Tyrosyl−DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)−DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC 50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural productbased TOP1 and TDP1 inhibitors.
As a recently discovered DNA repair
enzyme, tyrosyl-DNA phosphodiesterase
1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links.
Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors
and overcome cancer cell resistance to TOP1 inhibitors. On the basis
of our previous study, herein we report the synthesis of benzophenanthridinone
derivatives as TOP1 and TDP1 inhibitors. Seven compounds (C2, C4, C5, C7, C8, C12, and C14) showed a robust TOP1 inhibitory
activity (+++ or ++++), and four compounds (A13, C12, C13, and C26) showed a TDP1
inhibition (half-maximal inhibitory concentration values of 15 or
19 μM). We also show that the dual TOP1 and TDP1 inhibitor C12 induces both cellular TOP1cc, TDP1cc formation and DNA
damage, resulting in cancer cell apoptosis at a sub-micromolar concentration.
In addition, C12 showed an enhanced activity in drug-resistant
MCF-7/TDP1 cancer cells and was synergistic with topotecan in both
MCF-7 and MCF-7/TDP1 cells.
Porcine placenta was hydrolyzed using papain and trypsin in a combined formulation. An orthogonal experimental design (L 9 (3) 4 ) was applied in order to obtain porcine placenta hydrolysates (PPH) having the best antioxidant activities. The PPH was dried using vacuum drying (VD), spray drying (SD), and freeze drying (FD) and the effects of these drying methods on the antioxidative activity and solubility were investigated. The DPPH scavenging activity of these PPH reached 44.45 AE 0.46% and the molecular weight of 83.39% of these PPH peptides was below 3000Da. The proportion of highly antioxidative amino acid residues in these PPH reached 60.14%. The VD-PPH showed the lowest antioxidantive activities (DPPH, superoxide and hydroxyl radical scavenging activities, and lecithin liposome antioxidant activity) and the lowest solubility. The FD-PPH exhibited the highest antioxidative properties and the highest solubility. Both the antioxidative properties and the solubility of SD-PPH remained in between those of FD-PPH and VD-PPH. Spray drying can be a method of choice to produce PPH powders due to its higher throughput.
Porcine placenta is commonly used in Chinese as a traditional medicine. It has been reported by a number of researchers that the porcine placenta contains many compounds which have good health benefits. Response surface methodology (RSM) was applied to optimize the parameters of ultrasound power, ultrasound treat time, and extraction temperature on the extraction yield of porcine placenta water-soluble proteins (PPWP). The results indicated that, under optimum conditions of ultrasound power 257 w, extraction temperature at 49°C for 7 min, the extraction yield of PPWP was 32.7 %, which was significantly higher than that of the conventional extraction method (CEM) of 15.0 %. The experimental data were fitted to a second-order polynomial equation using multiple regression analysis and the estimated model showed a high capacity of predicting the dependent variables. Although not significantly, the antioxidant activity of PPWP from ultrasound-assist-extraction (UAE) were higher than those from CEM, indicated that UAE had a positive effect or at least no negative effect on the bioactivity of PPWP.
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