Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents
Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents
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DOI：
10.1016/j.bmc.2004.05.006
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发表时间：
2004-07-15
影响因子：
3.5
通讯作者：
Shoji, M
中科院分区：
文献类型：
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作者：
Adams, BK;Ferstl, EM;Shoji, M
埃默里大学和国家癌症研究所(NCI)合成了一系列新型姜黄素类似物，并对其抗癌和抗血管生成活性进行了筛选。这些化合物是对称的α、β-不饱和酮和饱和酮。大多数类似物显示出中等程度的抗癌活性。化合物10、11和14在NCI体外抗肿瘤细胞系筛选中表现出高度的细胞毒性。此外，这一筛选显示，这些化合物抑制肿瘤细胞生长的效力高于常用的化疗药物顺铂。在埃默里大学进行的独立体外筛选中，相同的化合物加4、5、8、9和13对肿瘤细胞显示出高度的细胞毒性。在抗癌筛选中有效的类似物在体外抗血管生成试验中也是有效的。化合物4、9、11和14在埃默里大学进行的抗血管生成试验中效果最好。在NCI进行的分析中，化合物14的效力几乎与抗血管生成药物TNP-470相同，后者已进行临床试验。在14个化合物的体外抗癌和抗血管生成效果良好的基础上，进行了进一步的体内试验。该化合物有效地缩小了在雌性裸鼠体内生长的人乳腺肿瘤的大小，并且毒性很小。这一数据，再加上引人注目的体外数据，表明化合物14可能是一种有效的化疗药物。作为后续工作，建立了基于14的三维定量结构关系。其交叉验证的r(2)(q(2))=0.83，预测的r(2)(p(2))=0.71。比较分析表明，该化合物可能是一种RNA/DNA抗代谢物质，但也暗示该化合物的细胞毒性可能来自一种目前未知的机制。(C)2004爱思唯尔有限公司。保留所有权利。
A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r(2)(q(2)) = 0.83 and a predictive r(2)(p(2)) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism. (C) 2004 Elsevier Ltd. All rights reserved.