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The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK-193˜LK-196 was described. The C2'-modified compound LK-196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK-196 had the self-evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation., (© 2016 John Wiley & Sons A/S.)

Overwhelming data indicate that cancer survivors are at higher risk of cardiovascular diseases because chemotherapy induces cardiotoxicity. Mechanistic explanation of this phenomenon is necessary to advise the clinical practice on the prevention of cardiotoxicity in cancer patients. Here we propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homeostasis of cardiac stem cells and depleting the resident cardiac stem cells pool. As a result, the heart loses the capability of regeneration and repair and demonstrates the cardiotoxicity symptoms. Our hypothesis is supported by several lines of emerging evidence: the high incidence of cardiotoxicity in paediatric cancer patients who still have more cardiac stem cells in the myocardium; the rescue of anthracycline cardiomyopathy by injection of cardiac stem cells; and the adverse cardiotoxicity induced by inhibitors of oncogenic kinases or pathways which target cardiac stem cells besides cancer cells. This may promote our growing appreciation that cardiac stem cells represent new targets of chemotherapy that contribute to cardiotoxicity and open up novel strategies for the preservation or expansion of the cardiac stem cells pool to overcome cardiotoxicity associated with chemotherapy., (© 2010 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Rationale: Gelsemine has been extensively studied because of its anti-tumor, immuno- modulatory, insecticidal itching and other significant effects. However, limited information on the pharmacokinetics and metabolism of gelsemine has been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of gelsemine in rat liver S9 by using rapid and accurate high-performance liquid chromatography/ quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). Methods: The incubation mixture was processed with 15% trichloroacetic acid. Multiple scans of gelsemine metabolites and accurate mass measurements were automatically performed simultaneously through data-dependent acquisition in only 30 min. The structural elucidations of these metabolites were performed by comparing their changes in accurate molecular masses and product ions with those of the parent drug. Results: Five metabolites of gelsemine were identified in rat liver S9. Of these, four metabolites of gelsemine were identified for the first time. The present results showed that the metabolic pathways of gelsemine are oxidation, demethylation, and dehydrogenation in rat liver S9. Conclusions: In this study, metabolites of gelsemine in liver S9 were identified and elucidated firstly using the HPLC/QqTOF-MS method. The proposed metabolic pathways of gelsemine in liver S9 will provide a basis for further studies of the in vivo metabolism of gelsemine in animals and humans. [ABSTRACT FROM AUTHOR]

Complexes [Zn(L)2(H2O)] ( 1), [Mn(L)2(CH3OH)2] ( 2), and [Fe(L)2(CH3OH)Cl] ( 3) (H-L = 6-hydroxyloxoisoaporphine) were synthesized and characterized. Complex 1 is a five-coordinate distorted tetragonal pyramid, whereas complexes 2 and 3 are six-coordinate distorted octahedral structures. Complexes 1- 3 exhibited selective cytotoxicity against MGC80-3, Hep-G2, BEL-7404, and T-24 cells, with IC50 values in the range of 8.19-15.98 µ m, and low cytotoxicity to HL-7702 cells. T-24 was the tumor cell most sensitive to complexes 1- 3. Complexes 1- 3 induced T-24 cell arrest in the G1 and G2/M phases, which led to the upregulation of p27, CDK2, p53, and p21, and downregulation of Cyclin E, Chk1, CDC25A, and Chk2. Complexes 1- 3 triggered apoptosis in T-24 cells by a mitochondrial-dysfunction pathway. The interaction of complexes 1- 3 with DNA occurs most likely by means of an intercalation and cleavage mode. [ABSTRACT FROM AUTHOR]

A new cobalt(II) complex ( 1) of 5-chloro-8-hydroxyquinoline was prepared and structurally characterized using , electrospray ionization , elemental analysis, single-crystal X-ray diffraction as well as powder X-ray diffraction. Its biological activities including DNA binding and anticancer activity were investigated. The DNA binding study of complex 1 suggested that it interacted with calf thymus DNA mainly via an intercalative binding mode. The in vitro anticancer activity of complex 1 was screened against a series of tumor cell lines as well as the normal liver cell line HL-7702 using MTT assay. complex 1 showed much higher cytotoxicity than corresponding metal salt and ligand towards the five tested tumor cell lines, in which T-24 was the most sensitive tumor cell line towards 1, with IC50 value of 7.04 ± 0.06 μM. complex 1 was found to greatly induce cell cycle arrest in T-24 cells at S phase, and consequently to induce cell apoptosis in a dose-dependent mode suggested by cell apoptosis analysis via Hoechst 33258 and acridine orange/ethidium bromide staining assays. The cell apoptosis mechanism of 1 was studied targeting the mitochondrion-mediated pathway, since the apoptotic mechanism in the T-24 cells treated by 1 was investigated by (ROS) detection, intracellular calcium concentration measurement and caspase-9/3 activity assay. The results suggested that the cell apoptosis induced by 1 was closely related to the loss of mitochondrial membrane potential, ROS production and enhancement of intracellular [Ca2+], which would trigger the caspase-9/3 activation via a mitochondrial dysfunction pathway. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Some G-rich sequences in the human genome have the potential to fold into a multimeric G-quadruplex (G4) structure and the formation of telomeric multimeric G4 has been demonstrated. Searching for highly specific multimeric G4 ligands is important for structure probing and for study of the function of G-rich gene sequences, as well as for the design of novel anticancer drugs. We found different numbers of positively charged side-arm substituents confer tetraphenylethene (TPE) derivatives with different multimeric G4 recognition specificity. 1,2-Bis{4-[(trimethylammonium)butoxy]phenyl}-1,2-tetraphenylethene dibromide (DATPE), which contains two side arms and gives a fluorescence response to only multimeric G4, has a low level of cytotoxicity and little or no effect on multimeric G4 conformation or stability. These features make DATPE a promising fluorescent probe for detection of multimeric G4 specifically in biological samples or in vivo. 1,1,2,2-Tetrakis{4-[(trimethylammonium)butoxy]phenyl}tetraphenylethene tetrabromide (QATPE), which contains four side arms, has a lower level of specificity for multimeric G4 recognition compared to DATPE but its binding affinity to multimeric G4 is higher compared to other structural DNAs. Its high multimeric G4-binding affinity, excellent multimeric G4-stabilizing ability, and the promotion of parallel G4 formation make QATPE a good candidate for novel anticancer drugs targeting multimeric G4 specifically, especially telomeric multimeric G4. This work provides information that might aid the design of specific multimeric G4 probes and the development of novel anticancer drugs. [ABSTRACT FROM AUTHOR]