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首页> 外文期刊>Chemistry: A European journal >Combined muta- and semisynthesis: A powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3
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Combined muta- and semisynthesis: A powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3

机译：混合诱变和半合成：一种强大的合成杂合方法，可用于获得基于安妥霉素P3的靶标特异性抗肿瘤药

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摘要

Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC _(50) <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis. Synthetic power: Four novel folate-ansamitocin conjugates were prepared by a combined muta-/semisynthetic approach. They exert strong selectivity between cell lines that have expressed and that are devoid of folate receptors (FR). The study demonstrates both the power of target-specific chemotherapy with ansamitocins and reveals the diverse options mutasynthesis combined with semisynthesis provides.
机译：据报道，四种新的肿瘤特异性叶酸/阿米托星偶联物的获得依赖于基于突变合成和半合成相结合的合成策略。分别通过突变合成或通过改良的发酵方案制备了两种溴-安那托霉素衍生物，它们用作在斯蒂勒条件下半合成引入烯丙基胺接头的起点。一系列的标准偶联步骤将蝶酸/谷氨酸/半胱氨酸单元引入到修饰的安托霉素中。所有新的衍生物，包括那些预期在将叶酸/阿米霉素结合物内化到癌细胞中以及二硫键的还原性裂解后产生的衍生物，对不同的化合物显示出良好的至强的抗增殖活性（IC _（50）<10 nM）。癌细胞系。最后，将四种结合物暴露于两种癌细胞系[子宫颈癌，KB-3-1（FR +）和肺癌，A-459（FR-）]，后者没有膜结合叶酸受体（FR -）。所有四种缀合物对FR +癌细胞系均显示出强的抗增殖活性，但对FR-癌细胞系无活性。追求的合成策略是基于突变合成和半合成的组合，并被证明对获取难以通过全合成制备的新的安索霉素衍生物具有强大的作用。合成能力：通过组合的突变/半合成方法制备了四种新颖的叶酸-安托霉素结合物。它们在已表达且不含叶酸受体（FR）的细胞系之间发挥强大的选择性。这项研究证明了用安神霉素进行靶点特异性化疗的功效，并揭示了可变合成与半合成相结合提供的多种选择。

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