Novel hybrids of brefeldin A and nitrogen mustards with improved antiproliferative selectivity: Design, synthesis and antitumor biological evaluation

• Published in: European journal of medicinal chemistry Vol. 150; pp. 53 - 63
• Main Authors: Han, Tong, Tian, Kangtao, Pan, Huaqi, Liu, Yongxiang, Xu, Fanxing, Li, Zhanlin, Uchita, Takahiro, Gao, Ming, Hua, Huiming, Li, Dahong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.04.2018; Elsevier
• Subjects: Antiproliferative activity; Brefeldin A; Chemistry, Medicinal; Hybrids; Life Sciences & Biomedicine; Nitrogen mustards; Pharmacology & Pharmacy; Science & Technology; Selectivity; Hybrids; Selectivity; Nitrogen mustards; Antiproliferative activity; Brefeldin A; PATHWAYS; APOPTOSIS; CELLS; MITOCHONDRIAL; NATURAL-PRODUCTS; CANCER; POTENTIAL ANTICANCER AGENTS; DIFFERENTIATION; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.02.088

A series of novel conjugates of brefeldin A (11a−c, 12a−c and 13a−c) were obtained by introducing a variety of nitrogen mustards at 4-OH or 7-OH position to explore more efficacious and less toxic antitumor agents. The antiproliferative activities were tested against three cancer cell lines (HL-60, PC-3 and Bel-7402) and one multidrug resistant cell line Bel-7402/5-FU. Among them, compound 11a was the strongest derivative with IC50 values of 4.48, 9.37, 0.2 and 0.84 μM, respectively, and more potent than nitrogen mustards. Though the antiproliferative potency was weaker than the lead compound brefeldin A, 11a displayed lower toxicity than brefeldin A (IC50 < 0.001 μM) with an IC50 of 9.74 μM against normal human liver L-O2 cells, showing good selectivity between normal and malignant liver cells. The mechanism studies confirmed that 11a could induce apoptosis, arrest cell cycle at the G1 phase and lead to mitochondrial dysfunction in Bel-7402 cells at submicromolar concentrations. Furthermore, 11a induced the intrinsic apoptotic mitochondrial pathway in Bel-7402 cells, evidenced by the enhanced expression of the pro-apoptotic protein Bax, cyto-c and p53, and the reduced expression of the anti-apoptotic protein Bcl-2. The caspase-9 and -3 levels were also up-regulated. [Display omitted] •Novel hybrids of brefeldin A and nitrogen mustards were designed and synthesized.•Some derivatives exhibited potent antiproliferative activity with low IC50 values.•Compound 11a showed good selectivity between human normal and tumor liver cells.•11a induced apoptosis and arrest cell cycle at G1 phase in Bel-7402 cells.•11a induced Bel-7402 cells apoptosis via the mitochondria-dependent pathway.