Mondal Sougata, Das Upasana, Ghosh Oyendrila, Maiti Bidisha, Halder Shuvam, Pal Uttam, Mukherjee Kalyan Kusum, Ghosh Supratim
Department of Anti-Cancer Drug Development and Chemotherapy, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Bhowanipore, Kolkata 700026, West Bengal, India.
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, USA, 475 Vine Street, Winston Salem, North Carolina 27157, United States.
ACS Omega. 2025 Apr 24;10(17):17416-17434. doi: 10.1021/acsomega.4c10710. eCollection 2025 May 6.
Natural products ranging from phytochemicals to metals are well-known for their therapeutic benefits on different cancer types, including acute leukemia. However, bioavailability significantly limited the applications of various polyphenolic molecules, such as curcumin, while toxicity challenged the medicinal applications of heavy metals, such as mercury (Hg). Specifically, in case of curcumin derivatives, simultaneous solubility, stability, and bioactivity in the aqueous medium remain unachieved, leading to poor clinical translation. We demonstrate for the first time that the above-mentioned challenges could be resolved by covalently bonding mercury to the α-carbon of curcumin. The resultant organomercury compound ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-4-yl)mercury or α-Mercurin is soluble in alkaline conditions and remains stable for at least 24 h. Cell viability assays demonstrated selective cytotoxicity of α-Mercurin against acute leukemia cells, compared to healthy human peripheral blood mononuclear cells, in vitro. Experimental IC on MOLT-4 and HL-60 cells remained in the lower micromolar range, and potential mode of action includes apoptosis. Ex vivo analysis also demonstrated that α-Mercurin can eliminate immature blasts from acute lymphoblastic leukemia patients' blood samples and also enhance expression of immune markers, with no notable toxicity on red blood cells as well as lymphocytes. Finally, intravenous administration of α-Mercurin showed no subacute toxicity, in vivo.
从植物化学物质到金属的天然产物因其对包括急性白血病在内的不同癌症类型的治疗益处而闻名。然而，生物利用度显著限制了各种多酚类分子（如姜黄素）的应用，而毒性则对重金属（如汞（Hg））的医学应用构成了挑战。具体而言，就姜黄素衍生物而言，在水性介质中同时实现溶解度、稳定性和生物活性仍未达成，导致临床转化效果不佳。我们首次证明，通过将汞共价键合到姜黄素的α-碳上，可以解决上述挑战。所得的有机汞化合物（(1E,6E)-1,7-双(4-羟基-3-甲氧基苯基)-3,5-二氧代庚-1,6-二烯-4-基）汞或α-汞素在碱性条件下可溶，并且至少稳定24小时。细胞活力测定表明，与健康人外周血单核细胞相比，α-汞素在体外对急性白血病细胞具有选择性细胞毒性。在MOLT-4和HL-60细胞上的实验IC50仍处于低微摩尔范围内，潜在的作用模式包括凋亡。体外分析还表明，α-汞素可以从急性淋巴细胞白血病患者的血样中消除未成熟的原始细胞，还能增强免疫标志物的表达，对红细胞和淋巴细胞没有明显毒性。最后，α-汞素的静脉注射在体内未显示亚急性毒性。
