Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners,Journal of Natural Products

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Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners
Journal of Natural Products ( IF 3.3 ) Pub Date : 2018-03-09 00:00:00 , DOI: 10.1021/acs.jnatprod.8b00111
Celine Nadaradjane , Chia-Ping Huang Yang , Alicia Rodriguez-Gabin , Kenny Ye , Keizo Sugasawa ₁ , Onur Atasoylu ₂ , Amos B. Smith ₃ , Susan Band Horwitz , Hayley M. McDaid

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(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, E_Max increased without concomitant improvements in EC₅₀ such that overall dose-response profiles resembled that of (+)-discodermolide.

中文翻译：

（+）-Discodermolide-Taxol杂种同源物的剂量-反应关系的改进

（+）-Discodermolide是一种微管稳定剂，具有治疗紫杉醇难治性恶性肿瘤的潜力。基于计算对接模型合成了包含紫杉醇C-3'-苯基侧链（紫杉醇）的（+）-Discodermolide同系物，该模型预测该部分将填充不足以被（+）-discodermolide占据的β-微管蛋白的芳香口袋，从而改善配体-靶标的相互作用。然而，最近证明，C-3'-苯基侧链占据了一个不同的空间，而是朝着β-微管蛋白的M-环延伸，并在此诱导了螺旋构象，据推测可以改善相邻微管原丝之间的侧向接触。。这一见解促使我们使用一组遗传多样的癌细胞系来评估杂交同源物的生物活性。杂合分子保留了与（+）-discodermolide相同的微管蛋白聚合特性。由于（+）-discodermolide是加速衰老的有效诱导剂，是导致耐药性的命运，因此也筛选了同类药物进行衰老诱导。流式细胞仪和转录分析表明，杂种在很大程度上保留了（+）-discodermolide的衰老诱导特性。在对紫杉醇敏感的细胞模型中，同源物相对于（+）-discodermolide具有更高的剂量反应参数，并且在某些情况下优于紫杉醇。但是，在容易衰老的细胞中，流式细胞仪和转录分析表明，杂种在很大程度上保留了（+）-discodermolide的衰老诱导特性。在对紫杉醇敏感的细胞模型中，同源物相对于（+）-discodermolide具有更高的剂量反应参数，并且在某些情况下优于紫杉醇。但是，在容易衰老的细胞中，流式细胞仪和转录分析表明，杂种在很大程度上保留了（+）-discodermolide的衰老诱导特性。在对紫杉醇敏感的细胞模型中，同源物相对于（+）-discodermolide具有更高的剂量反应参数，并且在某些情况下优于紫杉醇。但是，在容易衰老的细胞中，E _Max增加，而EC ₅₀却没有随之改善，因此总体剂量反应曲线类似于（+）-discodermolide。

更新日期：2018-03-09

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