Ligand and Linkage Isomers of Bis(ethylthiocarbamato) Copper Complexes with Cyclic C6H8 Backbone Substituents: Synthesis,Characterization, and Antiproliferation Activity

A series of isomeric bis(alkylthiocarbamate) copper complexes have been synthesized, characterized, and evaluated for antiproliferation activity. The complexes were derived from ligand isomers with 3-methylpentyl (H₂L²) and cyclohexyl (H₂L³) backbone substituents, which each yield a pair of linkage isomers. The thermodynamic products CuL^2a/3a have two imino N and two S donors resulting in three five-member chelate rings (555 isomers). The kinetic isomers CuL^2b/3b have one imino and one hydrazino N donor and two S donors resulting in four-, six-, and five-member rings (465 isomers). The 555 isomers have more accessible Cu^II/I potentials (E_1/2=−811/−768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E_1/2=−923/-854 mV). Antiproliferation activities were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL^2a was potent (^A549EC₅₀=0.080 μM) and selective (^IMR-90EC₅₀/^A549EC₅₀=25) for A549. Its linkage isomer CuL^2b had equivalent A549 activity, but lower selectivity (^IMR-90EC₅₀/^A549EC₅₀=12.5). The isomers CuL^3a and CuL^3b were less potent with ^A549EC₅₀ values of 1.9 and 0.19 M and less selective with ^IMR-90EC₅₀/^A549EC₅₀ ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity.     

三唑类白杨素衍生物的设计、合成及其抗增殖活性研究

合成了2个系列的白杨素衍生物,采用噻唑蓝(MTT)法测试了所有化合物针对六种肿瘤细胞的体外抗增殖活性,包括MGC-803, BEL-7402, HepG2, HeLa, A549以及SGC-7901细胞.实验结果显示, 7-[1-(3-氟苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1c)与7-[1-(2-氯苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1g)针对MGC-803细胞的活性与先导化合物白杨素及阳性对照药5-氟尿嘧啶相比显著提高.因此,化合物1c与1g具有深入研究用以开发抗癌药物的潜能.     

New Synthetic Route of Two Active Isomeric Metabolites of Erlotinib and Their Bioactivity Studies against Several Tumor Cell Lines

The synthesis and differential antiproliferative activity of two active isomeric metabolites of erlotinib were investigated. This synthetic process had demonstrated to avoid the unstable 4‐chloroquinazoline intermediates and long procedures. New intermediates and final compounds were identified by ¹H NMR, ¹³C NMR and ESI‐TOF MS, and their purities were determined by high performance liquid chromatography. In vitroproliferative assay indicated that these two metabolites possessed antiproliferative activity against some conventional tumor cell lines and EGFR tyrosine kinase over‐expression tumor cell lines as compared to erlotinib control, and their antitumor activity in cellular level was first reported here.     

Design, synthesis and characterisation of guanosine-based amphiphiles

A small library of sugar-modified guanosine derivatives has been prepared, starting from a common intermediate, fully protected on the nucleobase. Insertion of myristoyl chains and of diverse hydrophilic groups, such as an oligoethylene glycol, an amino acid or a disaccharide chain, connected through in vivo reversible ester linkages, or of a charged functional group provided different examples of amphiphilic guanosine analogues, named G1-G7 herein. All of the sugar-modified derivatives were positive in the potassium picrate test, showing an ability to form G-tetrads. CD spectra demonstrated that, as dilute solutions in CHCl(3), distinctive G-quadruplex systems may be formed, with spatial organisations dependent upon the structural modifications. Two compounds, G1 and G2, proved to be good low-molecular-weight organogelators in polar organic solvents, such as methanol, ethanol and acetonitrile. Ion transportation experiments through phospholipid bilayers were carried out to evaluate their ability to mediate H(+) transportation, with G5 showing the highest activity within the investigated series. Moreover, G3 and G5 exhibited a significant cytotoxic profile against human MCF-7 cancer cells in in vitro bioassays.     

Copper,BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer’s disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu²⁺ homeostasis is a prominent factor in the development of neurological pathologies. The N‐terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu²⁺ ions has been reported up to now. Cu²⁺ complexes of the peptide fragment BDNF(1–12) encompassing the sequence 1–12 of N‐terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT‐geometry optimizations. Coordination features of the acetylated form, Ac‐BDNF(1–12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1–12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu²⁺ coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1–12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu²⁺. The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu²⁺ may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.     

