Preparation and screening of twenty new ligands, all analogs of a, a, a :oc '-tetraaryl-1,3-dioxolane-4,5dimethanol (TADDOL), for the Ti-catalyzed asymmetric addition of methyltri(isopropoxy)titanium and diethylzinc to benzaldehyde are described. These ligands have the dioxolane ring of the TADDOL's replaced by cyclobutane, cyclopentane, cyclohexene, cyclohexane, bicyclo[2.2. llheptene and -heptane and hicyclo[2.2.2]octene and -octane moieties; several have H-atoms or alkyl groups in place of the aryl groups, and nine of them have C2 symmetry. X-Ray crystallography and molecular mechanics are used to analyze the structure of the ligands, and two structural features appear to correlate with selectivity: i) the torsion angle for the chelating 0-atom and the ortho-C-atom of the axial Ph group (a small, ca. 19", angle is optimum, Fig.8) and i i ) the 'degree of perpendicularity' of the axial Ph group (Fig.9). Competition experiments indicate that TADDOL l a catalyzes both the methyltitanium and diethylzinc additions 2 50 limes faster than the related dioxolane analogs 12a, 12c, and 12e (Scheme 7), indicating that both axial and equatorial aryl groups (see Footnote 6 ) are necessary for ligand-accelerated catalysis of these reactions. A refined mechanistic hypothesis is presented (Fig. 10) to explain the selectivities observed for these new ligands. Our analysis suggests that a combination of structural features appear necessary for good catalytic efliciency and high selectivity. These features, especially the rather subtle conformational effects, appear to be optimized (among the ligands tested) in the TADDOL's.Introduction. -The stereoselective addition of organometallics to the heterotopic faces of a carbonyl group has been the subject of intense study for over forty years, ever since Curtin [l], Cram [2], and Prelog [3] first began rationalizing the selective addition of nucleophiles to diastereotopic faces of aldehydes and ketones. Of particular interest has been the gradual development of theories regarding the factors that are responsible for facial selectivity. E.g., following Cram's original postulate, notable contributions to the theory were made over the years by Karahatsos [4], Felkin [5], Dunitz [6], Anh [7], and Heathcock [8] and coworkers, among others. ') 2, 3, 4, ')Visiting Professor (1993)(1994) from the

The methods of theoretical chemistry have been used to elucidate molecular properties of selected and novel antiangiogenic agents (semaxanib, sunitinib, N-methylsunitinib, sorafenib, motesanib, ABT-869, vatalanib, vandetanib, AEE 788, CP-547632, A-1, A-2, A-3, and A-4). The geometries and energies of these drugs have been computed using HF/6-31G(d), Becke3LYP/6-31G(d) and Becke3LYP/ 6-31??G(d,p) model chemistries. Wherever possible the most stable conformations of inhibitors studied are stabilized by means of intramolecular hydrogen bonds. Water has a remarkable effect on the geometry of the antiangiogenic agents studied. Computed partition coefficients (ALOGPS method) varied between 2.3 and 5. Compounds studied are described as lipophilic inhibitors. Semaxanib is inhibitor with lowest lipophilicity. The antiangiogenic agents studied are only slightly soluble in water; their computed solubility (log S) from interval between -3.4 and -5.4 is sufficient for fast absorption. Selection criteria for drug-like properties of VEGFR2 inhibitors investigated were designed. Based on these criteria, three compounds (A-2, A-3, and A-4) were selected for synthesis and biological testing for antianiogenic activity on VEGFR2 receptor.

BackgroundTyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis.MethodsIn the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles. Stable expression of EGFR/TAMs in EGFR-deficient CHO cells afforded robust EGF inducible TAM receptor phosphorylation and activation of downstream signaling.ResultsUsing a series of unbiased screening approaches, that include kinome-view analysis, phosphor-arrays, RNAseq/GSEA analysis, as well as cell biological and in vivo readouts, we provide evidence that each TAM has unique post-receptor signaling platforms and identify an intrinsic role for Axl that impinges on cell motility and invasion compared to Tyro3 and Mertk.ConclusionThese studies demonstrate that TAM show unique post-receptor signatures that impinge on distinct gene expression profiles and tumorigenic outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-016-0142-1) contains supplementary material, which is available to authorized users.

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