通过二氢青蒿素和青蒿素的杂交和二聚化实现抗黑色素瘤药物的立体选择性。
Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid.
机构信息
Department of Biological and Ecological Sciences, Univeristy of Viterbo, Via S.C. De Lellis s.n.c., 01100, Viterbo, Italy.
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
出版信息
ChemMedChem. 2021 Jul 20;16(14):2270-2277. doi: 10.1002/cmdc.202100196. Epub 2021 May 7.
A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC >300 μM) and high antimelanoma activity (IC =0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.
已经以立体控制方式合成了五种二氢青蒿素和青蒿琥酯的杂种和六种二聚体的文库，并针对转移性黑色素瘤细胞系（RPMI7951）评估了其抗癌活性。在新型衍生物中，三种青蒿琥酯二聚体表现出抗黑色素瘤活性和癌症选择性，对正常人类成纤维细胞（C3PV）系没有毒性。在这三个二聚体中，带有 4-羟基苯甲醇作为间隔基的二聚体没有细胞毒性作用（CC>300μM），并且具有高抗黑色素瘤活性（IC=0.05μM），比母体青蒿琥酯高两个数量级，与商业药物紫杉醇相当。此外，与前列腺（PC3）和乳腺癌（MDA-MB-231）肿瘤相比，该二聚体对黑色素瘤表现出癌症类型选择性。通过 DFO 和 EPR 分析假设了自由基机制的发生。定性结构活性关系强调了青蒿琥酯支架在控制毒性和抗黑色素瘤活性方面的作用。
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