Natural Compounds Isolated from Stachybotrys chartarum Are Potent Inhibitors of Human Protein Kinase CK2

A large number of secondary metabolites have been isolated from the filamentous fungus Stachybotrys chartarum and have been described before. Fourteen of these natural compounds were evaluated in vitro in the present study for their inhibitory activity towards the cancer target CK2. Among these compounds, stachybotrychromene C, stachybotrydial acetate and acetoxystachybotrydial acetate turned out to be potent inhibitors with IC₅₀ values of 0.32 µM, 0.69 µM and 1.86 µM, respectively. The effects of these three compounds on cell proliferation, growth and viability of MCF7 cells, representing human breast adenocarcinoma as well as A427 (human lung carcinoma) and A431 (human epidermoid carcinoma) cells, were tested using EdU assay, IncuCyte^® live-cell imaging and MTT assay. The most active compound in inhibiting MCF7 cell proliferation was acetoxystachybotrydial acetate with an EC₅₀ value of 0.39 µM. In addition, acetoxystachybotrydial acetate turned out to inhibit the growth of all three cell lines completely at a concentration of 1 µM. In contrast, cell viability was impaired only moderately, to 37%, 14% and 23% in MCF7, A427 and A431 cells, respectively.     

Guanidiniocarbonylpyrrole–Aryl Derivatives: Structure Tuning for Spectrophotometric Recognition of Specific DNA and RNA Sequences and for Antiproliferative Activity

We present a systematic study of different guanidiniocarbonylpyrrole‐aryl derivatives designed to interact with DNA or RNA both through intercalation of an aromatic moiety into the base stack of the nucleotide and through groove binding of a guanidiniocarbonylpyrrole cation. We varied 1) the size of the aromatic ring (benzene, naphthalene, pyrene and acridine), 2) the length and flexibility of the linker connecting the two binding groups, and 3) the total number of positive charges present at different pH values. The compounds and their interactions with DNA and RNA were studied by UV/Vis, fluorescence and CD spectroscopy. Antiproliferative activities against human tumour cell lines were also determined. Our studies show that efficient interaction with, for example, DNA requires a significantly large aromatic ring (pyrene) connected through a flexible linker to the pyrrole moiety. However, a positive charge, as in 12 , is also needed. Compound 12 allows for base‐pair‐selective recognition of ds‐DNA at physiological pH values. The antiproliferative activities of these compounds correlate with their binding affinities towards DNA, suggesting that their biological effects are most probably due to DNA binding.     

Catalysis Concepts in Medicinal Inorganic Chemistry

Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new catalysis strategy in which metal complexes are unconventionally employed as substrates rather than catalysts.     

Separation of six compounds from pigeon pea leaves by elution–extrusion counter‐current chromatography

A valid and reliable method was established to separate six compounds from pigeon pea leaves via elution‐extrusion counter‐current chromatography. A solvent system composed of n‐hexane/methanol/formic acid aqueous solution with pH = 3 (10:6:4, v/v) was screened to achieve satisfactory isolation from the ethanol extract of pigeon pea leaves. Four compounds, 9.2 mg of compound 1 (96.8%), 3.2 mg of 2 (88.0%), 6.2 mg of 4 (94.2%) and 25.2 mg of 5 (94.2%), were obtained by conventional elution from 100 mg of the precipitation fraction, respectively. Two compounds, 14.4 mg of 3 (96.3%) and 28.1 mg of 6 (96.6%), with high K values were obtained by the subsequent extrusion procedure. The compounds 1 – 6 were identified as 3‐methoxy‐5‐(2‐phenylethenyl)‐phenol, pinostrobin chalcone, pinostrobin, 2‐hydroxy‐4‐methoxy‐6‐(2‐phenylvinyl)‐benzoic acid, longistylin C and cajaninstilbene acid by quadrupole time‐of‐flight mass spectrometry, and ¹H and ¹³C NMR spectroscopy. The in vitro antiproliferation activities of compounds 1 , 5 and 6 against human hepatoma cell were evaluated and the half‐maximum inhibitory concentrations were acquired.