4-(3-烷基-2-氧代咪唑啉-1-基)-N-苯基苯磺酰胺（PAIB-SAs）是一类新型的前药，可以在乳腺癌细胞中由细胞色素P450 1A1（CYP1A1）生物活化为其有效的4-(2-氧代咪唑啉-1-基)-N-苯基苯磺酰胺代谢物（PIB-SAs）。PAIB-SAs在动物研究中的制剂和给药中的主要问题之一是其溶解度较差。为了克服这个困难，我们报道了18种新的PAIB-SAs的Na+、K+和Li+盐的设计、合成、化学表征、水溶解度评价、抗增殖活性和作用机制。我们的结果证明，后者对MCF7和MDA-MB-468乳腺癌细胞表现出高度选择性的抗增殖活性，这些细胞内源性表达CYP1A1，而对MDA-MB-231和HaCaT细胞不敏感。此外，PAIB-SA盐1-18的溶解度明显增加（3.9-9.4 mg/mL），而其中性对应物的溶解度较低（< 0.0001 mg/mL）。此外，最有效的PAIB-SA盐1-3和10-12阻滞了细胞周期在G2/M期的进展并破坏了细胞骨架的动态组装。最后，CYP1A1可将PAIB-SA盐N脱烷基化为相应的PIB-SA代谢物，后者具有很强的抗有丝分裂作用。总之，我们的结果表明，我们的水溶性PAIB-SA盐，特别是钠盐，仍然具有强效的抗增殖活性并易于CYP1A1生物活化。此外，这些PAIB-SA盐将有助于开发适用于进一步生物制药和药效学研究的制剂。版权所有©2023 Elsevier公司。保留所有权利。

4-(3-Alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs) are members of a new family of prodrugs bioactivated by cytochrome P450 1A1 (CYP1A1) in breast cancer cells into their potent 4-(2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamide metabolites (PIB-SAs). One of the predominant problems for the galenic formulation and administration of PAIB-SAs in animal studies is their poor hydrosolubility. To circumvent that difficulty, we report the design, the synthesis, the chemical characterization, the evaluation of the aqueous solubility, the antiproliferative activity and the mechanism of action of 18 new Na+, K+ and Li+ salts of PAIB-SAs. Our results evidenced that the latter exhibited highly selective antiproliferative activity toward MCF7 and MDA-MB-468 breast cancer cells expressing endogenously CYP1A1 compared to insensitive MDA-MB-231 and HaCaT cells. Moreover, PAIB-SA salts 1-18 are significantly more hydrosoluble (3.9-9.4 mg/mL) than their neutral counterparts (< 0.0001 mg/mL). In addition, the most potent PAIB-SA salts 1-3 and 10-12 arrested the cell cycle progression in the G2/M phase and disrupted the cytoskeleton's dynamic assembly. Finally, PAIB-SA salts are N-dealkylated by CYP1A1 into their corresponding PIB-SA metabolites, which are potent antimitotics. In summary, our results show that our water-soluble PAIB-SA salts, notably the sodium salts, still exhibit potent antiproliferative efficacy and remain prone to CYP1A1 bioactivation. In addition, these PAIB-SA salts will allow the development of galenic formulations suitable for further biopharmaceutical and pharmacodynamic studies.Copyright © 2023 Elsevier Inc. All rights reserved.