Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA:: Evaluation of yatakemycin key partial structures and its unnatural enantiomer
Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA:: Evaluation of yatakemycin key partial structures and its unnatural enantiomer
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DOI：
10.1021/ja064228j
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发表时间：
2006-12-13
影响因子：
15
通讯作者：
Boger, Dale L.
中科院分区：
文献类型：
--
作者：
Tichenor, Mark S.;Trzupek, John D.;Boger, Dale L.
作为对提供第一个yatakemycin全合成导致其结构修正和绝对立体化学归属的研究的补充，本文公开了第二代不对称全合成。由于各个Yatakemycin亚基与倍癌霉素SA（烷基化亚基）或CC-1065（中心和右侧亚基）的亚基相同，因此这些研究还提供了我们早期CC-1065全合成的改进，并且如本文所详述的，已经扩展到（+）-倍癌霉素SA的不对称全合成。进一步扩展的研究提供了关键的yatakemycin部分结构和类似物进行比较评估。这包括DNA选择性的定义（腺嘌呤中心的五个碱基对AT序列，例如。例如，在一个实施例中，对ent-（-）-yatakemycin的药效、相对速率、可逆性及其与天然对映体的比较（相同的选择性和效率），腺嘌呤N3加合物的结构表征证实了DNA反应的性质，并比较了天然产物的细胞毒性活性（L1210，IC 50 = 5 pM）与其非天然对映体的那些（IC 50 = 5 pM）和一系列关键部分结构，包括探测C-末端硫代甲酯的作用的那些。对映异构体之间的唯一区别特征是ent-（-）yatakemycin以较慢的速率（k（rel）= 0.13）烷基化DNA并且是可逆的，而（+）-yatakemycin不是。尽管如此，即使是ent-（-）-yatakemycin也比（+）-倍癌霉素SA以更快的速率和更大的热力学稳定性烷基化DNA，说明了这种“夹心”试剂的独特特征。
Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e. g., 5'-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)yatakemycin alkylates DNA at a slower rate (k(rel) = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.