Département de Chimie-Faculté des Arts et des Sciences, Université de Montréal, 2900 Edouard Montpetit, Succursale Centre-Ville, CP 6128, Montreal, QC, H3C3J7, Canada.
Département de Biochimie et Médecine Moléculaire, and CRCHUM-Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.
Sci Rep. 2021 May 10;11(1):9854. doi: 10.1038/s41598-021-87993-3.
We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.
我们设计并合成了一系列取代的双胍盐小分子库，并研究了它们抑制胰腺癌细胞生长的能力。我们首先研究了它们的体外和膜活性，然后探讨了它们在活细胞中的作用机制和体内活性。结果表明，苯乙炔基双胍盐具有更高的跨膜能力，能够增加线粒体的积累并增强抗癌活性。在机制上，最有效的化合物 1b 与二甲双胍一样，能够激活 AMPK，降低 NAD/NADH 比值和线粒体呼吸，但浓度低 800 倍。体内研究表明，化合物 1b 能够显著抑制小鼠胰腺癌细胞异种移植瘤的生长，而目前处于临床试验阶段的双胍类药物则几乎没有活性。
