Discovery of N-aryl-N'-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors.

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.

Synthesis and biological evaluation of 3-substituted-indolin-2-one derivatives containing chloropyrrole moieties.

Eighteen novel 3-substituted-indolin-2-ones containing chloropyrroles were synthesized and their biological activities were evaluated. The presence of a chlorine atom on the pyrrole ring was crucial to reduce cardiotoxicity. The presence of a 2-(ethyl-amino)ethylcarbamoyl group as a substituent at the C-4' position of the pyrrole enhanced the antitumor activities notably. IC50 values as low as 0.32, 0.67, 1.19 and 1.22 µM were achieved against non-small cell lung cancer (A549), oral epithelial (KB), melanoma (K111) and large cell lung cancer cell lines (NCI-H460), respectively.

5-p-Tolyl-1,2,3,3a-tetra-hydro-benzo[e]pyrrolo-[2,1-b][1,3]oxazepin-10(5H)-one.

The structure of the title compound, C(19)H(19)NO(2), contains a seven-membered ring, which is fused to one five- and one six-membered ring, and carries a tolyl substituent. The two benzene rings are oriented relative to each other at a dihedral angle of 86.90 (7)°. In the crystal, mol-ecules are linked by weak inter-molecular C-H⋯O hydrogen bonds.

(3aR*,5R*)-5-(4-Chloro-phen-yl)-1,2,3,3a-tetra-hydro-benzo[e]pyrrolo-[2,1-b][1,3]ox-azepin-10(5H)-one.

The title compound, C(18)H(16)ClNO(2), is the main product of a photoreaction. The two benzene rings make a dihedral angle of 86.40 (2)° with each other. The 1,3-oxazepine C atom to which the 4-chloro-phenyl group is attached and the C atom of the 4-chloro-phenyl group attached to the 1,3-oxazepine ring are chiral C atoms, but the crystal is a racemate in which the enanti-omers are linked by a pair of weak inter-molecular C-H⋯O hydrogen bond, forming an inversion dimer.

5-Methyl-1,2,3,3a-tetra-hydro-benzo[e]pyrrolo-[2,1-b][1,3]oxazepin-10(5H)-one.

The asymmetric unit of the title compound, C(13)H(15)NO(2), the main product of a photoreaction, contains two crystallographically independent mol-ecules. In both mol-ecules, the conformation of the seven-membered ring is twist sofa and that of the five-membered rings is envelope. In the crystal, mol-ecules are linked by weak inter-molecular C-H⋯O hydrogen bonds.

Comparison of conventional and primary sutureless surgery for repairing supracardiac total anomalous pulmonary venous drainage.

OBJECTIVE: The efficacy of using a sutureless approach in order to surgically manage postoperative pulmonary vein stenosis following total anomalous pulmonary venous drainage (TAPVD) has been reported, though outcomes of primary treatment of supracardiac TAPVD remain unclear. We retrospectively reviewed our cardiac center experience, and compared the differences in mid-term outcomes for those patients that received conventional surgery and those that underwent sutureless technique for the primary repair of supracardiac TAPVD. METHODS: A total of 43 patients (median age, 199 days; range, 35 days to 1572 days) with supracardiac TAPVD underwent surgical treatment at our cardiac center from 2014 to 2018 were studied retrospectively. Primary sutureless repair was conducted in 20 cases (46.5%). The pulmonary vein scores, left ventricular ejection fraction (LVEF), baseline of the included patients, postoperative, and outcomes data were analyzed between the two groups. RESULTS: The pulmonary vein scores, indicating the stenosis degree, of two groups were 0.1 ± 0.3 and 0.1 ± 0.3, left ventricular ejection fraction (LVEF) (%) were separately 66.2 ± 12.1 and 67.1 ± 13.6. The average cardiopulmonary bypass time of sutureless techniques group was much longer than conventional group (96.2 ± 32.6 min vs 75.6 ± 28.2 min, P < 0.05), but there was no difference in aortic cross-clamp time between the two groups. Followed up from 0.1 to 4 years, 3 cases died overall, with 1 (5.0%) individual dying from postoperative pulmonary venous obstruction (PVO) in sutureless group, and 2 (8.6%) dying in the conventional group respectively for postoperative infection and post-PVO. There were no differences in the length of stay in the ICU, grades of PVS after surgery, LVEF and reoperation rate between the two groups. CONCLUSIONS: The mortality, post-PVO, follow up results of supracadiac TAPVD showed no differences between sutureless and conventional techniques. Post-PVO supposed to be the main reason for postoperative mortality.