C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis.

The fibroblast growth factor receptors (FGFRs) are increasingly considered attractive targets for therapeutic cancer intervention due to their roles in tumor metastasis and angiogenesis. Here, we identified a new selective FGFR inhibitor, C11, and assessed its antitumor activities. C11 was a selective FGFR1 inhibitor with an IC50 of 19 nM among a panel of 20 tyrosine kinases. C11 inhibited cell proliferation in various tumors, particularly bladder cancer and breast cancer. C11 also inhibited breast cancer MDA-MB-231 cell migration and invasion via suppression of FGFR1 phosphorylation and its downstream signaling pathway. Suppression of matrix metalloproteinases 2/9 (MMP2/9) was associated with the anti-motility activity of C11. Furthermore, the anti-angiogenesis activity of C11 was verified in endothelial cells and chicken chorioallantoic membranes (CAMs). C11 inhibited the migration and tube formation of HMEC-1 endothelial cells and inhibited angiogenesis in a CAM assay. In sum, C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.

Highly selective and controllable synthesis of arylhydroxylamines by the reduction of nitroarenes with an electron-withdrawing group using a new nitroreductase BaNTR1.

A new bacterial nitroreductase has been identified and used as a biocatalyst for the controllable reduction of a variety of nitroarenes with an electron-withdrawing group to the corresponding N-arylhydroxylamines under mild reaction conditions with excellent selectivity (>99%). This method therefore represents a green and efficient method for the synthesis of arylhydroxylamines.

[Chemical approaches for trapping protein thiols and their oxidative modification].

Redox signal transduction, especially the oxidative modification of proein thiols, correlates with many diseases and becomes an expanding research area. However, there was rare method for quick and specific detection of protein thiols and their oxidative modification in living cells. In this article, we review the current chemical strategies for the detection and quantification of protein thiols and related cysteine oxidation. We also look into the future of the development of fluorescent probes for protein thiols and their potential application in the research of reactive cysteine proteomes and early detection of redox-related diseases.

Naphthalimides induce G(2) arrest through the ATM-activated Chk2-executed pathway in HCT116 cells.

Naphthalimides, particularly amonafide and 2-(2-dimethylamino)-6-thia-2-aza-benzo[def]chrysene-1,3-diones (R16), have been identified to possess anticancer activities and to induce G(2)-M arrest through inhibiting topoisomerase II accompanied by Chk1 degradation. The current study was designed to precisely dissect the signaling pathway(s) responsible for the naphthalimide-induced cell cycle arrest in human colon carcinoma HCT116 cells. Using phosphorylated histone H3 and mitotic protein monoclonal 2 as mitosis markers, we first specified the G(2) arrest elicited by the R16 and amonafide. Then, R16 and amonafide were revealed to induce phosphorylation of the DNA damage sensor ataxia telangiectasia-mutated (ATM) responding to DNA double-strand breaks (DSBs). Inhibition of ATM by both the pharmacological inhibitor caffeine and the specific small interference RNA (siRNA) rescued the G(2) arrest elicited by R16, indicating its ATM-dependent characteristic. Furthermore, depletion of Chk2, but not Chk1 with their corresponding siRNA, statistically significantly reversed the R16- and amonafide-triggered G(2) arrest. Moreover, the naphthalimides phosphorylated Chk2 in an ATM-dependent manner but induced Chk1 degradation. These data indicate that R16 and amonafide preferentially used Chk2 as evidenced by the differential ATM-executed phosphorylation of Chk1 and Chk2. Thus, a clear signaling pathway can be established, in which ATM relays the DNA DSBs signaling triggered by the naphthalimides to the checkpoint kinases, predominantly to Chk2,which finally elicits G(2) arrest. The mechanistic elucidation not only favors the development of the naphthalimides as anticancer agents but also provides an alternative strategy of Chk2 inhibition to potentiate the anticancer activities of these agents.

Novel 4H-1,3,4-oxadiazin-5(6H)-ones with hydrophobic and long alkyl chains: design, synthesis, and bioactive diversity on inhibition of monoamine oxidase, chitin biosynthesis and tumor cell.

A new series of nitrogen-containing heterocycles 4H-1,3,4-oxadiazin-5(6H)-ones derivatives with hydrophobic and long chains were designed and synthesized by direct cyclization reaction of N'-alkylation substituted aroylhydrazines with chloroacetyl chloride. The preliminary assays showed that some of the compounds displayed moderate to good inhibitory activities toward monoamine oxidase (MAO) at the concentration of 10(-5)-10(-3)M, and antitumor activities against human lung cancer A-549 and human prostate cancer PC-3 cell lines at muM level, which might provide new scaffold for anticancer agents. Furthermore, compounds 5i and 5m exhibited significant inhibitory activity on chitin biosynthesis, which might represent a novel class of highly potential inhibitors of chitin synthesis.

R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II.

Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, 2-(2-dimethylamino)-6-thia-2-aza-benzo-[def]-chrysene-1,3-diones (R16) was synthesized by substituting 5'-NH(2) of the naphthyl with a heterocyclic group to amonafide, with additional introduction of a thiol group. In a panel of various human tumor cell lines, R16 was more cytotoxic than its parent compound amonafide. It was also effective against multidrug-resistant cells. Importantly, the i.p. administration of R16 inhibited tumor growth in mice implanted with S-180 sarcoma and H(22) hepatoma. The molecular and cellular machinery studies showed that the R16 functions as a topoisomerase II (topo II) poison via binding to the ATPase domain of human topo IIalpha. The superior cytotoxicity of R16 to amonafide was ascribed to its potent effects on trapping topo II-DNA cleavage complexes. Moreover, using a topo II catalytic inhibitor aclarubicin, ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR) kinase inhibitor caffeine and topo II-deficient HL-60/MX2 cells, we further showed that R16-triggered DNA double-strand breaks, tumor cell cycle arrest, and apoptosis were in a topo II-dependent manner. Taken together, R16 stood out by its improved anticancer activity, appreciable anti-multidrug resistance activities, and well-defined topo II poisoning mechanisms, as comparable with the parent compound amonafide. All these collectively promise the potential value of R16 as an anticancer drug candidate, which deserves further development.