibly mediated by glucose transporters other than GLUT1), and revealing their capability to act as topoisomerase I and II inhibitors and to disrupt mitochondrial membrane integrity, leading to the generation of ROS, thus resulting in the promotion of oxidative stress and, eventually, cell death.

New Class of Betulinic Acid-Based Nanoassemblies of Cabazitaxel, Podophyllotoxin, and Thiocolchicine.

Betulinic acid is validated as a new self-assembly inducer for the formation of nanoparticles (NPs) in combination with different drugs. The target compounds are characterized by the presence of anticancer drugs acting on tubulin dynamics and of a linker that could be a carbon chain or a triazole-based one. Nanoparticles formed are characterized and their biological activity is evaluated.

Aged garlic extract and its constituent, S-allyl-L-cysteine, induce the apoptosis of neuroblastoma cancer cells due to mitochondrial membrane depolarization.

Aged garlic extract (AGE) has been demonstrated to have therapeutic properties in tumors; however its mechanisms of action have not yet been fully elucidated. A previous study revealed that AGE exerts an anti-proliferative effect on a panel of both sensitive [wild-type (WT)] and multidrug-resistant (MDR) human cancer cells. Following treatment of the cells with AGE, cytofluorimetric analysis revealed the occurrence of dose-dependent mitochondrial membrane depolarization (MMD). In this study, in order to further clarify the mechanisms of action of AGE, the effects of AGE on mitochondria isolated from rat liver mitochondria (RLM) were also examined. AGE induced an effect on the components of the electrochemical gradient (ΔµH +), mitochondrial membrane potential (ΔΨm) and mitochondrial electrochemical gradient (ΔpHm). The mitochondrial membrane dysfunctions of RLM induced by AGE, namely the decrease in both membrane potential and chemical gradient were associated with a higher oxidation of both the endogenous glutathione and pyridine nucleotide content. To confirm the anti-proliferative effects of AGE, experiments were performed on the human neuroblastoma (NB) cancer cells, SJ-N-KP and the MYCN-amplified IMR5 cells, using its derivative S-allyl-L-cysteine (SAC), with the aim of providing evidence of the anticancer activity of this compound and its possible molecular mechanism as regards the induction of cytotoxicity. Following treatment of the cells with SAC at 20 mM, cell viability was determined by MTT assay and apoptosis was detected by flow cytometry, using Annexin V-FITC labeling. The percentages of cells undergoing apoptosis was found to be 48.0% in the SJ-N-KP and 50.1% in the IMR5 cells. By cytofluorimetric analysis, it was suggested that the target of SAC are the mitochondria. Mitochondrial activity was examined by labeling the cells with the probe, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylimidacarbocyanine iodide (JC-1). Following treatment with SAC at 50 mM, both NB cell lines exhibited a marked increase in MMD. On the whole, the findings of this study indicate that both natural products, AGE and SAC, cause cytotoxicity to tumor cells via the induction of mitochondrial permeability transition (MPT).

Targeting multiple G-quadruplex-forming DNA sequences: Design, biophysical and biological evaluations of indolo-naphthyridine scaffold derivatives.

It is well recognized that the non-canonical DNA structures known as G-quadruplexes (G4s) have a potential anticancer significance and several compounds have been discovered and evaluated as promising G4 binders with anticancer activity. Here, starting from a promising hit with an indolo-naphthyridine scaffold, a small series of five indolo-naphthyridine based derivatives have been designed and evaluated as G4-targeting compounds. FRET biophysical studies were performed on multiple DNA G4 structures, leading to the identification of a multi-target G4 stabilizer with a slight preference for the c-KIT1 and a good G4 over duplex selectivity. The good affinity of this compound against c-KIT1 G4 was also confirmed by SPR and MST experiments, while biological assays revealed its cytotoxic activity on tumour cells. Finally, Molecular Dynamics simulations helped to elucidate the stabilization effect of the selected compound against the c-KIT1 G4.

