Design,Synthesis and Evaluation of 2,4-Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the β-tubulin. In this study, we designed and synthesized a set of nine 2,4-diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1), a noncancerous one (COS-7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK-LU-1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non-N-substituted 2,4-diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.     

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC₅₀ value of 1 μM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.     

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX-809 and VX-770

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R¹ and R² substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X-ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3-triazole will inform medicinal chemists as they consider using the triazole as an amide bioisostere.     

Drying-induced stresses in elastic and viscoelastic saturated materials

The paper presents a theoretical analysis of stresses generated during convective drying of kaolin, based on elastic and viscoelastic models. The equations of these models were solved analytically for a cylindrically shaped sample; the distribution and evolution of the radial and circumferential stresses are illustrated in diagrams. The acoustic emission method was used in experimental tests for identification on line of the time period during which the stresses reach their maximal values. A better correlation has been found between the experimental tests and the theoretical predictions obtained on the basis of the viscoelastic model.     

High oleic acid oil suppresses lung tumorigenesis in mice through the modulation of extracellular signal-regulated kinase cascade

This study was undertaken to estimate the effect of dietary high oleic acid oil (OA) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Diet containing 10% oil was fed to mice through experimental periods. On day 30 after NNK injection (100 mg/kg body weight, i.p.), the treatment increased the level of prostaglandin E₂ (PGE₂) as well as proliferating cell nuclear antigen, a marker of cell proliferation in a high linoleic acid oil (LA)-fed group but not in an OA-fed group. The NNK treatment also induced the activation of an extracellular signal-regulated kinase (Erk) cascade (Erk, Mek and Raf-1) in an LA-fed group. On the other hand, OA feeding abolished the NNK-induced activation of the Erk cascade. In conjugation with these events, OA feeding reduced lung tumor incidence and tumor multiplicity (percentage of mice with tumors) in mice compared with LA feeding at the 20th experimental week. These results suggest that OA suppresses lung tumorigenesis and that this suppression is correlated with the inhibition of PGE₂ production and inactivation of the Erk cascade.     

Preparation of Benzylamine by Highly Selective Reductive Amination of Benzaldehyde Over Ru on an Acidic Activated Carbon Support as the Catalyst

Platinum particles (<1.5 nm) have been shown to behave as bases in their interaction with -alumina. FTIR spectra of adsorbed pyridine probe molecules showed that the acid strength of the -alumina was decreased by the presence of (<1.5 nm) Pt particles. Ammonium chloride treatment converts the primary Pt clusters to H _x Pt _y Cl _z intermediates that de-anchor from the support. Consequently, agglomeration to 8 nm Pt particles was observed following treatment in hydrogen at a relatively mild temperature. For the treated catalyst the IR data of absorbed pyridine show a 3 cm^-1 increase relative to the original Pt/-Al₂O₃ catalyst, indicating a strengthening of the acidity. Changes in the Pt particle size were confirmed by FTIR spectroscopy of CO absorbed onto the Pt particles before and after treatment. Consecutive CO and pyridine probe adsorption demonstrated the electronic interplay between the Pt particles and the support. Pyridine adsorption onto the -alumina support of a Pt/Al₂O₃ catalyst pre-dosed with CO produces a nearly 40 cm^-1 lowering of the CO peak position, indicative of CO bond weakening. In the case of CO adsorbed onto a catalyst pre-dosed with pyridine, a shift in the pyridine IR spectrum was only observed from the original highly dispersed catalyst.     

Studies on curing urethane prepolymers with aniline–formaldehyde resins

Commercial aniline–cresol–formaldehyde resin, two model aniline–formaldehyde and aniline–cresol–formaldehyde resins, and methylenedianiline have been used as curatives for NCO-terminated urethane prepolymer prepared from polyoxypropylenediol and toluene-diisocyanate. Based on viscoelastic behavior of the investigated systems and changes in their IR spectra, it has been concluded that phenolic OH groups present in aniline–cresol–formaldehyde resin do not play an important role in the curing process carried out at RT despite earlier suggestions to the contrary. The explanation for specific behavior of systems where urethane prepolymers have been cured with commercial aniline–cresol–formaldehyde resin is presumably the presence of small amount of solvent (benzyl alcohol) in that resin, which may influence the reaction kinetics.     

Single-Site Calcium Initiators for the Controlled Ring-Opening Polymerization of Lactides and Lactones

Summary Single-site calcium initiators containing chelating tmhd (H-tmhd = 2,2,6,6-tetramethylheptane-33-dione) ligands [(THF)Ca(tmhd)_]2[-N(SiMe₃)₂](-tmhd) (2) and [(THF)Ca(tmhd)]₂[-OCH(Me)Ph](-tmhd) (3) have been synthesized and applied for the ring-opening polymerization of L-lactide and -caprolactone. Both 2 and 3 were highly reactive and promoted a fast polymerization of L-lactide and -caprolactone to high monomer conversions under mild conditions (THF as a solvent, room temperature). More importantly, results showed that the ring-opening polymerizations of lactides and lactones initiated by either 3 or 2 in the presence of equivalent 2-propanol are living, to provide polymers and block copolymers of controlled molecular weights and tailored end-groups. The polymerizations were first-order in monomer up to high conversions, in which the in situ initiating system 2/2-propanol revealed no induction period and much faster polymerization kinetics as compared to 3.     

Enhancing dead end filtration throughput using a non-traditional liquid handling procedure

The dead end filtration of dilute protein solutions is normally conducted with either a constant pressure or constant rate fluid delivery system. However both approaches often fall short in using all the available capacity of the filter. A novel automated fluid handling system has been recently developed by SciLog Inc, USA, which can increase the DEF yield by up to 35%. Karl Schick, director of research & development, presents and discusses throughput data supporting this claim.     

Polyaniline and polypyrrole prepared in the presence of surfactants: a comparative conductivity study

Polyaniline and polypyrrole have been prepared by chemical oxidative polymerization of the corresponding monomers in an aqueous medium containing an anionic surfactant—sodium bis(2-ethylhexyl) sulfosuccinate, dodecylbenzenesulfonic acid and its sodium salt, and sodium dodecyl sulfate. Determination of the yield, elemental composition and density proved, and FTIR spectroscopy confirmed, that the anionic surfactants become incorporated in the conducting polymers. The polymerizations in the presence of a cationic surfactant, tetradecyltrimethylammonium bromide, were carried out for comparison. While the conductivity of polypyrrole became enhanced after the introduction of an anionic surfactant, the changes in the conductivity of polyaniline were marginal. The conductivity changes in both polymers during thermal ageing were measured at 175 °C. The electrical stability of polyaniline was better than that of polypyrrole. The presence of a surfactant improved the stability of conductivity of polypyrrole but reduced the electrical stability of polyaniline.