In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers.

A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.

Design of Bis(1,10-phenanthroline) Copper(I)-Based Mechanochromic Indicators.

In the growing field of single-molecule mechanochromism, the potential of transition metal complexes is yet to be examined. In this work, we have synthesized a series of [Cu(phen)2]+ complexes: bis-Cu(I)-phenanthroline, bis-Cu(I)-phenanthroline-2-amine, and bis-Cu(I)-phenanthroline-2-acetamide. After that, we characterized the complexes by UV-vis spectroscopy and employed density functional theory (DFT) calculations to investigate the changes in UV-vis upon mechanical pulling via force calculations. The results of our examination of time-dependent (TD)-DFT-calculated UV-vis suggests that the bis-Cu(I)-phenanthroline-2-acetamide complex is predicted to have an observable shift of the metal-to-ligand charge transfer band upon pulling from 0 to 0.6 nN in the visible region. We have demonstrated the ability to synthesize and characterize bis-Cu(I)-phenanthroline-2-acetamide. In addition, the TD-DFT calculations predict an observable shift in the visible region of the UV-vis spectrum. This indicates that transition metal complexes are feasible candidates as mechanophores and are worthy of further exploration as to their potential role in a new subclass of mechanochromic indicators.

Prolyl oligopeptidase and its role in the organism: attention to the most promising and clinically relevant inhibitors.

Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment. Furthermore, it may also represent an interesting target for treatment of neuropsychiatric disorders, and as an antiangiogenesis or antineoplastic agent. In this review paper, we summarized naturally occurring POP inhibitors together with peptide-like inhibitors and their biological effects. Some of them have shown promising results and interesting pharmacological profiles. However, to date, there is no POP inhibitor available on the market although several clinical trials have been undertaken.

Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity.

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.