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity.

BACKGROUND/AIM: The identification of a series of oxadiazole-based compounds, as promising antiproliferative agents, has been previously reported. The aim of this study was to explore the SAR of newly-synthesized oxadiazole derivatives and identify their molecular targets. MATERIALS AND METHODS: A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by the MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed. RESULTS: Several candidates showed cytotoxicity towards two human tumor cell lines, HCT-116 (colorectal carcinoma) and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies. CONCLUSION: The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new anti-topoisomerase agents.

Heteronanoparticles by Self-Assembly of Ecdysteroid and Doxorubicin Conjugates To Overcome Cancer Resistance.

Heteronanoparticles (H-NPs) consisting of conjugates characterized by a squalene tail linked to doxorubicin and ecdysteroid derivatives are presented. Biological evaluation on A2780ADR cell line confirms not only the maintenance of the activity of the parental drug but also the ability to overcome cancer resistance. The in vitro cell uptake was demonstrated, and the involvement of an endosomal-mediated pathway was suggested.

New insights in the structure-activity relationships of 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors.

Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1-21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3, or Cl at 8-position. Most compounds showed a promising human kinase insert domain receptor (KDR) inhibition profile, with IC50 values in the submicromolar/low micromolar range, and promising antiproliferative activity on human umbilical vein endothelial cells (HUVECs) as well as on a panel of three human tumor cell lines. The angio-kinase selectivity profile was assessed for the most promising compound 16 against a set of six human kinases. Finally, computational studies allowed clarifying at molecular level the interaction pattern established by the compounds with KDR, highlighting key stable cation-π interactions, and thus providing the basis for further designing novel inhibitors.

Correction: Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks.

Correction for 'Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks' by Gaia Fumagalli, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02591a.

Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks.

The ability of 4-(1,2-diphenylbut-1-en-1-yl)aniline as a self-assembly inducer is reported. The conjugation of this moiety with aloin or podophyllotoxin resulted in spherical nanoparticles that were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and NanoSight technology. A preliminary biological evaluation on two cancer cell lines is reported.

Synthesis and biological evaluation of new camptothecin derivatives obtained by modification of position 20.

The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC(50) values ranging from 0.03 to 12.2 µM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.

Synthesis and biological evaluation of pyrroloiminoquinone derivatives.

Synthesis of 10 pyrroloiminoquinone derivatives is presented. The strategy is based around the elaboration of a common intermediate by reaction with primary amines. All the compounds obtained have been subjected to antiproliferative activity with three different cell lines (NCI-H460, HeLa, and HL-60). The capacity of 4 selected compounds to affect the enzymatic activity of the nuclear enzyme DNA topoisomerase II and to form the typical DNA fragmentation which occurs in the apoptotic process is discussed here.

Mitochondrial permeability transition induced by novel pyridothiopyranopyrimidine derivatives: potential new antimitochondrial antitumour agents.

New pyridothiopyranopyrimidine derivatives (PTP1 and PTP2) were synthesised. Evaluation of the antiproliferative activity showed a significant capacity of the two compounds to inhibit cell growth. Investigation of the mechanism of action reveals that PTP1 interferes with the mitochondrial functions by inducing both swelling of the mitochondrial matrix and collapse of the electrical potential. These phenomena are fully prevented by typical inhibitors of the mitochondrial permeability transition, and are accompanied by the release of cytochrome c in the cytosol. The estimation of the redox state of thiol groups and glutathione suggests that the induction of permeability transition mediated by PTP1 is the result of an oxidative stress. The ability of cyclosporin A to prevent the antiproliferative effect of PTP1 indicates the induction of mitochondrial permeability transition as the molecular event responsible for the inhibition of cell growth. PTP1 also induces DNA fragmentation in intact cells. As regards PTP2, the presence of the p-toluensulphonamido group makes the lead chromophore unable to induce any effect on mitochondria.