Synthesis and NMR-driven conformational analysis of taxol analogues conformationally constrained on the C13 side chain
Synthesis and NMR-driven conformational analysis of taxol analogues conformationally constrained on the C13 side chain
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DOI：
10.1021/jm001103v
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发表时间：
2001-05-10
影响因子：
7.3
通讯作者：
Snyder, JP
中科院分区：
文献类型：
--
作者：
Barboni, L;Lambertucci, C;Snyder, JP
合成了紫杉醇(紫杉醇)类似物，其侧链通过在2‘-碳和3’-苯环的邻位之间插入碳连接物而受到构象限制。对这些新紫杉类化合物的生物学评价表明，活性依赖于连接子的长度以及C2‘和C3’的构型。HOME系列中的两个类似物9a和24a显示出与紫杉醇类似的微管蛋白结合和细胞毒性。NAMFIS(溶液中分子柔性的核磁共振分析)对9a的平均二维核磁共振谱进行反卷积得到七种构象。在后一组中，疏水坍塌的“非极性”和“极性”类别由一种构象表示，每种构象预测的种群数量为12-15%。然而，剩下的五个构象被延伸，其中两个对应于T-构象(占总人口的47%)。后者与最近提出的T-紫杉醇结合构象很好地叠加在β-微管蛋白中。结果证明存在两个以前未被认识的结构特征，它们支持紫杉醇类活性：(1)C2‘和C3’之间的扭转角减小；(2)通过C1‘，C2’和2‘-羟基和3’-苯基的平均平面的正交排列，后者被前一个平面一分为二。相反，在2‘，3’处的异构化和将系链与CH2-CH2同源都不利于活性。这些类似物的活性降低显然分别是由于构型因素和空间因素。
Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2 ' -carbon and the ortho-position of the 3 ' -phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2 ' and C3 '. Two analogues in the home series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta -tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2 ' and C3 ' and (2) an orthogonal arrangement of the mean plane through C1 ', C2 ' and the 2 ' -hydroxyl and the 3 ' -phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2 ' ,3 ' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.