Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.

Three water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA) were synthesized and characterized. It was found that these ruthenium(II) complexes exhibited considerable in vitro anticancer activities and that they were the effective stabilizers of telomeric and G-quadruplex-DNA (G4-DNA) in promoter of c-myc, which acted as a telomerase inhibitor targeting G4-DNA and induced cell senescence and apoptosis. Interestingly, the in vitro anticancer activity of 6 (LC-003) was higher than those of 4 (LC-001) and 5 (LC-002), more selective for BEL-7404 cells than for normal HL-7702 cells, and preferred to activate caspases-3/9. The different biological behaviors of the ruthenium complexes could be correlated with the chiral nature of 4-(2,3-dihydroxypropyl)-formamide oxoaporphine. More significantly, 6 exhibited effective inhibitory on tumor growth in BEL-7402 xenograft mouse model and higher in vivo safety than cisplatin. These mechanistic insights indicate that 6 displays low toxicity and can be a novel anticancer drug candidate.

The anticancer traditional Chinese medicine (TCM), plumbagin (PLN), was isolated from Plumbago Zeylanica. Reaction of plumbagin with Cu(II) salt, afforded [Cu(PLN)(2)].2H(2)O (1). With 2,2'-bipyridine (bipy) as a co-ligand, PLN reacts with Cu(II) to give [Cu(PLN)(bipy)(H(2)O)](2)(NO(3))(2).4H(2)O (2). 1 and 2 were characterized by elemental analysis, IR, ESI-MS spectra. Their crystal structures were determined by single crystal X-ray diffraction methods. The in vitro cytotoxicity of PLN, 1 and 2 against seven human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. that of free PLN, suggesting that these compounds display synergy in the combination of metal ions with PLN. The binding properties of PLN, 1 and 2 to DNA were investigated through UV-vis, fluorescence, CD spectra, and gel mobility shift assay, which indicated that 1 and 2 were non-covalent binding and mainly intercalated the neighboring base pairs of DNA. PLN, 1 and 2 exhibit inhibition activity to topoisomerase I (TOPO I), but 1 and 2 were more effective than PLN.

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Highly sensitive detection of proteins is essential to biomedical research as well as clinical diagnosis. Here, we develped a novel label-free colorimetric aptasensor based on nicking enzyme assisted signal amplification and DNAzyme amplification for highly sensitive detection of protein. The system consists of a hairpin DNA probe carrying an aptamer sequence for target, a G-riched DNA probe containing two G-riched DNAzyme segments and the recognition sequence as well as cleavage site for nicking enzyme, a blocker DNA, and the nicking enzyme. The hybridization of the G-riched DNA with the blocker DNA prohibits the formation of the activated DNAzymes in the absence of target. Upon addition of target to the system, the hairpin probe is opened by the specific recognition of the target to its aptamer. The open hairpin probe hybridizes with a G-riched DNA and forms a DNA duplex, which triggers the selective cleavage of the G-riched DNA probe by nicking enzyme, leading to the release of the aptamer-target complex and the G-riched DNAzyme segments. The released open hairpin probe then hybridizes with another G-riched DNA probe, and the cycle starts anew, resulting in the continuous cleavage of the G-riched DNA probes, generating a much of G-riched DNAzyme segments. The G-riched DNAzyme segments interact with hemin and generates the activated DNAzyme that can catalyze the H2O2-mediated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(2-)) to the colored ABTS(•-), thus providing the amplified colorimetric detection of target. With the use of thrombin (Tb) as a proof-of-principle analyte, this sensing platform can detect Tb specifically with a detection limit as low as 1.5 pM, which is at least 4 orders of magnitude lower over the unamplified colorimetric assay. Moreover, the assay does not involve any chemical modification of DNA, which is simple and low-cost. This sensing platform provides a promising approach for the amplified analysis of target molecules.

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Abstract-This paper presents adaptive neural tracking control for a class of uncertain multi-input-multi-output (MIMO) nonlinear systems in block-triangular form. All subsystems within these MIMO nonlinear systems are of completely nonaffine purefeedback form and allowed to have different orders. To deal with the nonaffine appearance of the control variables, the mean value theorem (MVT) is employed to transform the systems into a block-triangular strict-feedback form with control coefficients being couplings among various inputs and outputs. A systematic procedure is proposed for the design of a new singularityfree adaptive neural tracking control strategy. Such a design procedure can remove the couplings among subsystems and hence avoids the possible circular control construction problem. As a consequence, all the signals in the closed-loop system are guaranteed to be semiglobally uniformly ultimately bounded (SGUUB). Moreover, the outputs of the systems are ensured to converge to a small neighborhood of the desired trajectories. Simulation studies verify the theoretical findings revealed in this work.Index Terms-Adaptive neural control, backstepping, neural networks (NN), coupling, multi-input-multi-output (MIMO) nonlinear systems.