Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells

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• 作者：Hua-Li Qin ; Jing Leng ; Cheng-Pan Zhang ; Ibrahim Jantan ; Muhammad Wahab Amjad ; Muhammad Sher ; Muhammad Naeem-ul-Hassan ; Muhammad Ajaz Hussain ; Syed Nasir Abbas Bukhari
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3549-3561
• 全文大小：482K
• 年卷期：0
• ISSN：1520-4804

文摘

Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure–activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC₅₀ value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF^V600E, EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF^V600E inhibitory activity with an IC₅₀ value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC₅₀ of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents.