Investigation of dissociation constants for individual and total naphthenic acids species using ultra performance liquid chromatography ion mobility time-of-flight mass spectrometry analysis.

Ultra-performance liquid chromatography ion mobility time-of-flight mass spectrometry (UPLC-IM-TOFMS) was utilized for the analysis of naphthenic acids (NAs) in fractions of pH-dependent sequential liquid-liquid extractions from oil sands process-affected water. Ion-mobility separation technique allowed the differentiation of OyS-NAs (2 ≤ y ≤ 4) from Ox-NAs (2 ≤ x ≤ 5) via drift time versus retention time separations. The results indicated that the addition of S atom to the O2-NA molecule led to a lower increase in the dissociation constant (pKa) compared to that caused by the addition of O atom. Because additional O is present as OH while the S atom is present as the CSC structure, the latter does not involve into the deprotonation process directly. The pKa value decreased along with increasing carbon number and |Z| number for O2-, O3-, O4-, and O2S-NA species, except for O5-, O3S-, and O4S-NA species, each of which are comprised of chemical structures with distinct functional groups. A calculation model was developed to estimate pKa values for individual and total NA species via nonlinear regression curve fitting, utilizing the relative abundances of detected NA species. pKa values were calculated as 3.9 for total NAs, 3.3 for O2-NAs, 4.4 for O3-NAs, 7.3 for O4-NAs, and 4.1 for O2S-NAs. Knowledge of NAs pKa is crucially important for the comprehensive understanding of their potential transformation route and toxicity as well as for the development of water remediation applications. Both the ion-mobility separation technique and the new calculation model could be widely applied for the investigation of other complicated pollutants present in water and wastewater.

Fractionation of oil sands-process affected water using pH-dependent extractions: a study of dissociation constants for naphthenic acids species.

The fractionation of oil sands process-affected water (OSPW) via pH-dependent extractions was performed to quantitatively investigate naphthenic acids (NAs, CnH2n+ZO2) and oxidized NAs (Ox-NAs) species (CnH2n+ZO3 and CnH2n+ZO4) using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOFMS). A mathematical model was also developed to estimate the dissociation constant pKa for NAs species, considering the liquid-liquid extraction process and the aqueous layer acid-base equilibrium. This model provides estimated dissociation constants for compounds in water samples based on fractionation extraction and relative quantification. Overall, the sum of O2-, O3-, and O4-NAs species accounted for 33.6% of total extracted organic matter. Accumulative extracted masses at different pHs revealed that every oxygen atom added to NAs increases the pKa (i.e., O2-NAs

Structure driven design of novel human ether-a-go-go-related-gene channel (hERG1) activators.

One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4-S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs.