A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones is described. The synthesis was developed on solid phase and was applied to provide a series of analogs in good yield. The key reactions are acylation of a cysteine derivative with 2,4-dichloropyrimidine-5-carbonyl chloride followed by cyclization to generate a 6-arylmethyl-7-carboxamido-2-chloro-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one, which is further derivatized with an amine to give the desired 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one.     

Characterization of macromolecules in liquid solutions by thermal diffusion. I. Dependence of the soret coefficient on the nature of the dispersing medium

Experiments have been carried out on thermal diffusion of macromolecular particles dispersed in various liquids, with the object of checking some predictions of the radiation-pressure theory of Soret effect in liquids and of establishing a method of physical characterization of macromolecules in liquid solutions. The experimental results confirm the importance of the ratio G between thermal conductivity K and (phase) velocity v of high-frequency elastic waves of the materials composing the mixture in determining the thermodiffusive behavior of a liquid solution. We have shown that the migration of the macromolecular component takes place in the same direction in which thermal energy is flowing or opposite to it, depending on whether G of the dispersed particles is smaller or larger relative to the G of the liquid. Another aspect of the same phenomenon may be observed when macroscopic pieces of nonmetallic materials are suspended in a liquid, and heat is made to flow through this solid plunger and the surrounding liquid. The experiments performed with molecular solutions and with macroscopic plungers mutually complement and confirm each other. Anomalous results obtained in the case of solutions of polyvinylpyrrolidone in methanol are also discussed, and the possibility that this might be the consequence of the existence of a marked velocity dispersion in the high-frequency region of the spectrum of thermal waves in both water and methyl alcohol is indicated. Finally the possibility is hinted that thermal diffusion might have been responsible for the phenomena of molecular selection and evolution which ultimately led to the origin of life on our planet.     

Assembly of shape-controlled nanocrystals by depletion attraction

Recently (Baranov et al., Nano Lett., 2010, 10, 743) we demonstrated that depletion attraction between semiconductor nanorods in solution can be employed for both their self-assembly and their separation from spherical nanoparticles. Here we show that depletion attraction can be used to fabricate binary superlattices of nanorods and 3D networks of octapod/tetrapod-shaped nanocrystals.     

Regioselectivity in the palladium-catalyzed addition of carbon nucleophiles to carbocyclic derivatives.

The regioselectivity of Pd-catalyzed malonate additions and arylations to cycloalkenyl esters can be predicted by completing a stereochemical analysis of the Pd-pi-allyl complex. The Pd-catalyzed malonate additions which have the greatest degree of regioselectivity are in which substituents have a steric influence in blocking the incoming nucleophile. Cyclopentenyl substrates displayed lower regioselectivity than the cyclohexyl counterparts presumably due to increased planarity of the system. Arylations using tin and hypervalent silicon reagents were compared.     

Solid-phase synthesis of N-9-substituted 2,8-diaminopurines

A general and efficient solid-phase synthesis of N-9-substituted 2,8-diaminopurines from 5-nitrouracil is described. The key synthetic transformation employs a carbodiimide-mediated cyclization of a thiourea. Thiourea formation on solid phase is performed using both thermal and microwave reaction conditions. Regiospecific solution-phase synthesis of key building blocks allows the incorporation of desired substituents at N-9 of the purine nucleus.     

Fragment‐Based Discovery of a Dual pan‐RET/VEGFR2 Kinase Inhibitor Optimized for Single‐Agent Polypharmacology

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment‐based chemical screen led to the identification of a novel RET inhibitor, Pz‐1. Modeling and kinetic analysis identified Pz‐1 as a type II tyrosine kinase inhibitor that is able to bind the “DFG‐out” conformation of the kinase. Importantly, from a single‐agent polypharmacology standpoint, Pz‐1 was shown to be active on VEGFR2, which can block the blood supply required for RET‐stimulated growth. In cell‐based assays, 1.0 nM of Pz‐1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg^?1 day^?1 per os, Pz‐1 abrogated the formation of tumors induced by RET‐mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz‐1 featured no detectable toxicity at concentrations of up to 100.0 mg kg^?1, which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.     

Development and characterization of an integrated silicon micro flow cytometer

This paper describes an innovative integrated micro flow cytometer that presents a new arrangement for the excitation/detection system. The sample liquid, containing the fluorescent marked particles/cells under analysis, is hydrodynamically squeezed into a narrow stream by two sheath flows so that the particles/cells flow individually through a detection region. The detection of the particles/cells emitted fluorescence is carried out by using a collection fiber placed orthogonally to the flow. The device is based on silicon hollow core antiresonant reflecting optical waveguides (ARROWs). ARROW geometry allows one to use the same channel to guide both the sample stream and the fluorescence excitation light, leading to a simplification of the optical configuration and to an increase of the signal-to-noise ratio. The integrated micro flow cytometer has been characterized by using biological samples marked with standard fluorochromes. The experimental investigation confirms the success of the proposed microdevice in the detection of cells. An erratum to this article can be found at