Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis,Metabolic Formation from Ferrociphenols,and Oxidative Transformation

Ferrociphenols ( FCs ) and their oxidized, electrophilic quinone methide metabolites ( FC‐QMs ) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM . These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs , and also open the way to a new series of organometallic antitumor compounds.     

Design,Synthesis and Evaluation of New Multifunctional Benzothiazoles as Photoprotective,Antioxidant and Antiproliferative Agents

A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC₅₀ was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile.     

Three‐Arm,Biotin‐Tagged Carbazole–Dicyanovinyl–Chlorambucil Conjugate: Simultaneous Tumor Targeting,Sensing, and Photoresponsive Anticancer Drug Delivery

The design, synthesis, and in vitro biological studies of a biotin–carbazole–dicyanovinyl–chlorambucil conjugate (Bio‐CBZ‐DCV‐CBL; 6 ) are reported. This conjugate ( 6 ) is a multifunctional single‐molecule appliance composed of a thiol‐sensor DCV functionality, a CBZ‐derived phototrigger as well as fluorescent reporter, and CBL as the anticancer drug, and Bio as the cancer‐targeting ligand. In conjugate 6 , the DCV bond undergoes a thiol–ene click reaction at pH<7 with intracellular thiols, thereby shutting down internal charge transfer between the donor CBZ and acceptor DCV units, resulting in a change of the fluorescence color from green to blue, and thereby, sensing the tumor microenvironment. Subsequent photoirradiation results in release of the anticancer drug CBL in a controlled manner.     

Heteropentanuclear Oxalato‐Bridged nd–4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis,Crystal Structures,Aqueous Stability and Antiproliferative Activity

A series of heteropentanuclear oxalate‐bridged Ru(NO)‐Ln (4d–4f) metal complexes of the general formula (nBu₄N)₅[Ln{RuCl₃(μ‐ox)(NO)}₄], where Ln=Y ( 2 ), Gd ( 3 ), Tb ( 4 ), Dy ( 5 ) and ox=oxalate anion, were obtained by treatment of (nBu₄N)₂[RuCl₃(ox)(NO)] ( 1 ) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1 , 2 , and 5 were in addition analyzed by X‐ray crystallography, 1 by Ru K‐edge XAS and 1 and 2 by ¹³C NMR spectroscopy. X‐ray diffraction showed that in 2 and 5 four complex anions [RuCl₃(ox)(NO)]^2? are coordinated to Y^III and Dy^III, respectively, with formation of [Ln{RuCl₃(μ‐ox)(NO)}₄]^5? (Ln=Y, Dy). While Y^III is eight‐coordinate in 2 , Dy^III is nine‐coordinate in 5 , with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu₄N⁺ ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium‐lanthanide complexes 2 – 5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC‐5) and compared with those obtained for the previously reported Os(NO)‐Ln (5d–4f) analogues (nBu₄N)₅[Ln{OsCl₃(ox)(NO)}₄] (Ln=Y ( 6 ), Gd ( 7 ), Tb ( 8 ), Dy ( 9 )). Complexes 2 – 5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes 6 – 9 in terms of IC₅₀ values. The highest antiproliferative activity with IC₅₀ values of 20.0 and 22.4 μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP‐MS data, indicating five‐ to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.     

Ruthenium–Arene–β‐Carboline Complexes as Potent Inhibitors of Cyclin‐Dependent Kinase 1: Synthesis,Characterization and Anticancer Mechanism Studies

A series of Ru^II–arene complexes ( 1 – 6 ) of the general formula [(η⁶‐arene)Ru(L)Cl]PF₆ (arene=benzene or p‐cymene; L=bidentate β‐carboline derivative, an indole alkaloid with potential cyclin‐dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X‐ray crystallography. Hydrolytic studies show that β‐carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3‐ to 12‐fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross‐resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1 – 6 may directly target CDK1, because they can block cells in the G2M phase, down‐regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial‐related pathways and intracellular reactive oxygen species (ROS) elevation.     

Cerium Alkoxides—Synthesis, Properties and Their Use in Michael Addition Reaction

Cerium(III) alkoxides served as an effective and attractive promoter for the Michael addition reaction with excellent chemical yields under mild conditions in short reaction time.     

Design,Sonosynthesis, Quantum‐Chemical Calculations,and Evaluation of New Mono‐ and Bis‐pyridine Dicarbonitriles as Antiproliferative Agents

A highly efficient, simple, and clean single‐step sonosynthetic procedure has been sophisticated for assembling new series of mono‐ and bis‐pyridine dicarbonitriles from ketones, HCl, and tetracyanoethylene. The presented protocol is applicable for the preparation of a broad range of uniquely substituted pyridine dicarbonitriles and seems to be superior in comparison with other previously reported methods. The antiproliferative impact of the newly synthesized derivatives was screened towards three representative cancer cell lines (MCF‐7, A549, and HCT116). Most of the evaluated derivatives showed a moderate to excellent anti‐proliferative activity towards the selected cell lines. Of these, compounds 4h , 4k , 10 , 12a , and 12b showed both potent anticancer activity (IC₅₀<10 μM) and lower cytotoxic effect (IC₅₀ > 58 μM) on non‐tumorigenic cells (MCF‐10A and NCM460), suggesting their promising potential to be lead molecules for future antitumor drug discovery. The structure‐activity relationships have been also discussed. Moreover, quantum chemical studies based on Density Functional Theory (DFT) of the synthesized compounds were investigated and found to be consistent with the in vitro inhibitory activities.     

