Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices.
Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices.
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DOI：
10.1002/chem.201803725
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发表时间：
2018-11-13
期刊：
影响因子：
--
通讯作者：
Unciti-Broceta A
中科院分区：
文献类型：
--
作者：
Adam C;Pérez-López AM;Hamilton L;Rubio-Ruiz B;Bray TL;Sieger D;Brennan PM;Unciti-Broceta A
SN-38是伊立替康的活性代谢产物，在肝脏水解时释放，介导强效抗肿瘤活性。然而，全身暴露于SN-38也会导致严重的副作用。为了通过控制SN-38产生的地点和时间来降低全身毒性，专门设计了一种新的前药，使其代谢稳定并经历快速钯介导的活化。用2，6-双（炔丙氧基）苄基阻断SN-38的酚羟基导致细胞毒性活性显著降低（高达44倍）。在非均相钯（Pd）催化剂的存在下，抗癌性能迅速恢复，以杀死结直肠癌和神经胶质瘤细胞，证明了这种新型的芳香族羟基掩蔽策略的有效性。与Pd活化的5 FU前药的组合增强了治疗的抗增殖效力，同时在不存在Pd源的情况下不显示活性，这说明了通过相同的生物正交催化剂实现多种批准的治疗剂的控制释放（顺序地或交替地）以增加抗癌活性的益处。
SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity.
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DOI：
10.3747/co.2007.147
发表时间：
2007-10-01
期刊：
Current oncology (Toronto, Ont.)
影响因子：
--
作者：
Perry, J;Chambers, A;Laperriere, N
通讯作者：
Laperriere, N
DOI：
10.1002/anie.201705609
发表时间：
2017-10-02
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Pérez-López AM;Rubio-Ruiz B;Sebastián V;Hamilton L;Adam C;Bray TL;Irusta S;Brennan PM;Lloyd-Jones GC;Sieger D;Santamaría J;Unciti-Broceta A
通讯作者：
Unciti-Broceta A
影响因子：
3
作者：
Nakatsu, S;Kondo, S;Barnett, GH
通讯作者：
Barnett, GH
影响因子：
12.9
作者：
Martínez-Calvo M;Couceiro JR;Destito P;Rodríguez J;Mosquera J;Mascareñas JL
通讯作者：
Mascareñas JL
影响因子：
21.8
作者：
Li, Jie;Yu, Juntao;Chen, Peng R.
通讯作者：
Chen, Peng R.