The development of an Amber-compatible organosilane force field for drug-like small molecules.

As members of the group IVA elements, silicon and carbon have long been thought of as isosteres of each other in drug design. However, the lack of silicon parameters in current main stream force fields hinders the computational study of this important element in drug discovery. Thus, in this study, we attempted to supplement the parameters of organosilanes in the General Amber Force Field (GAFF2). The parameters have been designed following the principles of GAFF2 to make it compatible with the Amber force field family. The accuracy of the parameters was discussed by comparing the pair interaction energy, the liquid properties, and the structures and alchemical binding free energy differences for a set of protein-ligand complexes.

Acidity/Reducibility Dual-Responsive Hollow Mesoporous Organosilica Nanoplatforms for Tumor-Specific Self-Assembly and Synergistic Therapy.

Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.

Solvent vapor annealing of block copolymers in confined topographies: commensurability considerations for nanolithography.

The directed self-assembly of block copolymer (BCP) materials in topographically patterned substrates (i.e., graphoepitaxy) is a potential methodology for the continued scaling of nanoelectronic device technologies. In this Communication, an unusual feature size variation in BCP nanodomains under confinement with graphoepitaxially aligned cylinder-forming poly(styrene)-block-poly(4-vinylpyridine) (PS-b-P4VP) BCP is reported. Graphoepitaxy of PS-b-P4VP BCP line patterns (CII ) is accomplished via topo-graphy in hydrogen silsequioxane (HSQ) modified substrates and solvent vapor annealing (SVA). Interestingly, reduced domain sizes in features close to the HSQ guiding features are observed. The feature size reduction is evident after inclusion of alumina into the P4VP domains followed by pattern transfer to the silicon substrate. It is suggested that this nano-domain size perturbation is due to solvent swelling effects during SVA. It is proposed that using a commensurability value close to the solvent vapor annealed periodicity will alleviate this issue leading to uniform nanofins.

Target-selective phototherapy using a ligand-based photosensitizer for type 2 cannabinoid receptor.

Phototherapy is a powerful, noninvasive approach for cancer treatment, with several agents currently in clinical use. Despite the progress and promise, most current phototherapy agents have serious side effects as they can lead to damage to healthy tissue, even when the photosensitizers are fused to targeting molecules due to nonspecific light activation of the unbound photosensitizer. To overcome these limitations, we developed a phototherapy agent that combines a functional ligand and a near infrared phthalocyanine dye. Our target is type 2 cannabinoid receptor (CB2R), considered an attractive therapeutic target for phototherapy given it is overexpressed by many types of cancers that are located at a surface or can be reached by an endoscope. We show that our CB2R-targeted phototherapy agent, IR700DX-mbc94, is specific for CB2R and effective only when bound to the target receptor. Overall, this opens up the opportunity for development of an alternative treatment option for CB2R-positive cancers.

Synthesis of helical and supplementary chirally doped PMO materials. Suitable catalysts for asymmetric synthesis.

Exciting helical mesoporous organosilicas including supplementary chirally doped moieties into their spiral walls were one-pot successfully synthesized with good structural order for, to the best of our knowledge, the first time. This one-step direct synthesis of helical chirally doped periodic mesoporous organosilica (PMO) materials was carried out by combination of a tartrate-based bis-organosilicon precursor with tetraethyl orthosilicate (TEOS) and two surfactants, cetyltrimethylammonium bromide and perfluoroctanoic acid (CTAB and PFOA). For comparison purposes, a conventional two-step postsynthetic grafting methodology was carried out. In this method, the chiral tartrate-based moieties were grafted onto the helical silica mesoporous materials previously prepared by the dual-templating approach (CTAB and PFOA). The chirally doped materials prepared by both methodologies exhibited helical structure and high BET surface area, pore size distributions, and total pore volume in the range of mesopores. Solid-state (13)C and (29)Si MAS NMR experiments confirmed the presence of the chiral organic precursor in the silica wall covalently bonded to silicon atoms. Nevertheless, one-pot direct synthesis led to a greater control of surface properties and presented larger incorporation of organic species compared with the two-step postsynthetic methodology. To further prove the potential feasibility of these materials in enantiomeric applications, Mannich diastereoselective asymmetric synthesis was chosen as catalytic test. In the case of the one-pot PMO material, the rigidity of the chiral ligand backbone provided by its integration into the inorganic helical wall in combination with the steric impediments supplied by the twisted geometry led to the reagents to adopt specific orientations. These geometrical constrictions resulted in an outstanding diastereomeric induction toward the preferred enantiomer.