Synthesis,Characterization, Cytotoxicity,and Hydrolytic Behavior of C2‐ and C1‐Symmetrical TiIV Complexes of Tetradentate Diamine Bis(Phenolato) Ligands: A New Class of Antitumor Agents

Carefully design your ligand! A new family of highly cytotoxic Ti^IV complexes demonstrates strong dependence of activity on the particular ligand employed, in which small structural modifications dramatically affect both hydrolytic behavior and biological activity (see picture). Different structure‐dependence patterns are observed for hydrolysis and cytotoxicity, which are, nonetheless, strongly related.

     

Stereoselective Synthesis of the Halaven C14–C26 Fragment from D‐Quinic Acid: Crystallization‐Induced Diastereoselective Transformation of an α‐Methyl Nitrile

Crystallization‐induced diastereoselective transformation (CIDT) of an α‐methyl nitrile completes an entirely non‐chromatographic synthesis of the halichondrin B C14–C26 stereochemical array. The requisite α‐methyl nitrile substrate is derived from D ‐quinic acid through a series of substrate‐controlled stereoselective reactions via a number of crystalline intermediates that benefit from a rigid polycyclic template. Therefore, all four stereogenic centers in the Halaven C14–C26 fragment were derived from the single chiral source D ‐quinic acid.     

Tetraamine‐Derived Bifunctional Chelators for Technetium‐99m Labelling: Synthesis,Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP‐Receptor‐Positive Tumours

Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, ^99mTc continues to be the ideal radioisotope for medical‐imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O₂ to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11‐tetraazaundecane derivatives ( 01 – 06 ) containing different functional groups at the 6‐position for the conjugation of biomolecules and subsequent labelling with ^99mTc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH ( 02 ), N₃ ( 04 ) and O‐succinyl ester ( 05 ) groups. A straightforward and easy synthesis of carboxyl‐functionalised tetraamine‐based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin‐antagonist peptide and subsequent labelling with ^99mTc afforded the radiotracer ^99mTc‐N4‐BB‐ANT, with radiolabelling yields of >97 % at a specific activity of 37 GBq μmol^?1. An IC₅₀ value of (3.7±1.3) nM was obtained, which confirmed the high affinity of the conjugate to the gastrin‐releasing‐peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of ^99mTc‐N4‐BB‐ANT showed high and specific uptake in PC3 xenografts and in other GRPr‐positive organs. The tumour uptake was (22.5±2.6) % injected activity per gram (% IA g^?1) at 1 h post injection (p.i.). and increased to (29.9±4.0) % IA g^?1 at 4 h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of ^99mTc‐N4‐BB‐ANT warrant its potential candidature for clinical translation.     

α‐Aminoxy Oligopeptides: Synthesis,Secondary Structure,and Cytotoxicity of a New Class of Anticancer Foldamers

α‐Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α‐aminoxy oligopeptides we used a straightforward combination of solution‐ and solid‐phase‐supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X‐ray crystal structure of an α‐aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right‐handed 2₈‐helical conformation with precisely two residues per turn and a helical pitch of 5.8 Å. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 2₈‐helix as the predominant conformation in organic solvents. In aqueous solution, the α‐aminoxy peptides exist in the 2₈‐helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α‐aminoxy peptides have an increased propensity to take up a 2₈‐helical conformation in the presence of a model membrane. This indicates a correlation between the 2₈‐helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α‐aminoxy peptides.     

Thiomaltol‐Based Organometallic Complexes with 1‐Methylimidazole as Leaving Group: Synthesis,Stability, and Biological Behavior

Thiomaltol, a potential S,O‐coordinating molecule, has been utilized for the complexation of four different organometallic fragments, yielding the desired Ru^II, Os^II, Rh^III, and Ir^III complexes having a “piano‐stool” configuration. In addition to the synthesis of these compounds with a chlorido leaving group, the analogous 1‐methylimidazole derivatives have been prepared, giving rise to thiomaltol‐based organometallics with enhanced stability under physiological conditions. The organometallic compounds have been characterized by NMR spectroscopy, elemental analysis, and X‐ray diffraction analysis. Their behavior in aqueous solution and their interactions with certain amino acids have been studied by ESI mass spectrometry. Their pH‐dependent stability has been investigated by ¹H NMR in aqueous solution, and their cytotoxicity against three different cancer cell lines has been investigated. Furthermore, their capacity as topoisomerase IIα inhibitors as well as their effect on the cell cycle distribution and reactive oxygen species (ROS) generation have been elucidated.