Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1.
Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1.
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DOI：
10.1002/anie.201001200
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发表时间：
2010-06-21
影响因子：
16.6
通讯作者：
Blumberg, Peter M.
中科院分区：
文献类型：
--
作者：
Keck, Gary E.;Poudel, Yam B.;Rudra, Arnab;Stephens, Jeffrey C.;Kedei, Noemi;Lewin, Nancy E.;Peach, Megan L.;Blumberg, Peter M.
苔藓抑素是一类海洋来源的天然产物，具有令人着迷的结构复杂性和令人着迷的生物活性。 [1]这些材料是从 Bugula neritina 中分离出来的，并且通过 Pettit 和同事的开创性工作确定了它们的结构。 [2]随后，大规模的收集和分离工作成功地从约 13000 公斤的源生物体中获得了约 18 克苔藓抑素 1，这是该家族中含量最丰富且目前研究最彻底的成员。 [3]全球材料供应支持了大量的生物学研究和大约 80 项针对各种癌症的临床试验。[4]最近，一项针对阿尔茨海默病的临床试验也已开始。 [5]尽管人们对苔藓抑素作为潜在治疗药物产生了浓厚的兴趣，但苔藓抑素 1 引发其生物反应的机制仅部分了解。已确定苔藓抑素 1 以高亲和力与蛋白激酶 C (PKC) 同工酶的调节 C1 结构域结合，从而激活这些酶。 [6]同样，它与其他六个信号蛋白家族（例如嵌合蛋白和 RasGRP）的同源调节 C1 结构域结合，以调节它们的活性。 [7]从生理学角度来说，所有这些蛋白质都通过其 C1 结构域发挥亲脂性第二信使 sn-1, 2-二酰基甘油的传感器的作用。然而，矛盾的是，虽然苔藓抑素 1 与二酰基甘油或其高亲和力类似物、佛波酯结合到相同的结合位点，但苔藓抑素 1 仅诱导用这些其他配体观察到的反应的一部分。 [8]此外，苔藓抑素1可阻断其本身不诱导的反应，特别是不促进肿瘤，这与大多数佛波酯（例如佛波醇12-肉豆蔻酸酯-13-乙酸酯，PMA）相反。尽管该家族化合物的合成引起了强烈的关注，但尚未合成苔藓抑素 1，尽管已经制备了结构相似且高亲和力的苔藓抑素 2、3 和 7。 [9]此外，还制备了苔藓抑素 16，其对 PKC 的亲和力（Ki= 118 nm）相对于苔藓抑素 1（Ki= 1.35 nm）明显降低。 [10]主要由 Wender 小组和我们小组也制备了几种苔藓抑素类似物。 [1, 11] 最近，我们小组一直致力于阐明苔藓抑素的结构特征，这些特征决定了其作为佛波酯拮抗剂的功能，而不是仅仅作为 PKC 配体的活性。我们之前曾报道过苔藓吡喃核心结构 [12] 和具有极大简化的 A 环和 B 环的苔藓吡喃类似物的合成，这些环可用作佛波酯模拟物，[13] 并表明苔藓抑素 1 的 A 环上的功能对于保持苔藓抑素样生物效应至关重要。 [14]在此，我们描述了旨在揭示 A 环的 C9 羟基取代基对苔藓抑素 1 引起的生物反应的影响的研究结果。在先前提出的苔藓抑素 1 与 PKC 的 C1 结构域结合的模型中，Itai 和同事的计算推导模型提出了 C9-OH 和 PKC 的 C1 结构域之间的显式氢键相互作用（四种之一）。蛋白质。[15]我们首先独立检查了苔藓抑素 1 及其 C9-脱氧类似物与 C1 结构域的对接。在开始对接之前，我们首先在水和辛醇溶剂中对苔藓抑素 1 进行构象搜索。在两种溶剂中发现的全局能量最小构象与晶体 [2] 和 NMR [16 …
The bryostatins are a family of natural products of marine origin that display both intriguing structural complexity and a fascinating profile of biological activity.[1] These materials were isolated (from Bugula neritina) and their structures determined through the pioneering work of Pettit and coworkers.[2] Subsequently, a monumental large-scale collection and isolation effort managed to yield some 18 g of bryostatin 1, the most abundant and now most thoroughly investigated member of this family, from some 13000 kg of the source organism.[3] This world s supply of material has supported numerous biological investigations and roughly 80 clinical trials against various cancers.[4] Recently, a clinical trial against Alzheimer s disease has also commenced.[5] Despite this intense interest in the bryostatins as potential therapeutics, the mechanisms by which bryostatin 1 elicits its biological responses are only partially understood. It has been established that bryostatin 1 binds with high affinity to the regulatory C1 domains of protein kinase C (PKC) isozymes and thereby activates these enzymes.[6] Likewise, it binds to the homologous regulatory C1 domains of six other families of signaling proteins, for example, the chimaerins and RasGRPs, to modulate their activities.