Intramolecular sila-Matteson rearrangement: a general access to silylated heterocycles.

A series of new silylated heterocycles has been efficiently prepared using an intramolecular silicon version of the Matteson rearrangement, providing two isomers of binuclear heterocycles. This method applies to a large variety of substrates, a direct relationship between the Hammett constants of the aromatic substituents and the isomer ratio being observed. Complementary experiments suggest that a common pentaorganosilicate species is involved.

Development of an in vitro reproductive screening assay for novel pharmaceutical compounds.

An in vitro reproductive cell-based toxicity assay was developed using MLTC-1 (murine Leydig tumour cell line) in order to examine the reproductive toxicity of two novel nanopharmaceutical compounds, namely ethylene glycol mono allyl ether and poly(ethylene glycol) octa-functionalized polyhedral oligomeric silsesquioxane. Three commonly used cytotoxicity assays, namely the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide], MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] and Crystal Violet assays, were compared, and the MTT assay proved to be the most accurate and reproducible for the MLTC-1 cell line. The doubling rate of the MLTC-1 cells was 30+/-3.5 h and the optimal seeding density for the MTT assay was 20000 cells per well, and the optimized MTT assay utilized a 4 h cell adherence followed by incubation with 0.5 mg/ml MTT for 1 h. The intra- and inter-assay CV (coefficient of variation) values were 12.3 and 11% respectively. MLTC-1 cells only produce the reproductive hormone progesterone in response to hCG (human chorionic gonadotropin), which stimulated progesterone production dose-dependently from 0 to 100 m.i.u. (milliinternational units)/ml (2706+/-1118 ng/ml). H(2)O(2) as a negative control killed 100% of cells at 1000 microg/ml. The two nanopharmaceutical compounds were cytotoxic at concentrations > or =0.1 microg/ml, but hCG decreased cytotoxicity to > or =1000 microg/ml (P<0.001). hCG-stimulated progesterone synthesis afforded some protection against the cytotoxic effects of the two novel nanotechnology compounds; therefore doses < or =100 microg/ml and an exposure period of 1 h would be recommended for testing in in vivo animal reproductive assays.

Novel silicon-containing polyurethanes from vegetable oils as renewable resources. Synthesis and properties.

Hydrosilylation of methyl 10-undecenoate (UDM) with phenyl tris(dimethylsiloxy)silane (PTDS) followed by a reduction of carboxylate groups was used to obtain a silicon-containing polyol with terminal primary hydroxyl groups (PSi194). Biobased silicon-containing polyurethanes, with a silicon content between 1.7% and 9.0%, were prepared from epoxidized methyl oleate-based polyether polyol (P184), PSi194, and 4,4'-methylenebis(phenyl isocyanate) (MDI). The thermal, mechanical, and flame-retardant properties of these materials were examined. The most notable change resulting from the incorporation of PSi194 is the appearance of melting endotherms of variable enthalpy and position and a downward shift in the T(g). The incorporation of silicon does not change the thermal stability but enhances the stability of the char under air atmosphere. Polyurethanes with higher silicon content no longer burn in ambient air without complementary oxygen, which suggests that these biobased materials are very interesting for applications that require fire resistance.

Coordination-driven self-assembly of supramolecular cages: heteroatom-containing and complementary trigonal prisms.

The self-assembly of three nanoscopic prisms of approximate size 1 x 4 nm is reported. Tetrahedral carbon, silicon, and phosphorus were used as structure-defining elements in these coordination-based cages. A carbon-based assembly completes a pair of nanoscopic complementary 3-D structures. The formation of the structures is supported by multinuclear NMR, ESI FT-ICR mass spectrometry, and elemental analysis data.