Synthesis and biological activity of isoprenoid bisphosphonates
Synthesis and biological activity of isoprenoid bisphosphonates
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DOI：
10.1016/j.bmc.2006.02.010
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发表时间：
2006-06-15
影响因子：
3.5
通讯作者：
Wiemer, David F.
中科院分区：
文献类型：
--
作者：
Shull, Larry W.;Wiemer, Andrew J.;Wiemer, David F.
双膦酸盐已在临床上用于治疗骨质疏松症和减少骨吸收以及伴随许多恶性肿瘤的病理性骨折，包括多发性骨髓瘤和前列腺癌、乳腺癌和肺癌。也有证据表明，一些双膦酸盐有直接的抗癌活性。扩大目前的双膦酸盐类别可能会导致通过抑制甲羟戊酸途径更有选择性和更有效地靶向这些癌症的化合物。为此，合成了一组具有不同长度的类异戊二烯链的二烷基二膦酸酯。发现这些化合物中的一些对人源性K562白血病细胞中致癌小GTP酶Ras和Rapla的翻译后加工具有生物活性。最重要的是，这些化合物损害蛋白质香叶基香叶基化，而不是蛋白质法尼基化。(c)2006爱思唯尔有限公司保留所有权利。
Bisphosphonates have been used in the clinic to treat osteoporosis and to reduce bone resorption and the accompanying pathological bone fractures that attend a number of malignancies including multiple myeloma and cancers of the prostate, breast, and lung. There is also evidence that some bisphosphonates have direct anticancer activity. Expansion of the current class of bisphosphonates may lead to compounds that more selectively and potently target these cancers through inhibition of the mevalonate pathway. To this end, a set of dialkyl bisphosphonates bearing isoprenoid chains of varying lengths has been synthesized. Some of these compounds were found to have biological activity on post-translational processing of the oncogenic small GTPases, Ras and Rapla, in human-derived K562 leukemia cells. Most importantly, these compounds impair protein geranylgeranylation and not protein farnesylation. (c) 2006 Elsevier Ltd. All rights reserved.