[7] Physiologically, all of these proteins function, through their C1 domains, as sensors for the lipophilic second messenger sn-1, 2-diacylglycerols. Paradoxically, however, whereas bryostatin 1 binds to the same binding site as do the diacylglycerols or their highaffinity analogues, the phorbol esters, bryostatin 1 induces only a subset of the responses observed with these other ligands.[8] Moreover, bryostatin 1 blocks those responses that it does not itself induce and, in particular, is not tumor promoting, which is in contrast to most phorbol esters (eg, phorbol 12-myristate-13-acetate, PMA). Despite the intense synthetic attention this family of compounds has attracted, bryostatin 1 has not as yet been synthesized, although the structurally similar and high-affinity bryostatins 2, 3, and 7 have been prepared.[9] In addition, bryostatin 16, which has markedly diminished affinity for PKC (Ki= 118 nm) relative to bryostatin1 (Ki= 1.35 nm), has also been prepared.[10] Several analogues of bryostatin have also been prepared, primarily by the group of Wender and by our group.[1, 11] Recently, our group has been focused on elucidating the structural features of bryostatin that are responsible for its function as a phorbol ester antagonist, as distinct from its activity simply as a ligand for PKC. We have previously reported on the synthesis of the bryopyran core structure [12] and of bryopyran analogues with greatly simplified A and B rings that function as phorbol ester mimics,[13] and have shown that functionality on the Aring of bryostatin1 is critical in preserving bryostatin-like biological effects.[14] Herein, we describe the results of studies designed to reveal the influence of the C9 hydroxy substituent of the A ring on the biological responses elicited by bryostatin 1. Among the models that have been put forward previously for the binding of bryostatin 1 to the C1 domain of PKC, the computationally derived model of Itai and co-workers proposed an explicit hydrogen-bonding interaction (one of four) between the C9ÀOH and the C1 domain of the protein.[15] We began by independently examining the docking of bryostatin 1 and its C9-deoxy analogue to the C1 domain. Before beginning the docking we first performed a conformational search of bryostatin 1 in implicit water and octanol solvents. The global energy-minimum conformation found in both solvents was essentially identical to the crystal [2] and NMR [16 …
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影响因子：
5.2
作者：
Manaviazar, Soraya;Frigerio, Mark;Hale, Karl J.
通讯作者：
Hale, Karl J.
影响因子：
5.1
作者：
SCHAUFELBERGER, DE;KOLECK, MP;FORENZA, S
通讯作者：
FORENZA, S
影响因子：
15
作者：
Choi, TL;Lee, CW;Grubbs, RH
通讯作者：
Grubbs, RH
影响因子：
2.1
作者：
Kamano, Y;Zhang, HP;Herald, CL
通讯作者：
Herald, CL
影响因子：
1.8
作者：
TANAKA, K;OHTA, Y;TAGA, T
通讯作者：
TAGA, T