Anti-cancer agents in medicinal chemistry, 2015, 15.

Design, Synthesis, and Evaluation of Genistein Analogues as Anti-Cancer Agents

Pahoua Xiong, Rubing Wang, Xiaojie Zhang, et al

Department of Chemistry, California State University Fresno, 2555 E. San Ramon Avenue M/S SB 70

Genistein is a bioactive isoflavone derived from soybeans. The tie-in between the intake of genistein and the decreased incidence of some solid tumors (including prostate cancer) has been demonstrated by epidemiological studies. The potential of genistein in treating prostate cancer has also been displayed by in vitro cell-based and in vivo animal experiments. Genistein has entered clinical trials for both chemoprevention and potential treatment of prostate cancer. Even though the low oral bioavailability has presented the major challenges to genistein's further clinical development, chemical modulation of genistein holds the promise to generate potential anti-prostate cancer agents with enhanced potency and/or better pharmacokinetic profiles than genistein. As part of our ongoing project to develop natural products-based anti-prostate cancer agents, the current study was undertaken to synthesize eight genistein analogues for cytotoxic evaluation in three prostate cancer cell lines (PC-3, DU-145, LNCaP; both androgen-sensitive and androgen-refractory cell lines), as well as one aggressive cervical cancer cell line (HeLa). Eight genistein analogues have been successfully synthesized with Suzuki-Miyaura coupling reaction as a key step. Their in vitro anti-cancer potential was evaluated by trypan blue exclusion assay and WST-1 cell proliferation assay against a panel of four human cancer cell lines. The acquired data suggest i) that the C-5 and C-7 hydroxyl groups in genistein are very important for the cytotoxicity and anti-proliferative activity; and ii) that 1-alkyl-1H-pyrazol-4-yl and pyridine-3-yl might act as good bioisosteres for the 4'-hydroxyphenyl moiety in genistein.

荷兰《药物化学中的抗癌药物》，2015年

抗癌试剂金雀异黄素类似物的设计、 合成和评估

熊帕厚，王如冰，张晓杰，等

美国加利福尼亚州立大学弗雷斯诺分校化学学院

金雀异黄素是一种大豆衍生的具有生物活性的异黄酮。金雀异黄素的摄入和一些固体肿瘤 （包括前列腺癌） 的发病率下降之间的关系已经通过流行病学研究得到证明。金雀异黄素治疗前列腺癌的潜力同样在体外细胞实验和体内动物实验得到证实。金雀异黄素的化学预防和潜在治疗前列腺癌作用已进入临床试验阶段。尽管口服生物利用度低为金雀异黄素的进一步临床发展提出了重大挑战，对金雀异黄素的化学调节可以制得潜在的药代动力学和疗效更强的抗前列腺癌的试剂。目前我们正在开发基于天然产品的抗前列腺癌试剂，合成了8种金雀异黄素类似物，在三种前列腺癌细胞 (PC-3，DU 145，LNCaP;；两种雄激素敏感以及雄激素难治性细胞)，以及一种侵略性子宫颈癌细胞 (HeLa) 中进行细胞毒性评价。以铃木偶联反应为关键步骤成功合成了8种金雀异黄素类似物。通过台盼蓝排斥试验和 WST-1 淋巴细胞增殖测试评价它们对体外四种人体肿瘤细胞的抗癌潜力。所获得的数据表明i）金雀异黄素的 C-5 和 C-7 氢氧基官能团对细胞毒性和抗增殖活性非常重要；和ii） 1-烷基 -氢-吡唑-4-基和吡啶-3-基可能作为生物电子等排体用于金雀异黄素的 4'-羟基苯基基团。