Fragmentation of conjugate bases of esters derived from multifunctional alcohols including triacylglycerols

Enolate anions of esters from 1,2 and 1,3 diols undergo an internal nucleophilic substitution reaction that produces a β-ketoester and an alkoxide ion within the molecular species. These intermediate ions undergo two competitive fragmentation pathways. The first pathway corresponds to a second nucleophilic substitution of the ketoester by the alkoxide that yields a neutral cyclic ether and the β-ketoacid carboxylate. The latter then loses carbon dioxide and produces the enolate anion of the corresponding ketone. The second proposed pathway is stepwise: it starts with a proton transfer from the methylene group between the two carbonyls to the alkoxide anion that produces an alcohol and the enolate ion of the β-ketoester inside the molecular species. The latter undergoes cleavage of the ester bond induced by the negative charge to yield an ion-dipole complex composed of a neutral acylketene and an alkoxide ion. The direct dissociation of this ion-dipole complex competes with an internal proton exchange to yield a new complex that consists of an alcohol molecule and the anion of the acylketene, which can also dissociate. The fragmentation pathway that leads to the ketone enolate is sensitive to the relative positions (1,2 or 1,3) of the esters on the molecular backbone. This position-sensitive reaction is useful for the assignment of the primary and secondary positions in triacylglycerols, even in mixtures, as shown by some examples.     

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460–1047 nm) and entrapment efficiency ranging from 36.4–44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan^®). Observed bacterial suppression was detected in rabbit’s eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.     

LW-compact operators and domination problem

Positivity - This paper introduces a ‘new’ class of operators. An operator T from a Banach lattice E into a Banach space Y will be called an LW-compact if T carries L-weakly compact...     

Conformation study of poly(p‐dioxanone) fibers by polarized Raman spectroscopy,X‐ray diffraction,and conformation analysis

The molecular orientation distribution of poly(p‐dioxanone) (PPDX) uniaxially oriented commercial fibers was determined by polarized Raman spectroscopy and X‐ray diffraction. The order parameters 〈P₂₀₀〉 and 〈P₄₀₀〉 of the orientation distribution function were determined by polarized Raman spectroscopy. For the C?O stretching band, the values of 〈P₂₀₀〉 and 〈P₄₀₀〉 obtained are equal to ?0.40 ± 0.04 and 0.28 ± 0.04, respectively. These results clearly indicate that the carbonyl groups are highly oriented perpendicular to the fiber axis. X‐ray diffraction led to a fiber repeat value of 0.628 nm for these samples, and to 〈P₂₀₀〉 and 〈P₄₀₀〉 values of 0.93 and 0.82, respectively, for the c‐axis orientation, indicating a high orientation in the draw direction of the fibers. A Monte‐Carlo conformational search led to 20 low‐energy conformations, but only one of these was found compatible with both the fiber repeat and the angle between the C?O bond and the fiber axis. This conformation, a 2₁ helix with a tg^?ttg^? succession of torsion angles, is proposed as the existing conformation in the crystalline state. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 406–417, 2008     

Synthesis of Branched‐Chain Sugars with a DHAP‐Dependent Aldolase: Ketones are Electrophile Substrates of Rhamnulose‐1‐phosphate Aldolases

Dihydroxyacetone phosphate (DHAP)‐dependent rhamnulose aldolases display an unprecedented versatility for ketones as electrophile substrates. We selected and characterized a rhamnulose aldolase from Bacteroides thetaiotaomicron (RhuABthet) to provide a proof of concept. DHAP was added as a nucleophile to several α‐hydroxylated ketones used as electrophiles. This aldol addition was stereoselective and produced branched‐chain monosaccharide adducts with a tertiary alcohol moiety. Several aldols were readily obtained in good to excellent yields (from 76 to 95 %). These results contradict the general view that aldehydes are the only electrophile substrates for DHAP‐dependent aldolases and provide a new C?C bond‐forming enzyme for stereoselective synthesis of tertiary alcohols.     

Investigation of indirubin derivatives: a combination of 3D-QSAR,molecular docking,and ADMET towards the design of new DRAK2 inhibitors

Kinase-related apoptosis-inducing kinase 2 (DRAK2) is a serine/threonine kinase and belongs to the death-associated protein kinase DPAK family, which is responsible for induction of apoptosis in many cell types. Thus, DRAK2 is regarded as a promising target for treatment of autoimmune diseases. To investigate the binding between DRAK2 and indirubin inhibitors and design potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking were performed. Comparative Molecular Similarity Indices Analysis (CoMSIA) was developed using 33 molecules having pIC₅₀ ranging from 8.523 to 5.000 (IC₅₀ in nM). The best CoMSIA model gave a significant coefficient of determination (R²?=?0.93), as well as a (leave-one-out cross-validation coefficient Q² of 0.81. The predictive ability of this model was evaluated by external validation using a test set of eight compounds and yielded a predicted coefficient of determination R²_test of 0.94. The contour maps could provide structural features to improve inhibitory activity. Good consistency between contour maps and molecular docking strongly suggests that the molecular modeling is reliable. Based on these satisfactory results, we designed several new DRAK2 inhibitors and their inhibitory activities were predicted using different models, which are developed on different training and test sets. Additionally, these newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations compared to the best inhibitor from the studied dataset. This study could be useful in lead identification and optimization for early drug discovery of DRAK2 inhibitors.     

Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR,molecular docking,and in silico ADMET

Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays a vital role in the replication initiation of DNA synthesis. Overexpression of the CDC7 in various tumor growths and in cell proliferation makes it a promising target for treatment of cancers. To investigate the binding between the CDC7 and furanone inhibitors, and in order to design highly potent inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) with molecular docking was performed. The optimum CoMSIA model showed significant statistical quality on all validation methods with a determination coefficient (R²?=?0.945), bootstrapping R² mean (BS-R²?=?0.960), and leave-one-out cross-validation (Q²) coefficient of 0.545. The predictability of this model was evaluated by external validation using a test set of nine compounds with a predicted determination coefficient R²_test of 0.96, besides the mean absolute error (MAE) of the test set was 0.258 log units. The extracted contour maps were used to identify the important regions, where the modification was necessary to design a new molecule with improved activity. Furthermore, a good consistency between the molecular docking and contour maps strongly demonstrates that the molecular modeling is reliable. Based on those obtained results, we designed several new potent CDC7 inhibitors, and their inhibitory activities were validated by the molecular models. Additionally, those newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations.     

Pseudo-almost Periodic and Pseudo-almost Automorphic Solutions to Evolution Equations in Hilbert Spaces

In this work we prove some existence and uniqueness results for pseudo-almost periodic and pseudo-almost automorphic solutions to a class of semi-linear differential equations in Hilbert spaces using theoretical measure theory. The main technique is based upon some appropriate composition theorems combined with the Banach contraction mapping principle and the method of the invariant subspaces for unbounded linear operators. A few illustrative examples will be discussed at the end of the paper.