Bayrak Nilüfer, Sever Belgin, Ciftci Halilibrahim, Otsuka Masami, Fujita Mikako, TuYuN Amaç Fatih
Department of Chemistry, Faculty of Science, Istanbul University, Fatih, İstanbul 34126, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey.
Biomedicines. 2023 Dec 24;12(1):50. doi: 10.3390/biomedicines12010050.
The development of new anticancer drugs is still ongoing as a solution to the unsatisfactory results obtained by chemotherapy patients. Our previous studies on natural product-based anticancer agents led us to synthesize a new series of Plastoquinone (PQ) analogs and study their anticancer effects. Four members of PQ analogs (-) were designed based on the scaffold hopping strategy; the design was later completed with structural modification. The obtained PQ analogs were synthesized and biologically evaluated against different cancer genotypes according to NCI-60 screening in vitro. According to the NCI results, bromo and iodo-substituted PQ analogs ( and ) showed remarkable anticancer activities with a wide-spectrum profile. Among the two selected analogs ( and ), showed promising anticancer activity, in particular against leukemia cell lines, at both single- and five-dose NCI screenings. This compound was also detected by MTT assay to reveal significant selectivity between Jurkat cells and PBMC (healthy) compared to imatinib. Further in silico studies indicated that was able to occupy the ATP-binding cleft of Abl TK, one of the main targets of leukemia, through key interactions similar to dasatinib and imatinib. is also bound to the minor groove of the double helix of DNA. Based on computational pharmacokinetic studies, possessed a remarkable drug-like profile, making it a potential anti-leukemia drug candidate for future studies.
作为解决化疗患者疗效不尽人意问题的一种方法，新型抗癌药物的研发仍在进行中。我们之前对基于天然产物的抗癌药物的研究促使我们合成了一系列新的质体醌（PQ）类似物，并研究它们的抗癌效果。基于骨架跃迁策略设计了四种PQ类似物（-）；随后通过结构修饰完成了设计。根据美国国立癌症研究所（NCI）的体外筛选，合成了所得到的PQ类似物，并针对不同癌症基因型进行了生物学评估。根据NCI的结果，溴代和碘代PQ类似物（和）显示出具有广谱特征的显著抗癌活性。在两种选定的类似物（和）中，在NCI的单剂量和五剂量筛选中均显示出有前景的抗癌活性，尤其是对白血病细胞系。通过MTT试验还检测到，与伊马替尼相比，该化合物在Jurkat细胞和外周血单核细胞（健康细胞）之间具有显著的选择性。进一步的计算机模拟研究表明，能够通过与达沙替尼和伊马替尼类似的关键相互作用占据白血病的主要靶点之一Abl TK的ATP结合裂隙。还与DNA双螺旋的小沟结合。基于计算机药代动力学研究，具有显著的类药特性，使其成为未来研究中潜在的抗白血病药物候选物。
