Anticancer Drugs (V)─—Synthesis of Etoposide Derivatives

ＡｎｔｉｃａｎｃｅｒＤｒｕｇｓ（Ｖ）─—ＳｙｎｔｈｅｓｉｓｏｆＥｔｏｐｏｓｉｄｅＤｅｒｉｖａｔｉｖｅｓＴＩＡＮＸｕａｎ,ＹＡＮＺｅ－ｑｕｎ,ＬＩＪｉｎ－ｘｉｎａｎｄＣＨＥＮＹａｏ－ｚｕ（ＮａｔｉｏｎａｌＬａｂｏｒａｔｏｒｙｏｆＡｐｐｌｉｅｄＯｒｇａｎ...     

Etoposide interferes with the process of chromatin condensation during alga Chara vulgaris spermiogenesis

DNA topoisomerase II plays an essential role in animal spermiogenesis, where changes of chromatin structure are connected with appearance of transient DNA breaks. Such topo II activity can be curtailed by inhibitors such as etoposide and suramine. The aim of the present study was to investigate, for the first time, the effect of etoposide on spermatid chromatin remodeling in the green alga Chara vulgaris. This inhibitor prolonged the early spermiogenesis stages and blocked the formation of the phosphorylated form of histone H2AX at stages VI–VII. The lack of transient DSBs at these stages impairs the elimination of supercoils containing nucleosomes which lead to disturbances in nucleoprotein exchange and the pattern of spermatid chromatin fibrils at stages VI–VIII. Immunofluorescent and ultrastructural observations revealed that during C. vulgaris spermiogenesis topo II played an important role similar to that in mammals. Some corresponding features had been pointed out before, the present studies showed further similarities.     

VP-16与DNA分子间电子转移的光谱学研究

运用脉冲辐解和圆二色谱技术,对用于治疗肿瘤的依托泊甙(VP-16)与鸟苷酸(GMP)和小牛胸腺DNA分子间电子转移的光谱进行了探讨。用脉冲辐解技术发现了VP-16与GMP之间的电子转移,测得两者之间的反应速率常数为3.16×107 L·mol-1·s-1,并对它们的吸收光谱进行了归属,同时用圆二色谱技术发现了VP-16与小牛胸腺DNA之间相互作用。从而为医学工作者进一步了解和探讨VP-16的抗肿瘤机理提供了直接的理论依据。     

Synthetic approach to condensed heterocyclic analogues from etoposide revisited. Synthesis of A-ring pyridazine etoposide

The synthetic approach to condensed heterocyclic analogues from etoposide was revisited. The described procedure allows the synthesis of A-ring pyridazine etoposide 13, featuring the use of tetrakis(triphenylphosphine)palladium as catalyst under optimized conditions in the key Stille cross coupling between bistriflate 14 and the vinylstannane without epimerization at C-2. The TBDMS-protecting group was critical to cleanly obtain the pivotal intermediate 19.     

Etoposide Induces Mitochondria-Associated Apoptotic Cell Death in Human Gastric Carcinoma Cells

Recent observations indicate that the resistance of apoptosis is an important process of tumor metastasis and metastases are the cause of 90% of human cancer death. Etoposide, a semisynthetic derivative of the podophyllotoxins, is a clinically used anti-cancer reagent, but the effects of it on metastatic gastric carcinoma cells are totally unknown. In this study, etoposide induced apoptotic cell death in human gastric adenocarcinoma cell line SGC-7901, derived from metastatic lymph nodes, as evidenced by the analysis of DNA fragmentation, apoptotic body formation, caspase activation, and apoptosis specific changes in cell morphology is demonstrated. The depolarization of mitochondrial membrane and the release of cytochrome c were most early events in etoposide treated SGC-7901 cells, and were followed by caspase-3 activation and PARP cleavage. Caspase-8 activation was not detected under the same condition. Thus, it was proposed that etoposide induces caspase-associated apoptotic cell death in human metastatic gastric carcinoma, which is initiated by mitochondrial cytochrome c release.