The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent.
The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent.
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DOI：
10.1021/ar500203h
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发表时间：
2014-08-19
影响因子：
18.3
通讯作者：
Snyder, James P.
中科院分区：
文献类型：
--
作者：
Kingston, David G. I.;Snyder, James P.
紫杉醇 (PTX) 于 1991 年引入临床，已被证明是一种有效的抗微管药物，可用于治疗一系列其他棘手的癌症。它与多西紫杉醇 (DTX) 一起并与顺铂等其他药物联合使用，已被证明是一线疗法。不幸的是，PTX 和 DTX 具有严重的缺点，例如使人衰弱的副作用、耐药性的快速发作以及相当复杂的分子结构，这给合成操作的简便性带来了巨大的挑战。因此，过去 15 年见证了许多基于与 PTX 分子骨架的直观结构相似性关系来合成和测试高度修饰的类似物的努力，以及模拟在大分子微管蛋白-PTX 复合物中观察到的配体构象特征的努力。通过在 PTX 的远端中心之间构建模仿电子晶体学结合姿势的构象异构体的桥，已经实现了效价的高度成功改进，IC50 提高了 50 倍。通过用更简单的部分取代浆果赤霉素核心来截短 PTX 以获得类似 PTX 的效力并应用各种灵活的基于合成的化学物质，进行了许多次尝试，但不太成功。已报道的研究成果以一系列令人着迷的浆果赤霉素替代品为特征，但在微管拆卸试验和针对一系列细胞类型的细胞毒性测量中均未能超越 PTX 的生物活性。大多数结构保留了 PTX C13 侧链的主要元素，同时寻求一种更小的刚性自行车作为浆果赤霉素替代品，并用取代基装饰以模仿 C2 苯甲酰基部分和氧杂环丁烷环。我们推测过去的研究因溶解度和膜渗透性问题而受到阻碍，但主要是由于存在广泛的紫杉烷结合袋以及 PTX 和修剪后的类似物之间分子大小的差异。其中许多分子的分子体积是 PTX 的 50-60%，与微管蛋白的接触较少，与 PTX 药效团严重不匹配，消除导致 ΔGbind 的结合位点水的能力降低，以及意外的结合姿势。如果更简单的 PTX 结构的分子设计是基于感知或已知的 PTX 结合构象，则后者是一个关键缺点。我们得出的结论是，基于紫杉醇药效团的高细胞毒性微管蛋白组装剂的设计和合成仍然是一个未解决的挑战，但可以通过关注紫杉烷结合位点的结构来克服这一挑战，该结构独立于 PTX-微管蛋白复合物所代表的有效但不是唯一的密切配合。
Paclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ease of synthetic manipulation. Consequently, the past 15 years has witnessed many efforts to synthesize and test highly modified analogs based on intuitive structural similarity relationships with the PTX molecular skeleton, as well as efforts to mimic the conformational profile of the ligand observed in the macromolecular tubulin–PTX complex. Highly successful improvements in potency, up to 50-fold increases in IC50, have been achieved by constructing bridges between distal centers in PTX that imitate the conformer of the electron crystallographic binding pose. Much less successful have been numerous attempts to truncate PTX by replacing the baccatin core with simpler moieties to achieve PTX-like potencies and applying a wide range of flexible synthesis-based chemistries. Reported efforts, characterized by a fascinating array of baccatin substitutes, have failed to surpass the bioactivities of PTX in both microtubule disassembly assays and cytotoxicity measurements against a range of cell types. Most of the structures retain the main elements of the PTX C13 side chain, while seeking a smaller rigid bicycle as a baccatin replacement adorned with substituents to mimic the C2 benzoyl moiety and the oxetane ring. We surmise that past studies have been handicapped by solubility and membrane permeability issues, but primarily by the existence of an expansive taxane binding pocket and the discrepancy in molecular size between PTX and the pruned analogs. A number of these molecules offer molecular volumes 50–60% that of PTX, fewer contacts with the tubulin protein, severe mismatches with the PTX pharmacophore, lessened capacity to dispel binding site waters contributing to ΔGbind, and unanticipated binding poses. The latter is a critical drawback if molecular designs of simpler PTX structures are based on a perceived or known PTX binding conformation. We conclude that design and synthesis of a highly cytotoxic tubulin-assembly agent based on the paclitaxel pharmacophore remains an unsolved challenge, but one that can be overcome by focus on the architecture of the taxane binding site independent of the effective, but not unique, hand-in-glove match represented by the PTX–tubulin complex.
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影响因子：
120.1
作者：
Galsky, Matthew D.;Dritselis, Argyris;Oh, William K.
通讯作者：
Oh, William K.
影响因子：
1.8
作者：
Dubois, J;Thoret, S;Guénard, D
通讯作者：
Guénard, D
DOI：
10.1073/pnas.0403459101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Ganesh, T;Guza, RC;Kingston, DGI
通讯作者：
Kingston, DGI
影响因子：
7.3
作者：
Desino, Kelly E.;Ansar, Sabah;Audus, Kenneth L.
通讯作者：
Audus, Kenneth L.
仅具有氧杂环丁烷D环和侧链结构的紫杉醇模拟物的设计、合成和生物学评价
影响因子：
3.4
作者：
Chen, Xing-Xiu;Gao, Feng;Wang, Dan
通讯作者：
Wang, Dan