Epidemiological evidence has accentuated the repurposing of metformin hydrochloride for cancer treatment. However, the extreme hydrophilicity and poor permeability of metformin hydrochloride are responsible for its poor anticancer activity in vitro and in vivo. Here, we report the synthesis and characterization of several lipophilic metformin salts containing bulky anionic permeation enhancers such as caprate, laurate, oleate, cholate, and docusate as counterions. Of various counterions tested, only docusate was able to significantly improve the lipophilicity and lipid solubility of metformin. To evaluate the impact of the association of anionic permeation enhancers with metformin, we checked the in vitro anticancer activity of various lipophilic salts of metformin using drug-sensitive (MYCN-2) and drug-resistant (SK-N-Be2c) neuroblastoma cells as model cancer cells. Metformin hydrochloride showed a very low potency (IC₅₀ ≈ >100 mM) against MYCN-2 and SK-N-Be2c cells. Anionic permeation enhancers showed a considerably higher activity (IC₅₀ ≈ 125 μM to 1.6 mM) against MYCN-2 and SK-N-Be2c cells than metformin. The association of metformin with most of the bulky anionic agents negatively impacted the anticancer activity against MYCN-2 and SK-N-Be2c cells. However, metformin docusate showed 700- to 4300-fold improvement in anticancer potency compared to metformin hydrochloride and four- to five-fold higher in vitro anticancer activity compared to sodium docusate, indicating a synergistic association between metformin and docusate. A similar trend was observed when we tested the in vitro activity of metformin docusate, sodium docusate, and metformin hydrochloride against hepatocellular carcinoma (HepG2) and triple-negative breast cancer (MDA-MB-231) cells.

中文翻译：

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二甲双胍亲脂性盐的合成和表征，以改善其对癌症治疗的用途。

流行病学证据强调了盐酸二甲双胍在癌症治疗中的用途。然而，盐酸二甲双胍的极强亲水性和差的渗透性是其体外和体内抗癌活性差的原因。在这里，我们报告了几种亲脂性二甲双胍盐的合成和表征，这些盐含有大体积的阴离子渗透增强剂，如癸酸根，月桂酸根，油酸根，胆酸盐和多库酯作为抗衡离子。在测试的各种抗衡离子中，只有多库酯能够显着改善二甲双胍的亲脂性和脂质溶解性。为了评估阴离子渗透促进剂与二甲双胍结合的影响，我们在体外进行了检查使用药物敏感性（MYCN-2）和耐药性（SK-N-Be2c）神经母细胞瘤细胞作为模型癌细胞对二甲双胍的各种亲脂性盐具有抗癌活性。盐酸二甲双胍表现出非常低的效力（IC ₅₀ ≈> 100毫摩尔）对MYCN-2和SK-N-Be2c细胞。阴离子渗透增强剂表现出显着更高的活性（IC ₅₀ ≈125μM至1.6毫米）对着MYCN-2和SK-N-Be2c细胞中比二甲双胍。二甲双胍与大多数笨重的阴离子制剂的结合会对MYCN-2和SK-N-Be2c细胞的抗癌活性产生负面影响。然而，与盐酸二甲双胍相比，二甲双胍对二甲双胍的抗癌作用提高了700至4300倍，在体外则提高了4至5倍与多库酯钠相比具有更强的抗癌活性，表明二甲双胍和多库酯具有协同作用。当我们测试二甲双胍对二甲双胍，多库那酸钠和盐酸二甲双胍对肝细胞癌（HepG2）和三阴性乳腺癌（MDA-MB-231）细胞的体外活性时，观察到类似的趋势。