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膳食成分，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，具有抑制许多癌细胞系生长的潜力，同时毒性较小，因为它用于日常食物。本研究提出了以姜黄素为原料，合成具有较强抑制肿瘤细胞生长能力，同时又保持其较低毒性的新化合物，为肿瘤治疗药物的开发提供一条新的思路。在第一轮筛选中，我们合成了一种新的姜黄素类似物GO-035，其生长抑制能力提高了4倍。然后我们合成了50多个GO-035衍生物。最后，已经发现了两种称为GO-Y 030和GO-Y 031的类似物，其对结肠直肠癌细胞系的生长抑制能力为40倍或更高。这些化合物的共同特征是具有烷氧基对称加成到芳环两端的类戊烷。与顺铂、5-FU和伊立替康等化疗药物相比，这些化合物对来自胃、结肠、肺、胰腺、卵巢、黑色素瘤等的多种癌细胞系具有更强的生长抑制潜力。这些化合物的机械方面的改进是在比姜黄素低得多的浓度下诱导G2/M期停滞、细胞凋亡和各种癌蛋白包括β-连环蛋白、Ki-Ras、细胞周期蛋白-D1、c-Myc和erbb 2的下调的更高潜力。另一方面，即使在100微摩尔浓度下，对原代肝细胞也没有有害影响。对喂食这些化合物（每日饮食中0.1%（w/w））的小鼠无毒性作用。这些化合物的这些特征被认为不仅对于化疗而且对于化学预防是理想的。

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.