Design of the anti-tumor agents targeting the functional proteins involved in cancer cell growth

新的组蛋白脱乙酰酶(HDAC)抑制剂的设计我们成功地合成了含有6-氨基-2-萘基的HDAC抑制剂K-32，在P388细胞接种小鼠的实验中显示了显著的存活效应(%T/C，185)。研究发现，K-32对癌细胞增殖的抑制作用涉及p21/WAF1的诱导和G2/M期的阻滞。在2-氨基苯甲型HDAC抑制剂中，具有3，4-二氟苯甲基的K-198在临床分期中对正常成纤维细胞的毒性低于SAHA和MS-275。此外，含有1，3-苯二恶基的K-197表现出与SAHA大致相同的毒性。这两个化合物在人体血浆稳定性试验中表现出较高的回收率。对K-32、K-197和K-198的进一步研究正在进行中，以探索其对人类癌症的治疗效果。设计新的与Her2/neu蛋白结合的低分子抑制剂我们证明了绿色儿茶素：(-)-表没食子儿茶素和(-)-表没食子儿茶素没食子酸酯抑制了高表达Her2/neu的SKBR3的细胞生长。这些儿茶素似乎通过抑制Her2二聚化和/或其磷酸化来抑制细胞生长。此外，我们还发现邻氨基硫酚衍生物K-154是一种抗前列腺癌的化合物，这种化合物可能是通过在K-154的SH与Her2蛋白的半胱氨酸之间形成S-S键而发挥作用的。因此，K-154可以作为先导化合物来寻找替代赫赛汀的癌症治疗药物。

Design of new histone deacetylase (HDAC) inhibitorsWe succeeded in the synthesis of 6-amino-2-naphthyl-containing HDAC inhibitor K-32 which exhibited a marked survival effect (%T/C, 185) in the P388 cell-inoculated mice experiment. It was found out that the inhibitory effect on cancer cell proliferation by K-32 involves p21/WAF1 induction and G2/M phase arrest. Among the 2-aminobenzyl-type HDAC inhibitors, K-198 possessing a 3,4-difluorobenzyl group was less toxic to the normal fibroblast cell than SAHA and MS-275 under clinical stages. Furthermore, K-197 comprising a 1,3-benzodioxol group showed more or less the same toxicity as did SAHA. These two compounds exhibited a high recovery in human plasma stability test. Further study on K-32, K-197 and K-198 is underway to investigate the therapeutic efficacy against human cancers.Design of new low-molecular inhibitors bound to the Her2/neu proteinWe demonstrated that green catechins : (-)-epigallocatechin and (-)-epigallocatechin gallate inhibited the cell growth of Her2/neu-overexpressing SKBR3. These catechins seem to suppress the cell growth through inhibition of Her2 dimerization and/or its phosphorylation. Additionally, we discovered the o-aminothiophenol derivative K-154 as an SKBR3 antiprolierative compound ; this compound might have displayed an efficacy through a S-S bond formation between the SH of K-154 and a cysteine of Her2 protein. Thus, K-154 can be a lead compound to seek a cancer therapeutic agent acting as substitute for Herceptin.