Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.
Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.
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DOI：
10.1021/acsomega.1c07146
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发表时间：
2022-03-15
期刊：
影响因子：
4.1
通讯作者：
Johnson TA
中科院分区：
文献类型：
--
作者：
Morris JD;Takahashi-Ruiz L;Persi LN;Summers JC;McCauley EP;Chan PYW;Amberchan G;Lizama-Chamu I;Coppage DA;Crews P;Risinger AL;Johnson TA
本文中，我们报道了对三阴性乳腺癌（TNBC）细胞系具有活性的天然来源的微管稳定剂，包括紫杉醇、斐济素B/laulimalide（3）、斐济素B二乙酸酯（4）和3的两种新的半合成类似物，包括斐济素J（5）和斐济素L（6）。与紫杉醇类似，化合物3在五种分子上不同的TNBC细胞系中表现出经典的微管稳定活性和有效的（GI 50 = 0.7-17 nM）抗增殖功效。或者，分别由C-20或C-15和C-20的氧化产生的化合物5或6导致具有降低的效力（GI 50 = 4-9 μM）的独特特征，但在一些系中改善了功效，这表明了不同的作用机制。在4和6上的C-15、C-20二乙酸酯和二氧代修饰导致在生化测定中缺乏经典微管稳定活性的化合物。虽然4对细胞微管也没有可检测到的影响，但6促进了细胞骨架的重组，导致微管在细胞周边的积累。具有单个C-20氧代取代的化合物5显示混合表型，共享3和6的性质。这些结果证明了C-15/C-20手性中心的重要性，这似乎是该化学型的有效微管稳定活性所需的，并且这些位点的氧化促进了与经典微管稳定不同的意外的细胞骨架改变，可能通过不同的作用机制。
Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (3), fijianolide B di-acetate (4), and two new semisynthetic analogs of 3, which include fijianolide J (5) and fijianolide L (6). Similar to paclitaxel, compound 3 demonstrated classic microtubule stabilizing activity with potent (GI50 = 0.7–17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines. Alternatively, compounds 5 or 6, generated from oxidation of C-20 or C-15 and C-20 respectively, resulted in a unique profile with reduced potency (GI50 = 4–9 μM), but improved efficacy in some lines, suggesting a distinct mechanism of action. The C-15, C-20 di-acetate, and dioxo modifications on 4 and 6 resulted in compounds devoid of classic microtubule stabilizing activity in biochemical assays. While 4 also had no detectable effect on cellular microtubules, 6 promoted a reorganization of the cytoskeleton resulting in an accumulation of microtubules at the cell periphery. Compound 5, with a single C-20 oxo substitution, displayed a mixed phenotype, sharing properties of 3 and 6. These results demonstrate the importance of the C-15/C-20 chiral centers, which appear to be required for the potent microtubule stabilizing activity of this chemotype and that oxidation of these sites promotes unanticipated cytoskeletal alterations that are distinct from classic microtubule stabilization, likely through a distinct mechanism of action.
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