Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin
Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin
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DOI：
10.1021/jo049953w
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发表时间：
2004-12-24
影响因子：
3.6
通讯作者：
Grissom, CB
中科院分区：
文献类型：
--
作者：
Bagnato, JD;Eilers, AL;Grissom, CB
秋水仙碱与对烷氧苯乙酮在C7上衍生，并通过酸不稳定的腙连接剂与钴胺素（维生素B-12）偶联。钴胺素部分导致癌细胞优先吸收钴胺素-秋水仙碱前药，因此腙连接体在溶酶体中水解以暴露秋水仙碱，秋水仙碱作为一种有效的细胞毒素，通过稳定微管并导致细胞死亡。该生物偶联物在细胞培养基和中性pH下是稳定的，但在pH为4.5时水解，半衰期为138 min。秋水仙碱-钴胺素生物偶联物在培养中对乳腺癌、脑癌和黑色素瘤细胞系的LC50值为纳摩尔。秋水仙碱与钴胺素的结合有望通过限制目前微管蛋白靶向化疗药物的非选择性给药引起的副作用来提高药物的治疗指数。
Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B-12) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin-colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine-cobalamin bioconjugate exhibits nanomolar LC50 values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs.