Biomedical subjects
Publications and source records attributed to Mark Seierstad.
A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
Over the past decade, the pharmaceutical industry has begun to address an addition to ADME/Tox profiling--the ability of a compound to bind to and inhibit the human ether-a-go-go-related gene (hERG)-encoded cardiac potassium channel. With the compilation of a large and diverse set of compounds measured in a single, consistent hERG channel inhibition assay, we recognized a unique opportunity to attempt to construct predictive QSAR models. Early efforts with classification models built from this training set were very encouraging. Here, we report a systematic evaluation of regression models based on neural network ensembles in conjunction with a variety of structure representations and feature selection algorithms. The combination of these modeling techniques (neural networks to capture non-linear relationships in the data, feature selection to prevent over-fitting, and aggregation to minimize model instability) was found to produce models with very good internal cross-validation statistics and good predictivity on external data.
A negatively charged analogue of meta-benzyne, 3,5-didehydrobenzoate, was synthesized in a Fourier transform ion cyclotron resonance mass spectrometer, and its reactivity was compared to that of the same ion generated previously in a flowing afterglow apparatus and to its positively charged cousin, N-(3,5-didehydrophenyl)-3-fluoropyridinium. 3,5-Didehydrobenzoate was found to react as a nucleophile with electrophilic reagents. In contrast, N-(3,5-didehydrophenyl)-3-fluoropyridinium does not react with the same electrophilic reagents but reacts instead with nucleophilic reagents. Neither ion is able to abstract hydrogen atoms from typical hydrogen atom donors. The absence of any radical reactivity for these meta-benzynes is consistent with predictions that radical reactions of singlet biradicals should be hindered as compared to their monoradical counterparts. High-level calculations predict that the carboxylate moiety does not significantly perturb the singlet-triplet splitting of 3,5-didehydrobenzoate relative to the parent meta-benzyne.
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The influence of several Lewis acids on the stereochemical course of the [4 + 2] cycloaddition of nitroalkene 1 and chiral, nonracemic propenyl ether 8 has been examined. All of the Lewis acids examined favored ul relative diastereoselection ("exo" approach); TiCl(4), TiBr(3)(Oi-Pr), SnCl(4), and ATPh were the most selective. Within the titanium-based Lewis acids, it was found that increasing the halide-to-alkoxide ratio increased the degree of ul (relative) selectivity, as did switching from chloride to bromide. The internal diastereoselectivity was also dependent on the Lewis acid; most titanium isopropoxide-halides (bromide and chloride) and SnCl(4) were highly selective for (1,3-lk) approach, with the selectivity increasing with increasing halide content. Two aluminum-based Lewis acids (MAPh and ATPh) were selective for the opposite sense of internal diastereoselection. The high lk (relative) diastereoselectivity observed only with TiCl(2)(Oi-Pr)(2) is proposed to arise either from Coulombic stabilization of an endo approach or precomplexation of the vinyl ether to the Lewis acid. The switch in internal diastereoselectivity seen in the exo manifold is thought to arise from subtle changes in the steric nature of the Lewis acid-nitroalkene complex.
Intermolecular [3 + 2] cycloadditions between two cyclic nitronates and a series of dipolarophiles are examined. High facial selectivity is observed in all cases and is analyzed with the aid of ab initio transition structure calculations. Monosubstituted dipolarophiles reacted with exclusive regiocontrol. Disubstituted dipolarophiles reacted with varying degrees of regiocontrol, which was dependent on the substituent. A theoretical approach for predicting regioselectivity is discussed. Exo selectivity was generally favored due to steric effects, and was especially high with cis-disubstituted dipolarophiles.