Benzophenone-nucleoside derivatives as telomerase inhibitors: Design, synthesis and anticancer evaluation in vitro and in vivo.

Based on telomerase, thirteen novel phenstatin moiety linked stavudine derivatives (8a∼8e and 11a∼11f) were synthesized. The structures were determined by NMR and TOF-HRMS. The screening results showed that some compounds had better anti-cancer activity in vivo and in vitro. Among them, Compound 8d showed high inhibitory activity against telomerase and showed good antiproliferative activity against SGC-7901 cell with IC50 value 0.77 µM by inducing cell cycle arrest at G2 phase. It also could improve SGC-7901 cell apoptosis, mitochondrial membrane potential assay indicated that the dissipation of MMP might participate in apoptosis induced by title compound. In vivo studies showed that compound 8d displayed potent anticancer activity with inhibition tumor growth.

A novel 7-azaisoindigo derivative-induced cancer cell apoptosis and mitochondrial dysfunction mediated by oxidative stress.

This research focused on a novel 7-azaisoindigo derivative [namely N(1)-(n-butyl)-7-azaisoindigo, 7-AI-b], and investigated its molecular antitumor mechanism by exploring the means of cell death and the effects on mitochondrial function. 7-AI-b inhibited cancer cell proliferation in a dose- and time-dependent way. The morphological and nuclei changes in H(2) B-GFP-labeled HeLa cells were observed using a live cell system. The results suggested that cell death induced by 7-AI-b is closely related to apoptosis. 7-AI-b induced release of cytochrome C from mitochondria to cytosol and activation of caspase-3, showing that the apoptosis is mediated by the mitochondrial pathway. Furthermore, our data indicated that 7-AI-b triggers apoptosis through reactive oxygen species (ROS): cellular ROS levels were increased after 3 h exposure of 7-AI-b, which was reversed by the ROS scavenger N-acetyl-L-cysteine. As a consequence, 7-AI-b-mediated cell death, mitochondrial transmembrane potential collapse and ATP level were partly blocked by N-acetyl-L-cysteine. Further study showed that 7-AI-b could induce mitochondrial dysfunction: collapse of the mitochondrial transmembrane potential and reduction of intracellular ATP level. In summary, the novel synthesized 7-AI-b was demonstrated to be effective in killing cancer cells via an ROS-promoted and mitochondria- and caspase-dependent apoptotic pathway.

Synthesis and biological evaluation of 7-azaisoindigo derivatives.

A series of novel 7-azaisoindigo derivatives 3-14 were designed, synthesized, and structurally characterized by IR, 1H-NMR, 13C-NMR, mass spectra, and elemental analyses. Their antiproliferative activities were evaluated in a hormone-independent prostate cancer cell line DU145. Among them, compounds 8, 9, 14 showed the highest activities. Our study also showed that compounds 7, 11, 12 exhibited higher inhibitory activities on CDK2/cyclin A than that of the positive control meisoindigo. Western blot analysis on DU145 cells treated with compounds 7 and 9 demonstrated that 7-azaisoindigo derivatives could decrease the level of CDK2 activity (phosphorylation) and the expression of cyclin D1, and increase the expression of endogenous cyclin-dependent inhibitor p27.

Synthesis and biological activities of 2,4-diaminopteridine derivatives.

Substituted 2,4-diaminopteridine derivatives 10a-10l were prepared in moderate to good yield. Their structures were confirmed by 1H-NMR and MS spectroscopy, as well as by elemental analysis. Their inhibitory properties against inducible nitric oxide synthase (iNOS) were evaluated in vitro. Biological tests indicated that compound 10a, 10d, 10e, 10h, 10i, and 10l showed potent inhibitory activities similar to that of methotrexate (MTX), while the activities of compound 10b, 10c, 10f, 10g, 10j, and 10k are stronger than MTX. Two compounds, i. e., 10b (IC(50 )= 18.85 microM) and 10i (IC(50) = 24.08 microM) were further studied for their effect on septic shock in rats and immunologically liver injured mice (in vivo). The results demonstrated that 10b and 10i had the capacity to increase the blood pressure in septic shock and showed notable protective activities on immunological hepatic injury.

Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4-d]pyrimidine nucleoside derivatives-induced cancer cell death.

Eight novel oxdiazolo[3,4-d]pyrimidine nucleoside derivatives (I-VIII) were synthesized to investigate their anti-tumor effects and possible mechanisms. Four human cancer cell lines including Hela, ECA109, HepG2 and A459 cells were used. Compounds VI and VIII showed significant inhibition on cancer cell proliferation by MTT assay and IC50 values were around 30-70 micromol l(-1). Both compounds could release nitric oxide (NO), led to a significant intracellular free Ca2+ overloading and resulted in mitochondrial dysfunction, showing a decrease in mitochondrial membrane potential in HepG2 cells in a dose-dependent manner. Furthermore, compound VIII induced obvious DNA damage on HepG2 cells. These data indicate that compounds VI and VIII are two active antitumor compounds, and both DNA damage and mitochondrial dysfunction are involved in the mechanisms underlying oxadiazolo[3,4-d]pyrimidine nucleoside derivative-induced cancer cell death, which might also be related to the released NO.