Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates.
Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates.
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DOI：
10.1021/jo100448q
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发表时间：
2010-04
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通讯作者：
I. Vlahov;H. Santhapuram;Fei You;Yu Wang;Paul J. Kleindl;Spencer J. Hahn;Jeremy F. Vaughn;Daniel S. Reno;C. Leamon
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作者：
I. Vlahov;H. Santhapuram;Fei You;Yu Wang;Paul J. Kleindl;Spencer J. Hahn;Jeremy F. Vaughn;Daniel S. Reno;C. Leamon
为了更好地调节长春花碱-叶酸结合物的生物分布，合成了一种新的叶酸间隔物EC145，它将1-氨基-1-脱氧-D-葡萄糖醇-γ-谷氨酸亚基结合到一个肽骨架中。以葡萄糖内酯为原料，经四步反应合成了适用于Fmoc策略固相肽合成的Fmoc-3，4；5，6-di-O-isopropylidene-1-amino-1-deoxy-D-glucitol-gamma-glutamate 20。将交替的谷氨酸和20个部分添加到半胱氨酸负载的树脂上，然后添加叶酸、去保护和裂解，得到了新的叶酸间隔：Pte-gammaGlu-(Glu(1-amino-1-deoxy-D-glucitol)-Glu)(2)-Glu(1-amino-1-deoxy-D-glucitol)-Cys-OH(21)。将21添加到适当修饰的脱乙酰长春花肼(DAVLBH)中，得到具有改进的治疗指数的结合物(25)。在室温中性缓冲液中用DTT处理25例表明，在内化内体的还原环境下，游离的DAVLBH将被释放。
To better regulate the biodistribution of the vinblastine-folate conjugate, EC145, a new folate-spacer that incorporates 1-amino-1-deoxy-D-glucitol-gamma-glutamate subunits into a peptidic backbone, was synthesized. Synthesis of Fmoc-3,4;5,6-di-O-isopropylidene-1-amino-1-deoxy-D-glucitol-gamma-glutamate 20, suitable for Fmoc-strategy solid-phase peptide synthesis (SPPS), was achieved in four steps from delta-gluconolactone. Addition of alternating glutamic acid and 20 moieties onto a cysteine-loaded resin, followed by the addition of folate, deprotection, and cleavage, resulted in the isolation of the new folate-spacer: Pte-gammaGlu-(Glu(1-amino-1-deoxy-D-glucitol)-Glu)(2)-Glu(1-amino-1-deoxy-D-glucitol)-Cys-OH (21). The addition of 21 to an appropriately modified desacetylvinblastine hydrazide (DAVLBH) resulted in a conjugate (25) with an improved therapeutic index. Treatment of 25 with DTT in neutral buffer at room temperature demonstrated that free DAVLBH would be released under the reductive environment of the internalized endosome.