b) TURBOMOLE: R. Ahlrichs. M. Blr. M. Haser. H. Horn. C. Kolmel. Chem. P/7? 5 . Lcjtt. 1989. 162. 165-169. The ring foldingangle at the B--B diagoiial is 32.3'in 2u, and 31.3-in 2u,; the barriers LO ring inversion of the folded four-membered ring are calculated as 4.5 kcalinol-' for 2u, and 5.5 kcalmol-I for 2u, and thus are significantly smaller than for a homodiboriranide without strong C-B hyperconjugation (7.9 kc;ilinol-' [4]).
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative ICs correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma..
Abstract:The conformational preferences of chiral vinylogous aminosulfonic acids (vs-amino acids) and of the corresponding oligomers (vs-peptides) were investigated by a combination of X-ray crystallography, variable-temperature (VT) 'H NMR spectroscopy, FT-IR spectroscopy, and NOE experiments. The major source of conformational freedom in the monomers is the rotation around the C-C bond connecting the double bond with the allylic stereocenter (N-C*-C=C). The allylic conformational preferences can be altered in the oligomers by the formation of secondary structures enforced by hydrogen bonding. Twelve-membered-ring hydrogen bonding is detected in the crystal structure of vs-dipeptide 9, while fourteen-membered-ring hydrogen bonding is the most common folding pattern for the peptides oligomers in chloroform solution. The experimental results are complemented by computer modeling: suitable force-field (FF) parameters for the unsaturated sulfonamide group were developed from ab initio calculations. A Goodman-Still systematic pseudo-Monte-Carlo search was used for the conformational search. The conformers were minimized in chloroform with the GBjSA model. The calculations correctly predicted both the size of the hydrogen-bonded ring and its relative importance, in agreement with the experimental data in solution.
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