Development of a nobel strategy for chemoprevention of colorectal carcinogenesis by using newly synthesized organic compounds derived from natural dietary constituents

姜黄素是姜黄的一种饮食成分，被广泛用作香料。姜黄素是一种经过充分研究的植物化学物质，有可能抑制许多癌细胞的生长，而这种化学物质的毒性较小，因为它被用于日常食物。在本研究中，我们提出了从姜黄素中合成具有更强的抑制肿瘤细胞生长能力而又保持其较低毒性的新化合物的目标，并建立了治疗癌症的诺贝尔奖策略。在第一轮筛选中，我们合成了一种新的姜黄素类似物GO-035，它具有4倍以上的生长抑制能力。我们已经合成了50多个由GO-035衍生的化合物。最终发现两个类似物GO-Y030和GO-Y031对结直肠癌细胞株具有40倍以上的生长抑制能力。这些化合物的共同特征是具有烷氧基在两端的芳环上对称加成的五烷基。与顺铂、5-FU和伊立替康等化疗药物相比，这些化合物对胃、结肠、肺、胰腺、卵巢、黑色素瘤等多种肿瘤细胞株具有更强的生长抑制作用。这些化合物在力学方面的改进是在远低于姜黄素的浓度下，具有更高的诱导G2/M期停滞和细胞凋亡的潜能，并下调多种癌蛋白的表达，包括β-连环蛋白、Ki-Ras、Cyclin-D1、c-Myc和ERBB2。另一方面，即使在100微摩尔的浓度下，也不会对原代肝细胞产生有害影响。给小鼠灌胃0.1%(w/w)的这些化合物对小鼠无毒性作用。这些化合物的这些特点被认为不仅是化疗的理想选择，也是化学预防的理想选择。

Curcumin is a dietary constituent of turmeric that is widely used as a spice. Curcumin is a well-studied phytochemical that has a potential to suppress the growth of many cancer cell lines, while that has less toxicity as it is used for daily food. In this study, we have raised the goal to synthesize the new compounds from curcumin bearing the strengthen ability to suppress the growth of tumor cells, but keeping its less toxicity, and to establish a nobel strategy for medication of cancer treatment. The first cycle of the screening, we synthesized a new curcumin analog, GO-035 that have 4 times higher growth suppressive ability. Then we have synthesized over 50 compounds derived from GO-035. Finally two analogs termed GO-Y030 and GO-Y031 have been found out that have 40 times or more growth suppressive abilities against colorectal cancer cell lines. The common characteristic feature of these compounds is a pentanoid having the symmetrical addition of the alkoxy groups to the aromatic rings at both ends. These compounds have a stronger growth suppressive potential against a variety of cancer cell lines derived from stomach, colon, lung, pancreas, ovary, melanoma and so on, compared with chemotherapeutic agents such as cis-platine, 5-FU and irinotecan. The improvements of mechanical aspects of these compounds are the higher potentials to induce a G2/M phase arrest, apoptosis and down-regulation of various oncoproteins including beta-catenin, Ki-Ras, Cyclin-D1, c-Myc and erbb2 at much lower concentration than curcumin. On the other hands, there is no harmful effect on the primary hepatocytes at even 100 micromolar. There is no toxic effect on the mice fed with these conpounds (0.1% (w/w)in daily diet). These features of the compounds is thought to be ideal for not only chemotherapy but also chemoprevention.