Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25
Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25
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DOI：
10.1021/acs.jnatprod.7b00967
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发表时间：
2018-03-01
影响因子：
5.1
通讯作者：
Mooberry, Susan L.
中科院分区：
文献类型：
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作者：
Ola, Antonius R. B.;Risinger, April L.;Mooberry, Susan L.
塔卡内酯是从塔卡属植物中分离出来的一类独特的微管稳定剂，对耐药肿瘤有疗效。我们之前的研究表明，与含有C-15羟基的AJ相比，C-15乙酰氧基他卡洛内酯（AF）具有更好的体内抗肿瘤功效。为了进一步提高这类化合物的体内药效，我们半合成并测试了28个新的C-7或C-15单取代或C-7和C-25双取代的他卡隆内酯类化合物的生物活性，涵盖了从甲酸到蒽醌-2-羰基氯的广泛取代基。所得到的具有不同C-7/C-15/C-25修饰的他卡卡内酯类似物的IC50值从2.4 nM到bbb20 μ M，可以进行广泛的体外结构活性评估。由于C-7或C-15取代基的水解，无论大小或空间体积如何，这种半合成策略都无法提供具有改善治疗窗口的他卡洛内酯。然而，两种最有效的新型他卡洛内酯，在C-7或C-15处具有异戊酸修饰，在肿瘤内给药时，在耐药异种移植模型中显示出有效且高度持久的抗肿瘤活性。这项研究表明，靶向递送他卡洛内酯到肿瘤可能是一个有效的，持久的方法来治疗耐药肿瘤。
The taccalonolides are a unique class of microtubule stabilizers isolated from Tacca spp. that have efficacy against drug resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semisynthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC50 values from 2.4 nM to >20 mu M, allowing for extensive in vitro structure activity evaluations. This semisynthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors.