Letis Antonios S, Seo Ean-Jeong, Nikolaropoulos Sotiris S, Efferth Thomas, Giannis Athanassios, Fousteris Manolis A
Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Patras, Patras GR-26500, Greece.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
Bioorg Med Chem. 2017 Jul 1;25(13):3357-3367. doi: 10.1016/j.bmc.2017.04.021. Epub 2017 Apr 20.
A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20-28 showed IC values in the range of 0.019µM-0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20-28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells.
一系列含有胆酸部分的新型青蒿素衍生物杂种已被合成，并针对其对敏感的CCRF - CEM细胞和多药耐药的CEM/ADR5000细胞的抗白血病活性进行了评估。新型杂种20 - 28对CCRF - CEM细胞的IC值范围为0.019µM - 0.192µM，对CEM/ADR5000细胞的IC值在0.345µM至7.159µM之间。酰胺杂种25被证明是对CCRF - CEM和CEM/ADR5000细胞均最具活性的化合物，其IC值分别为0.019±0.001µM和0.345±0.031µM。对杂种20 - 28的相对低的交叉耐药性在5.7倍至46.1倍范围内被测定。CEM/ADR5000细胞对所有测试化合物的耐药性均高于CCRF - CEM细胞。有趣的是，观察到对23的交叉耐药性最低（5.7倍），而杂种25对CEM/ADR5000细胞显示出18.2倍的交叉耐药性。在针对CEM/ADR5000细胞方面比临床使用的阿霉素更有效的杂种25可能作为一种有前景的抗白血病药物用于对抗敏感和多药耐药细胞。
