Machine Learning Informs RNA-Binding Chemical Space**

Small molecule targeting of RNA has emerged as a new frontier in medicinal chemistry, but compared to the protein targeting literature our understanding of chemical matter that binds to RNA is limited. In this study, we reported R epository O f BI nders to N ucleic acids (ROBIN), a new library of nucleic acid binders identified by small molecule microarray (SMM) screening. The complete results of 36 individual nucleic acid SMM screens against a library of 24 572 small molecules were reported (including a total of 1 627 072 interactions assayed). A set of 2 003 RNA-binding small molecules was identified, representing the largest fully public, experimentally derived library of its kind to date. Machine learning was used to develop highly predictive and interpretable models to characterize RNA-binding molecules. This work demonstrates that machine learning algorithms applied to experimentally derived sets of RNA binders are a powerful method to inform RNA-targeted chemical space.     

Mass spectrometric analysis of the marine lipophilic biotoxins pectenotoxin-2 and okadaic acid by four different types of mass spectrometers

The performances of four different mass spectrometers [triple-quadrupole (TQ), time-of-flight (ToF), quadrupole ToF (Q-ToF) and ion trap (IT)] for the detection of the marine lipophilic toxins pectenotoxin-2 (PTX2) and okadaic acid (OA) were investigated. The spectral data obtained with the different mass spectrometric analyzers were used to propose fragmentation schemes for PTX2 in the positive electrospray mode and for OA in the negative electrospray mode. TQ data were used to obtain product ions, while ToF and Q-ToF-MS produced accurate mass data of the precursor ion and product ions, respectively. IT data provided a better understanding of the fragmentation pathways using MS(n) experiments. With respect to analytical performance, all four mass analyzers showed a good linearity (R(2) > 0.97) and repeatability (CV < 20%). Detection limits (LoDs) (S/N = 3) were the lowest on triple-quad MS: 12.2 and 2.9 pg on-column for PTX2 and OA, respectively.     

Development and validation of automated SPE-HPLC-MS/MS methods for the quantification of asenapine, a new antipsychotic agent, and its two major metabolites in human urine

To support the evaluation of the pharmacokinetic parameters of asenapine (ASE) in urine, we developed and validated online solid‐phase extraction high‐performance liquid chromatography methods with tandem mass spectrometry detection (SPE‐LC‐MS/MS) for the quantification of ASE and two of its major metabolites, N‐desmethylasenapine (DMA) and asenapine‐N⁺‐glucuronide (ASG). The linearity in human urine was found acceptable for quantification in a concentration range of 0.500–100 ng/mL for ASE and DMA and 10.0–3000 ng/mL for ASG, respectively. Copyright © 2012 John Wiley & Sons, Ltd.     

Are Monophospha(III)amidines and -guanidines with Ionizable Hydrogens Tautomeric? Towards a Deeper Understanding of Two Related Hetero-element Functional Groups

This paper presents definitive structural evidence for N,P(III)-monophosphaamidines in P=C and N=C isomeric forms from a combination of new syntheses, single-crystal X-ray diffraction (SC-XRD), solid-state NMR and FTIR. Evidence is also provided for C-amino-(σ²,λ³)-phosphaalkene and C-(σ³,λ³)-phosphinoimine tautomerism in solution using multi-nuclear NMR methods. Synthesis and SC-XRD structure determination of a trisubstituted N,N’,P(III)-monophosphaguanidine is presented, the first structure of a phospha(III)guanidine with two ionizable H atoms. The structural evidence is convincing for an N=C geometry, resulting in both N−H and P−H in the molecule. A detailed computational investigation using DFT methods is presented, with the goal of understanding the tautomeric structure preferences both at the fundamental level (parent molecules with all substituents on the heteroatoms being hydrogen) and using the full structures containing the very bulky 2,6-diisopropylphenyl (Dipp) substituents employed in this study. Arguments are espoused for treating phospha(III)amidines and -guanidines as new types of functional groups, similar to but distinct from the familiar organic analogues. Limited reactivity studies and a voltammetry study of one phospha(III)amidine are included with the supporting information.