Modeling receptor flexibility in the structure-based design of KRASG12C inhibitors

Journal of Computer-Aided Molecular Design - KRAS has long been referred to as an ‘undruggable’ target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of...     

A solid-supported,enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of (-)-saframycin A

A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.     

Mapping of protein:protein contact surfaces by hydrogen/deuterium exchange,followed by on-line high-performance liquid chromatography-electrospray ionization Fourier-transform ion-cyclotron-resonance mass analysis

Furfural contents in adapted and follow-up infant formulas were measured by RP-HPLC. The evolution of furfural compound contents during storage (a year at 20 and 37 degrees C) was studied. 2-Furylmethylketone and 5-methyl-2-furaldehyde were not detectable in analysed samples. The differences in the furfural compounds at point zero between both infant formulas has to be ascribed to the differences in protein and iron contents. An increase in free 5-hydroxymethyl-2-furfuraldehyde (HMF), 2-furaldehyde (F) and HMF+F contents was observed in all samples, although the differences were not statistically significant. The storage temperature affected the total HMF content and the storage time affected the total HMF and F contents.     

Synthesis of C-protected alpha-amino aldehydes of high enantiomeric excess from highly epimerizable N-protected alpha-amino aldehydes

A new procedure for the preparation of C-protected alpha-amino aldehydes of high enantiomeric excess is illustrated using five differently substituted alpha-(N-Fmoc)amino aldehydes as starting materials. Highly epimerization-prone substrates were converted to the corresponding morpholino nitrile-protected alpha-amino aldehydes with minimal racemization (products >/= 89% ee). Morpholino nitrile derivatives of phenylglycinal were crystallized and subjected to X-ray structural analysis, allowing for definitive determination of the stereochemistry of amino nitrile formation. A rationale for the stereoselectivity of amino nitrile formation is presented.     

On the structure of palau'amine: evidence for the revised relative configuration from chemical synthesis

Hexacyclic congeners 3 and 4 of palau'amine, which incorporate both guanidine functional groups and have the cis configuration of the azabicyclo[3.3.0]octane core, are prepared in 14 steps from cycloadduct 6. Synthetic access to these analogues allows the first direct comparison of NMR data for hexacyclic diguanidine structures having the originally proposed cis-azabicyclo[3.3.0]octane fragment with data for natural alkaloids of the palau'amine family. This comparison provides convincing evidence in favor of the recently proposed structural revision of these marine alkaloids, fully supporting the trans configuration of the central azabicyclo[3.3.0]octane ring system of palau'amine and congeners.     

Efficient, stereoselective synthesis of trans-2,5-disubstituted morpholines

[reaction: see text] Enantio- and diastereoselective syntheses of trans-2,5-disubstituted morpholine derivatives are described. The routes are initiated by the reaction of enantiopure epoxides (2) with amino alcohols (3) and address the problem of regioselective hydroxyl activation-ring closure of the resulting amino diol adducts for (amino alcohol-derived) alkyl substituents of different steric demands.     

Synthesis of biotin‐tagged chemical cross‐linkers and their applications for mass spectrometry

Chemical cross‐linking combined with mass spectrometry (MS) has been used to elucidate protein structures and protein‐protein interactions. However, heterogeneity of the samples and the relatively low abundance of cross‐linked peptides make this approach challenging. As an effort to overcome this hurdle, we have synthesized lysine‐reactive homobifunctional cross‐linkers with the biotin in the middle of the linker and used them to enrich cross‐linked peptides. The reaction of biotin‐tagged cross‐linkers with purified HIV‐1 CA resulted in the formation of hanging and intramolecular cross‐links. The peptides modified with biotinylated cross‐linkers were effectively enriched and recovered using a streptavidin‐coated plate and MS‐friendly buffers. The enrichment of modified peptides and removal of the dominantly unmodified peptides simplify mass spectra and their analyses. The combination of the high mass accuracy of Fourier transform ion cyclotron resonance (FT‐ICR) MS and the tandem mass spectrometric (MS/MS) capability of the linear ion trap allows us to unambiguously identify the cross‐linking sites and additional modification, such as oxidation. Copyright © 2009 John Wiley & Sons, Ltd.