Phosphoinositide-3-kinases (PI3Ks): combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110alpha

The p110alpha isoform of the class IA PI3Ks was recently genetically validated as a promising target for anticancer therapy. However, up to now, only one compound (PIK75 = 1) has been reported as a very potent and selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hindered the discovery of new p110alpha selective compounds. In view of this, we combined target-based (homology modeling) and ligand-based (3D-QSAR) approaches in an attempt to define an integrated interaction model for p110alpha inhibition. Twenty-five analogues of 1 were docked within the putative p110alpha binding site, and the molecular alignment generated was subsequently used to derive QSAR models based on scoring function, free energy of binding, CoMFA. and CoMSIA. The predictive power of these models was then analyzed using a challenging test set of 5 compounds. CoMSIA, and particularly CoMFA, models were found to outperform the other methods, predicting accurately the potency of 100% of the compounds in the test set, thereby validating our p110alpha homology model for use in further drug development.     

Effects of masking noise on vowel and sibilant contrasts in normal-hearing speakers and postlingually deafened cochlear implant users

The role of auditory feedback in speech production was investigated by examining speakers' phonemic contrasts produced under increases in the noise to signal ratio (N/S). Seven cochlear implant users and seven normal-hearing controls pronounced utterances containing the vowels /i/, /u/, /e/ and /ae/ and the sibilants /s/ and /I/ while hearing their speech mixed with noise at seven equally spaced levels between their thresholds of detection and discomfort. Speakers' average vowel duration and SPL generally rose with increasing N/S. Average vowel contrast was initially flat or rising; at higher N/S levels, it fell. A contrast increase is interpreted as reflecting speakers' attempts to maintain clarity under degraded acoustic transmission conditions. As N/S increased, speakers could detect the extent of their phonemic contrasts less effectively, and the competing influence of economy of effort led to contrast decrements. The sibilant contrast was more vulnerable to noise; it decreased over the entire range of increasing N/S for controls and was variable for implant users. The results are interpreted as reflecting the combined influences of a clarity constraint, economy of effort and the effect of masking on achieving auditory phonemic goals-with implant users less able to increase contrasts in noise than controls.     

In-Vitro Screenings for Biological and Antioxidant Activities of Water Extract from Theobroma cacao L. Pod Husk: Potential Utilization in Foods

Increasing production of cocoa (Theobroma cacao L.) leads to a higher environmental burden due to its solid waste generation. Cocoa pod husk, one of the major solid wastes of cocoa production, contains rich bioactive compounds unveiling its valorization potential. With that in mind, our research aimed to explore the biological and antioxidant activities of aqueous extracts from cocoa pod husks. In this present work, cocoa pod husk was extracted using water and subsequentially partitioned using n-hexane, ethyl acetate, and methanol. The antimicrobial investigation revealed that the ethyl acetate solubles were active against the Staphylococcus aureus, Escherichia coli, and Candida albicans, where at a 20% w/v concentration, the inhibition diameters were 6.62 ± 0.10, 6.52 ± 0.02, and 11.72 ± 0.36 mm, respectively. The extracts were found non-toxic proven by brine shrimp lethality tests against Artemia salina with LC₅₀ scores ranging from 74.1 to 19,054.6 μg/mL. The total phenolic content and total flavonoid content were obtained in the range of 47.44 to 570.44 mg/g GAE and 1.96 to 4.34 mg/g QE, respectively. Antioxidant activities of the obtained extracts were revealed by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay with EC₅₀ reached as low as 9.61 μg/mL by the ethyl acetate soluble. Phytochemical screening based on gas chromatography—mass spectroscopy analysis on the sample with the highest antioxidant activities revealed the dominant presence of three phytosterols, namely gamma-sitosterol, stigmasterol, and campesterol.     

Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐catalysed coupling of 2‐(difluoromethyl)imidazo[1,2‐a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5‐triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.     

Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides: the role of redox equilibria

Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide), the lead bioreductive drug with selective toxicity for hypoxic cells in tumors, is thought to act by forming an active oxidizing radical of high one-electron reduction potential, E(1), when reduced by reductases. It has a dual mechanism of action, both generating DNA radicals, following its one-electron reduction and subsequently oxidizing these DNA radicals to form labile cations or hydrolyzable lactones through transferring an O atom, resulting in DNA strand breaks. These parallel secondary reactions have been proposed to be also initiated by its two-electron reduced metabolite, the 1-oxide. We have used pulse radiolysis to show that the benzotriazinyl radical of a highly soluble analogue of tirapazamine, the 3-(N,N-dimethyl-1,2-ethanediamine) analogue, is able to oxidize tirapazamine itself. We have found that both tirapazamine and the 1-oxides are in equilibrium with their respective benzotriazinyl radicals, with high concentrations of the more soluble 1-oxide maintaining a high concentration of the more reactive oxidizing radical of tirapazamine. The one-electron reduction potentials, E(1), of the 1-oxides and related compounds have been measured and, together with the E(1) values of tirapazamine and the 2-nitroimidazole radiosensitizer, misonidazole, are shown to predict the published percentages of electron transfer. This radical chemistry study gives an insight into the mechanisms of the potentiation of radical damage, reported for DNA, that underlies the hypoxic cytotoxicity of electron affinic compounds. The E(1) values of the benzotriazinyl radicals of the benzotriazine compounds govern the position of the redox equilibria, which determine the amount of initial radical damage. The E(1) values of the 1,4-dioxides and 1-oxide compounds govern the degree of potentiation of the initial radical damage once formed.     

Quantum filtering for multiple input multiple output systems driven by arbitrary zero-mean jointly Gaussian input fields

In this paper, we treat the quantum filtering problem for multiple input multiple output (MIMO) Markovian open quantum systems coupled to multiple boson fields in an arbitrary zero-mean jointly Gaussian state, using the reference probability approach formulated by Bouten and van Handel as a quantum version of a well-known method of the same name from classical nonlinear filtering theory, and exploiting the generalized Araki-Woods representation of Gough. This includes Gaussian field states such as vacuum, squeezed vacuum, thermal, and squeezed thermal states as special cases. The contribution is a derivation of the general quantum filtering equation (or stochastic master equation as they are known in the quantum optics community) in the full MIMO setup for any zero-mean jointly Gaussian input field states, up to some mild rank assumptions on certain matrices relating to the measurement vector.     

An Asymptotic Property of Schachermayer's Space under Renorming

Let X be a Banach space with closed unit ball B. Given k , X is said to be k-β, respectively, (k + 1)-nearly uniformly convex ((k + 1)-NUC), if for every ε > 0 there exists δ, 0 < δ < 1, so that for every x B and every ε-separated sequence (x_n) B there are indices (n_i)^k_{i = 1}, respectively, (n_i)^{k + 1}_{i = 1}, such that (1/(k + 1))||x + ∑^k_{i = 1} x_ni|| ≤ 1 − δ, respectively, (1/(k + 1))||∑^{k + 1}_{i = 1} x_ni|| ≤ 1 − δ. It is shown that a Banach space constructed by Schachermayer is 2-β, but is not isomorphic to any 2-NUC Banach space. Modifying this example, we also show that there is a 2-NUC Banach space which cannot be equivalently renormed to be 1-β.     

ISOMERS OF 3,7,11-TRIMETHYLDODECA-2,4,6,8,10- PENTAENAL (A LINEAR ANALOGUE OF RETINAL) and LOWER HOMOLOGUES IN THEIR INTERACTION WITH BOVINE OPSIN and BACTERIOOPSIN

Abstract— The all-trans and 3 mono-cir isomers of the title linear pentaenal have been prepared. Results of their interaction with bovine opsin and bacterioopsin are presented. Likewise, the negative results on two lower member homologs are described. Implications on the specificity of the binding sites are discussed.     

Development of QSAR models for microsomal stability: identification of good and bad structural features for rat,human and mouse microsomal stability

High throughput microsomal stability assays have been widely implemented in drug discovery and many companies have accumulated experimental measurements for thousands of compounds. Such datasets have been used to develop in silico models to predict metabolic stability and guide the selection of promising candidates for synthesis. This approach has proven most effective when selecting compounds from proposed virtual libraries prior to synthesis. However, these models are not easily interpretable at the structural level, and thus provide little insight to guide traditional synthetic efforts. We have developed global classification models of rat, mouse and human liver microsomal stability using in-house data. These models were built with FCFP_6 fingerprints using a Naïve Bayesian classifier within Pipeline Pilot. The test sets were correctly classified as stable or unstable with satisfying accuracies of 78, 77 and 75% for rat, human and mouse models, respectively. The prediction confidence was assigned using the Bayesian score to assess the applicability of the models. Using the resulting models, we developed a novel data mining strategy to identify structural features associated with good and bad microsomal stability. We also used this approach to identify structural features which are good for one species but bad for another. With these findings, the structure-metabolism relationships are likely to be understood faster and earlier in drug discovery.