Stachydrine is a hydrophilic quaternary amine salt with good antitumor effect, but its application is limited due to its rapid metabolism and low bioavailability. We synthesized and evaluated nine prodrugs of stachydrine, which showed suitable hydrophobicity (CLogP: -2.58-4.78, vs SS-0: -3.32) and better in vitro anticancer activity (IC50: 0.34 μM-14.03 mM, vs SS-0: 38.97 mM-147.19 mM) in comparison with stachydrine. Among them, SS-12, SS-16 and SS-18 are the most effective compounds against 4T1 cells, and the IC50 is 2.15-24.14 μM. Especially, compared with stachydrine, SS-12 significantly blocked the cell cycle in the G0/G1 phase, reduced the mitochondrial membrane potential, and induced the apoptosis of 4T1 cells through mitochondria pathway, which increased the expressions of Bax and cleaved caspase-3 protein, decrease the expression of Bcl-2. The pharmacokinetics of SS-12 showed a rational bioavailability (79.6%), and a longer retention time (T1/2 = 7.62 h) than that of stachydrine (T1/2 ≈ 1.16 h) in rats. Compared with stachydrine, SS-12 significantly enhanced the anticancer efficacy (56.32% of tumor-inhibition rates, vs SS-0: 3.89%), meanwhile, ameliorated the tumor-induced organ damage in mice. Therefore, SS-12 may be a promising prodrug of stachydrine against breast cancer.
Keywords: Bioavailability; Breast cancer; Derivative; Drug design; Stachydrine.
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