DNA Interactions and Biological Activity of 2,9-Disubstituted 1,10-Phenanthroline Thiosemicarbazone-Based Ligands and a 4-Phenylthiazole Derivative.

Four 1,10-phenanthroline derivatives (1-4) were synthesized as potential telomeric DNA binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1 and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values (30-80 µM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 µM). However, the neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties, such as PhenDC3 and PhenQE8.

Delivery of Therapeutic Biopolymers Employing Silica-Based Nanosystems.

The use of nanoparticles is crucial for the development of a new generation of nanodevices for clinical applications. Silica-based nanoparticles can be tailored with a wide range of functional biopolymers with unique physicochemical properties thus providing several advantages: (1) limitation of interparticle interaction, (2) preservation of cargo and particle integrity, (3) reduction of immune response, (4) additional therapeutic effects and (5) cell targeting. Therefore, the engineering of advanced functional coatings is of utmost importance to enhance the biocompatibility of existing biomaterials. Herein we will focus on the most recent advances reported on the delivery and therapeutic use of silica-based nanoparticles containing biopolymers (proteins, nucleotides, and polysaccharides) with proven biological effects.

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex.

A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).

Easy Access to Polyfunctionalized Chiral Decalins.

An unexpected ring expansion that converts hydrindanes into decalins via an unprecedented dyotropic reaction involving a mesylate group has been observed, and this paved the way for easy access to polyfunctionalized chiral decalins. These polyfunctionalized chiral decalins can be very useful building blocks for the synthesis of the thia analogues of many natural compounds. They can also be used in asymmetric catalysis and also in the synthesis of the new analogues of vitamin D with a modified D ring and side chain. The use of chiral sulfoxide ligands for asymmetric catalysis or asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds is a very important topic in the field of organic chemistry, hence our results could be useful to the scientific community.

Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.

Synthetic analogs of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)2D3 with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2″-hydroxy-2″-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S). These compounds act as weak VDR agonist in transcriptional assays with compound 3 being the most active. X-ray crystallographic analysis of the VDR ligand-binding domain accommodating the three compounds indicates that the oxolane group branched at carbon C22 is not constrained as in case of compound with oxolane group branched at C20 leading to the loss of interactions of the triene group and increased flexibility of the C/D-rings and of the side chain.

Gemini analogs of vitamin D.

The Gemini analogs are the last significant contribution to the family of vitamin D derivatives in medicine, for the treatment of cancer. The first Gemini analog was characterized by two symmetric side chains at C-20. Following numerous modifications, the most active analog bears a C-23-triple bond, C-26, 27- hexafluoro substituents on one side chain and a terminal trideuteromethylhydroxy group on the other side chain. This progression was possible due to improvements in the synthetic methods for the preparation of these derivatives, which allowed for increasing molecular complexity and complete diastereoselective control at C-20 and the substituted sidechains.

Synthesis and biological evaluation of a new vitamin D2 analogue.

A new vitamin D(2) analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivo.

Diverging pathways to topologically complex polycyclic bis-acetals and their ring system interchange.

Carbinol-tethered octalin-diols (1), which differ only by the C11 configuration at the angular position, were transformed selectively to three types of structurally unrelated original scaffolds such as unsymmetrical octahydroanthracenes (5/7), furofuranes (6), or spirans (8/9) via a two-step protocol. The 11S* configuration ensures a C13-C4 Friedel-Crafts type C-C bonding (through an unprecedented oxidative cleavage-triggered domino process) while the 11R* configuration allows for a C13-C2 Marson-type Friedel-Crafts C-C bonding (through a nucleophilic acetal opening).

An application of two MIFs-based tools (Volsurf+ and Pentacle) to binary QSAR: the case of a palinurin-related data set of non-ATP competitive glycogen synthase kinase 3ß (GSK-3ß) inhibitors.

VolSurf+ and GRIND descriptors extract the information present in MIFs calculated by GRID: the first are simpler to interpret and generally applied to ADME-Tox topics, whereas the latter are more sophisticated and thus more suited for pharmacodynamics events. Here we present a study which compares binary QSAR models obtained with VolSurf+ descriptors and GRIND for a data set of non-ATP competitive GSK-3ß inhibitors chemically related to palinurin for which the biological activity is expressed in binary format. Results suggest not only that the simpler Volsurf+ descriptors are good enough to predict and chemically interpret the investigated phenomenon but also a bioactive conformation of palinurin which may guide future design of ATP non-competitive GSK-3 inhibitors.

Competing domino processes: path-discriminating ability of epoxide stereochemistry at the angular position.

Structurally different products can be reached selectively from unsaturated vicinal bicyclic diols, which differ only by the epoxide configuration at the angular position. It is possible to modify the regiochemical outcome of the domino process in such a way as to create a different pathway, [4 + 2] versus [4 + 3 + 2], and control product distribution by using the configuration bias. No previous example of a domino variant of the [4 + 3 + 2] process appears to have been documented.

Radial Distribution Function descriptors for predicting affinity for vitamin D receptor.

The QSAR is an alternative method for the research of new and better Vitamin D analogues with affinity for the VDR receptor. This paper describes the results of applying the Radial Distribution Function (RDF descriptors) approach for predicting the VDR affinity of 38 vitamin D analogues. The model described 80% of the experimental variance, with a standard deviation of 0.35. Leave-one-out, bootstrapping and external set validation were carried out with the aim of evaluating the predictive power of the model. The values of their respective squared correlations coefficients were 0.72, 0.70 and 0.79. The RDF approach was compared with four other predictive models, but none of these could explain more than 71.0% of the variance with six variables in their respective models.