Biogenetically-inspired total synthesis of epidithiodiketopiperazines and related alkaloids.
Biogenetically-inspired total synthesis of epidithiodiketopiperazines and related alkaloids.
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DOI：
10.1021/ar500454v
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发表时间：
2015-04-21
影响因子：
18.3
通讯作者：
Movassaghi M
中科院分区：
文献类型：
--
作者：
Kim J;Movassaghi M
天然产物化学在历史上一直是发现新的化学转化的主要竞技场和洞察关键生物过程的源泉。它仍然是化学和生物学领域进步的热情孵化器，也是这些科学领域之间思想交流的中介。正是由于这种精神，我们的小组已经采取了兴趣，并追求合成一个复杂的家庭的天然产物称为二聚epipolithiodiketopiperazine（ETP）生物碱。我们在这里介绍了我们的雄心壮志所关注的高度复杂的靶分子，我们为这些目标所做的系统和不懈的努力，我们在追求中开发的化学，以及我们对它们作为有效抗癌分子的翻译潜力的洞察力。二聚体ETP生物碱是真菌代谢物，其特征在于高度复杂的分子结构，包括具有许多立体中心的密集官能化核心结构，其中六个是完全取代的，以及一对邻位季碳立体中心，除了已被认为是酸、碱和氧化还原敏感的独特ETP基序之外，还装饰在多环结构上。一个环二肽组成的一个必需的色氨酸残基和一个高度可变的辅助氨基酸是在这些结构的核心;调查的转换，把这个简单的核心复杂的生物碱是在我们的研究计划的核心。自从20世纪70年代首次分离出该类的创始成员毛壳素A（等，，）和轮枝菌素A（等，）以来，二聚体表二硫代二酮哌嗪生物碱由于其复杂性而在很大程度上抵抗合成。这是尽管他们的强大的细胞毒性和抑菌活性，这是很好的赞赏，在他们的发现时。在过去的十年中，越来越多的研究已经发现了这些分子可以独特地影响的强大的新生物过程，例如毛壳素A对组蛋白甲基转移酶的抑制（等人，，）。事实上，六氢吡咯并吲哚生物碱的完整集合具有多种有效的生物学特性，包括细胞毒性、抗肿瘤、抗白血病、抗病毒、抗生素和抗线虫活性（，，）。这种活动的混杂反映了其结构的多样性。在逆生物合成分析的概念下，我们已经完成了十几种天然产物的合成，包括生物连接素，萼状，毛壳素，gliocladin，naseseazine和verticillin生物碱的成员。更重要的是，这些分子已成为开发新策略的重要场所，以解决结构挑战，包括但不限于C3-C3′邻位四元中心、异二聚体连接、C3-Csp 2连接、二酮哌嗪氧化、立体选择性硫醇化、同系物特异性多硫化和C12-羟基掺入。这些天然产物的合成导致了结构的确认，并且有时会进行修改，例如（+）-naseseazines A和B的情况，以及获得许多合理的生物遗传学相关中间体和新的合成ETP衍生物。此外，我们的研究为制定全面的SAR谱和鉴定具有亚纳摩尔IC 50的先导化合物对广泛的癌症类型铺平了道路。
Natural products chemistry has historically been the prime arena for the discovery of new chemical transformations and the fountain of insights into key biological processes. It remains a fervent incubator of progress in the fields of chemistry and biology and an exchange mediating the flow of ideas between these allied fields of science. It is with this ethos that our group has taken an interest in and pursued the synthesis of a complex family of natural products termed the dimeric epipolythiodiketopiperazine (ETP) alkaloids. We present here an Account of the highly complex target molecules to which we pegged our ambitions, our systematic and relentless efforts toward those goals, the chemistry we developed in their pursuit, and the insight we have gained for their translational potential as potent anticancer molecules. The dimeric ETP alkaloids are fungal metabolites that feature a highly complex molecular architecture comprising a densely functionalized core structure with many stereogenic centers, six of which are fully substituted, and a pair of vicinal quaternary carbon stereocenters, decorated on polycyclic architectures in addition to the unique ETP motif that has been recognized as acid-, base-, and redox-sensitive. A cyclo-dipeptide consisting of an essential tryptophan residue and a highly variable ancillary amino acid lies at the core of these structures; investigation of the transformations that take this simplistic core to the complex alkaloids lies at the heart of our research program. The dimeric epidithiodiketopiperazine alkaloids have largely resisted synthesis on account of their complexity since the 1970s when the founding members of this class, chaetocin A ( et al. , , ) and verticillin A ( et al. , , ), were first isolated. This was despite their potent cytotoxic and bacteriostatic activities, which were well appreciated at the time of their discovery. In the past decade, an increasing number of studies have uncovered powerful new biological processes that these molecules can uniquely effect, such as the inhibition of histone methyltransferases by chaetocin A ( et al. , , ). In fact, the complete collection of hexahydropyrroloindoline alkaloids features a diverse range of potent biological properties including cytotoxic, antitumor, antileukemic, antiviral, antibiotic, and antinematodal activities (, , ). This mélange of activities is reflective of their structural diversity. Under the precepts of retrobiosynthetic analysis, we have accomplished the syntheses of more than a dozen natural products, including members of the bionectin, calycanthaceous, chaetocin, gliocladin, naseseazine, and verticillin alkaloids. More importantly, these molecules have acted as venerable venues for the development of new strategies to address structural challenges including, but not limited to, C3–C3′ vicinal quaternary centers, heterodimeric linkages, C3–Csp2 linkages, diketopiperazine oxidation, stereoselective thiolation, homologue-specific polysulfidation, and C12-hydroxyl incorporation. Synthesis of these natural products has resulted in the structural confirmation, and sometimes revision such as the case of (+)-naseseazines A and B, as well as access to many plausible biogenetically relevant intermediates and new synthetic ETP derivatives. Furthermore, our studies have paved the way for the formulation of a comprehensive SAR profile and the identification of lead compounds with in vitro subnanomolar IC50’s against a broad range of cancer types.