Natural-Based Indirubins Display Potent Cytotoxicity toward Wild-Type and T315I-Resistant Leukemia Cell Lines.

Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 µM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both c-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue 22 exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue 22 is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases.

Reflectivity properties of an anisotropic slab waveguide with isolated substrate.

The scattering properties for both TE and TM modes of an abruptly ended two-layered slab waveguide with anisotropic core and isolated substrate are examined by an improved iteration technique, which is based on the integral equation method with accelerating parameters. The relative dielectric constants of the core for the three Cartesian directions are considered to be different, but cases with isotropic core are also considered. The electric field distribution on the terminal plane and the reflection coefficients of the dominant TE and TM guided modes, as well as the near-field distribution and the far-field radiation pattern, are computed, while numerical results are presented for several cases of the core anisotropy.

Metal iris influence on guided-mode diffraction.

The effects of the presence of metal irises on guided-mode propagation through a symmetrical three-layer slab waveguide are examined by using the integral equation method. The aperture electric field distribution is expressed in terms of a finite series of Chebyshev polynomials. The modal reflection and transmission coefficients, the near-field structure, and the far-field radiation pattern are calculated, while numerical results are presented for several iris apertures.

Reflectivity of buried slab waveguides.

The scattering properties of an abruptly ended buried slab waveguide for both TE and TM modes are examined by an improved iteration technique that is based on the integral equation method with "accelerating" parameters. The waveguide is considered a symmetrical slab, for which the weakly guiding conditions are invalid, and it is embedded in a different dielectric material. The tangential electric field distribution on the terminal plane, the reflection coefficient of the first TE and TM guided modes, and the far-field radiation pattern are computed. Numerical results are presented for several ended waveguides, while special attention is given to the far-field radiation pattern rotation and the terminal field distributions.