STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG MONOTERPENE, INHIBITORS OF PROTEIN ISOPRENYLATION AND CELL-PROLIFERATION
STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG MONOTERPENE, INHIBITORS OF PROTEIN ISOPRENYLATION AND CELL-PROLIFERATION
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DOI：
10.1016/0006-2952(94)90341-7
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发表时间：
1994-04-20
影响因子：
5.8
通讯作者：
GOULD, MN
中科院分区：
文献类型：
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作者：
CROWELL, PL;REN, ZB;GOULD, MN
单萜d-柠檬烯抑制p21 ras和其他小G蛋白的翻译后异戊二烯化，这一机制可能有助于其在化学诱导的啮齿动物癌症的化学预防和治疗中的功效。在本研究中，测定了26种柠檬烯样单萜抑制蛋白质异戊二烯化和细胞增殖的相对能力。许多单萜被发现比柠檬烯更有效地作为小G蛋白异戊二烯化和细胞增殖的抑制剂。柠檬烯衍生的单萜的相对效力被发现为：单羟基=酯=醛>硫醇>酸=二醇=环氧化物>三醇=未取代的。所有抑制蛋白质异戊二烯化的单萜都以选择性的方式这样做，使得21-26 kDa的蛋白质优先受到影响。紫苏醇，最有效的萜烯之一，减少21-26 kDa的蛋白质异戊二烯化的50%的控制水平在1 mM的浓度，但对67，47或17 kDa的蛋白质的异戊二烯化没有影响。特别是，p21 ras法尼基化被抑制40%，由1 mM紫苏醇。在相同浓度下，紫苏醇完全抑制人结肠癌HT-29细胞的增殖。在单萜异戊二烯化抑制剂中观察到的结构-活性关系支持小G蛋白在细胞增殖中的作用，并表明许多柠檬烯衍生的单萜作为抗肿瘤剂值得进一步研究。
The monoterpene d-limonene inhibits the post-translational isoprenylation of p21ras and other small G proteins, a mechanism that may contribute to its efficacy in the chemoprevention and therapy of chemically induced rodent cancers. In the present study, the relative abilities of 26 limonene-like monoterpenes to inhibit protein isoprenylation and cell proliferation were determined. Many monoterpenes were found to be more potent than limonene as inhibitors of small G protein isoprenylation and cell proliferation. The relative potency of limonene-derived monoterpenes was found to be: monohydroxyl = ester = aldehyde> thiol > acid = diol = epoxide > triol = unsubstituted. All monoterpenes that inhibited protein isoprenylation did so in a selective manner, such that 21-26 kDa proteins were preferentially affected. Perillyl alcohol, one of the most potent terpenes, reduced 21-26 kDa protein isoprenylation to 50% of the control level at a concentration of 1 mM, but had no effect on the isoprenylation of 67, 47 or 17 kDa proteins. In particular, p21ras farnesylation was inhibited 40% by 1 mM perillyl alcohol. At the same concentration, perillyl alcohol completely inhibited the proliferation of human HT-29 colon carcinoma cells. The structure-activity relationships observed among the monoterpene isoprenylation inhibitors support a role for small G proteins in cell proliferation, and suggest that many limonene-derived monoterpenes warrant further investigation as antitumor agents.