Synthesis of the Calicheamicin Aryltetrasaccharide Domain Bearing a Reducing Terminus: Coupling of Fully Synthetic Aglycone and Carbohydrate Domains by the Schmidt Reaction
Synthesis of the Calicheamicin Aryltetrasaccharide Domain Bearing a Reducing Terminus: Coupling of Fully Synthetic Aglycone and Carbohydrate Domains by the Schmidt Reaction
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带有还原末端的加利车霉素芳基四糖结构域的合成：通过施密特反应偶联全合成的糖苷配基和碳水化合物结构域
DOI：
10.1002/anie.199203381
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发表时间：
1992
影响因子：
--
通讯作者：
S. Danishefsky
中科院分区：
文献类型：
--
作者：
R. Halcomb;S. Boyer;S. Danishefsky
机制上新颖的、高效的抗肿瘤剂加利车霉素（I）和埃斯波霉素（2）“”、dl以及新制癌素[2a 1和动力霉素（2）“”]的鉴定已经刺激了合成、生物模拟、和计算方面的各种倡议。['，61此类努力的创造性互动的最终目标是开发更容易获得的化合物，这些化合物比天然产品表现出更高的治疗指数。1的糖苷配基部分被认为是细胞毒性双自由基效应物种类的来源。“]我们的实验室已经完成了完全功能化的糖苷配基calicheamicinone（3）的合成。用合成消旋体进行的实验显示，它保留了药物1的DNA切割特性，尽管效力显著降低。适当活化的糖苷配基保留了从寡核苷酸构建体的C-H键直接夺取氢的一些显著能力[1a，b1]，然而，它在加利车霉素所表现的DNA切割类型中缺乏任何显著的序列选择性。[12最近，已经实现了3及其脱氨基甲酰基形式的中间体的酶促拆分。[14 a. b1这一进展提供了在合成序列中获得对映体纯的“后期”中间体的途径。当然，使用具有明确绝对构型的糖苷配基中间体避免了使用外消旋体作为偶联组分所引起的结构不明确性。
The identification of the mechanistically novel, highly potent antitumor agents calicheamicin (I)['w and esperamicin (2)"', dl as well as neocarzinostatin [2a1 and dynemycin [''] has spurred a variety of initiatives in synthesis,[31 bio~ imulation,[~~ and computation.[', 61 An ultimate goal of the creative interactivity of such efforts is the development of more accessible compounds which manifest higher therapeutic indices than do the natural products.['] The aglycone sector of 1 is recognized as the source of the cytoxic diradical effector species."] Our laboratory has completed the synthesis of the fully functionalized aglycone, calicheamicinone (3).[" l Experiments conducted with the synthetic racemate,["] showed it to retain the DNA-cleaving properties of the drug 1 though with significantly reduced potency. Suitably activated aglycone retains some of the remarkable capacity for direct hydrogen abstraction from C-H bonds of oligonucleotide constructs [1 a, b1 however, it lacks any significant sequence selectivity in DNA cleavage of the type manifested by calicheamicin.[12~ 13] Recently, enzymatic resolution of intermediates en route to 3 and the descarbamoyl version thereof has been achieved.[14 a. b1 This advance provides access to enantiomerically pure''late''intermediates in the synthetic sequence. Of course the use of aglycone intermediates of unambiguous absolute configuration obviates the structural ambiguities arising from the employment of a racemate as a coupling component.