Platinum(II) Terpyridine Anticancer Complexes Possessing Multiple Mode of DNA Interaction and EGFR Inhibiting Activity.

Platinum(II) terpyridine complexes has attracted increasing attention as they have displayed great potential as antitumor agents due to their high intercalation affinity with nucleic acids. Epidermal growth factor receptor (EGFR) is often overexpressed in various tumor cells, leading to uncontrolled growth of tumor, and is regarded as an important target for developing novel antitumor drugs. Herein, we report four platinum(II) terpyridine complexes bearing EGFR inhibiting 4-anilinoquinazoline derivatives as potent multi-targeting antiproliferation agents against a series of cancer cells. EGFR inhibition assay revealed that these complexes are highly potent EGFR inhibitors. But competitive DNA binding assay and docking simulations also suggested that these complexes exhibited multiple modes of DNA interaction, especially great affinity toward DNA minor groove. Finally, cellular uptake and distribution measurements by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) demonstrated that both nucleus DNA and membrane proteins are important targets for their anticancer mechanisms. The complexes herein can therefore be regarded as promising multi-targeting anticancer agents.

Solvent-dependent structural dynamics of an azido-platinum complex revealed by linear and nonlinear infrared spectroscopy.

The vibrational and anisotropic relaxation dynamics and structural dynamics of a potential anticancer prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2], were investigated using time-resolved infrared pump-probe spectroscopy and ultrafast two-dimensional infrared (2D IR) spectroscopy. Herein, two representative bio-friendly solvents, H2O and DMSO, were used, in which the local structural and dynamical variations were monitored using the antisymmetric linear combination of the two N3 stretching vibrational modes as an infrared probe. It was found that the vibrational relaxation process of the N3 antisymmetric stretching (as) mode in H2O is two to three times faster than that in DMSO. The anisotropic relaxation process of the anticancer prodrug was observed to be hindered in DMSO; this indicated a tighter solvent environment around the sample molecule in this solvent. The vibrational frequency time correlation of the N3 antisymmetric stretching mode in H2O decays with a time constant of 1.94 ps, in agreement with the hydrogen bond formation and breaking times of water. In DMSO, the frequency time correlation of the N3 as mode decays on a much longer time scale; this further indicates its sensitivity to the out-layer DMSO structural dynamics, which are relatively static in the experimental time window.

A Photoactive Platinum(IV) Anticancer Complex Inhibits Thioredoxin-Thioredoxin Reductase System Activity by Induced Oxidization of the Protein.

Thioredoxin (Trx) is an important enzyme in the redox signaling pathway and is usually overexpressed in tumor cells. We demonstrate herein that the photoactive platinum(IV) anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(Py)2] (1) can bind to His, Glu, and Gln residues of Trx upon the irradiation of blue light. More importantly, complex 1 can also induce the oxidation of Met, Trp, and the Cys catalytic sites to form disulfide bonds by generating reactive oxygen species (ROS) upon photoactivation. These eventually lead to inhibition of activity of Trx enzyme and the Trx system and further increase in the cellular ROS level. We speculate that the oxidative damage not only inhibits Trx activity but also greatly contributes to the anticancer action of complex 1.

L1/2 regularization: a thresholding representation theory and a fast solver.

The special importance of L1/2 regularization has been recognized in recent studies on sparse modeling (particularly on compressed sensing). The L1/2 regularization, however, leads to a nonconvex, nonsmooth, and non-Lipschitz optimization problem that is difficult to solve fast and efficiently. In this paper, through developing a threshoding representation theory for L1/2 regularization, we propose an iterative half thresholding algorithm for fast solution of L1/2 regularization, corresponding to the well-known iterative soft thresholding algorithm for L1 regularization, and the iterative hard thresholding algorithm for L0 regularization. We prove the existence of the resolvent of gradient of ||x||1/2(1/2), calculate its analytic expression, and establish an alternative feature theorem on solutions of L1/2 regularization, based on which a thresholding representation of solutions of L1/2 regularization is derived and an optimal regularization parameter setting rule is formulated. The developed theory provides a successful practice of extension of the well- known Moreau's proximity forward-backward splitting theory to the L1/2 regularization case. We verify the convergence of the iterative half thresholding algorithm and provide a series of experiments to assess performance of the algorithm. The experiments show that the half algorithm is effective, efficient, and can be accepted as a fast solver for L1/2 regularization. With the new algorithm, we conduct a phase diagram study to further demonstrate the superiority of L1/2 regularization over L1 regularization.