Research progress of DNA-PK inhibitors in the cancer treatment / 药学学报

The most toxic DNA damage is DNA double strand breaks (DSBs), which are mainly repaired by non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK) belongs to phosphatidylinositol-3-kinase-related protein kinase family (PIKK) and plays a key role in NHEJ. DNA-PK is overexpressed in a variety of cancer cells and is related to the occurrence, development and drug resistance of malignant tumors. In this article, the representative DNA-PK inhibitors with anticancer effects are reviewed, in order to provide a reference to discovery novel DNA-PK inhibitors.

Design, synthesis and biological evaluation of peptidyl-prolyl cis-trans isomerase Pin1 inhibitors / 药学学报

Peptidyl-prolyl cis-trans isomerase Pin1 is over-expressed in prostate cancer cells and the level of expression correlates with the malignancy grade and prognosis in patients. In this work, twenty-one 2-(1H-benzimidazol-2-ylthio) acetic acid derivatives were designed and prepared with the aid of the crystal structure of Pin1 and our previous work. The chemical structures of the target compounds were confirmed by 1H NMR, 13C NMR, ESI-MS and IR. The inhibitory activity of compounds 6a-6i and 13a-13i against Pin1 were determined using a protease-coupled assay. The results indicated that twenty compounds were significantly superior to the positive control drug Juglone, and 6g, 6h and 13i exhibited the most potent Pin1 inhibitory activity, with IC50 values at the sub-micromolar level. The in vitro anti-proliferative activities of these analogs were evaluated by the MTT assay and several showed a moderate effect in human prostate cancer PC-3 cells. Molecular docking studies demonstrated that both the benzimidazole skeleton and the thioacetic acid fragment were indispensable for the compounds to interact with key residues in the catalytic domain of Pin1.

Design, synthesis and antiproliferative activity in cancer cells of novel dihydropyrazolyl and pyrazolyl artemisinin-phenyl ethers / 中国中药杂志

To explore potent anticancer agent based on artemisinin scaffold, a series of 10--phenyl ethers derivatives containing dihydropyrazolyl or pyrazolyl moiety have been designed and synthesized. Their structures were determined by LC-MS and ¹H-NMR date. Inhibitory effects of the target compounds in human breast cancer MCF-7, MCF/Adr, MDA-MB-231 cells and prostate cell line PC-3 were determined by MTT assay. Those derivatives displayed good antiproliferative activity against the tested cancer cells. Particularly, target compounds exhibited significant cytotoxicity against drug-resistance cells MCF/Adr, which was worthy for further investigation.

Design, synthesis and antiproliferative activity in cancer cells of novel 18β-glycyrrhetinic acid derivatives / 药学学报

To investigate the anticancer effects of ring C in 18β-glycyrrhetinic acid (GA), a series of GA derivatives featured with 9(11)-ene moiety in ring C were designed and synthesized. The structures were confirmed by IR, LC-MS and 1H NMR. Their inhibitory effects towards human prostate cancer PC-3 and leukemia HL-60 cell lines were determined. Most of the derivatives displayed stronger antiproliferative activities than GA. Particularly, compound 14 showed promising anticancer activity with the GI50 values of 4.48 µmol · L(-1) and 1.2 µmol · L(-1) against PC-3 and HL-60 cells respectively, which is worth further study.

Design, synthesis and antiproliferative activities of artemisinin derivatives substituted by N-heterocycles / 药学学报

Increasing attention has been focused on the antitumor activity of artemisinin derivatives in recent years, for artemisinin had been reported to have cytotoxic effects against HL-60, P388 and MCF-7 tumor cells. We report here the synthesis and evaluation for antitumor activity of a series of artemisinin-ether derivatives bearing tetrahydropyrrole, morpholine, piperidine, substituted piperidines and azoles with various linkers. Sixteen 10-O-substituted dihydroartemisinin derivatives were designed and synthesized, all of which have never been reported in literatures and whose antiproliferative effects on human breast cancer MCF-7, MCF-7/Adr and HL-60 cells were determined by MTT assay or direct cell counting. Each of these artemisinin derivatives possessed better effects than dihydroartemisinin evidently against HL-60 and MCF-7 cells growth, while less potent than doxorubicin. All target compounds exhibited significantly improved potency compared to DHA and doxorubicin on the doxorubicin-resistant MCF-7/Adr cells, so did they in their sensitive counterparts MCF-7 cells. Among them, compounds GF02, GH04 and ZH04 showed strong activity against these three cell lines growth. Further research is undergoing.

Synthesis and antitumor activity of S-hexyl(heptyl) substituted ethanethioate derivatives / 药学学报

To simplify the macrocyclic fragment and to modify the zinc binding group of the natural product apicidin, two series of S-hexyl (heptyl) ethanethioate derivatives were designed and synthesized. Twenty-six compounds were synthesized and confirmed with 1H NMR, IR, MS and HR-MS spectrum, which were not reported. Take vorinostat as control, their antiporliferative activities against cancer cell lines, MCF-7 and HL-60, were tested with MTT assay or trypan blue staining method. Generally in both series it was found that, the chiral carbon atom at 7 position is not necessary, compounds II-1, II-3, II-6 and II-13 showed good activity on HL-60 cells in vitro, with the IC50 values less than 10 micromol x L(-1). II-7 and II-8 showed stronger activity against MCF-7 than Vorinostat, with the IC50 of 3.19 and 6.29 micromol x L(-1), respectively.

Application of phosphates and phosphonates prodrugs in drug research and development / 药学学报

Based on the character of the molecular structure, the prodrugs of phosphates and phosphonates were divided into two categories. The first is the drug which contained the phosphate group, introducing protected groups to increase lipophilicity and improve bioavailability. The other one is the drug which had no phosphate group, introducing the phosphate group into molecules to enhance the solubility, regulate the distribution coefficient and enhance the drug-like property. This review focuses on the application of phosphates and phosphonates in drug research and development based on improvement of physico-chemical property, drug safety and the pharmacokinetics.