Abstract
A series of dehydroabietic acid (DHAA) acyl-thiourea derivatives were designed and synthesized as potent antitumor agents. The in vitro pharmacological screening results revealed that the target compounds exhibited potent cytotoxicity against HeLa, SK-OV-3 and MGC-803 tumor cell lines, while they showed lower cytotoxicity against HL-7702 normal human river cells. Compound 9n (IC50 = 6.58 ± 1.11 μM) exhibited the best antitumor activity against the HeLa cell line and even displayed more potent inhibitory activity than commercial antitumor drug 5-FU (IC50 = 36.58 ± 1.55 μM). The mechanism of representative compound 9n was then studied by acridine orange/ethidium bromide staining, Hoechst 33,258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay and flow cytometry, which illustrated that this compound could induce apoptosis in HeLa cells. Cell cycle analysis indicated that compound 9n mainly arrested HeLa cells in the S phase stage. Further investigation demonstrated that compound 9n induced apoptosis of HeLa cells through a mitochondrial pathway.
Highlights
As one of the main causes of mortality worldwide, cancer has became a global health problem
dehydroabietic acid (DHAA) acyl-thiourea derivatives were synthesized as outlined in Scheme 1
The structures of DHAA acyl-thiourea derivatives 8–9 were confirmed by 1H NMR, 13C NMR and high-resolution mass spectroscopy
Summary
As one of the main causes of mortality worldwide, cancer has became a global health problem. Many DHAA derivatives containing functional groups have been designed and synthesized to screen for new potential antitumor agents [14,15,16]. Continuing our research program on the synthesis of DHAA derivatives as potent antitumor agents, the present work in this paper is to design and synthesize a series of new DHAA acyl-thiourea derivatives by the introduction of acyl-thiourea group in the carboxylic acid group of DHAA (Scheme 1). Many acyl-thiourea derivatives exhibit good inhibitory activity against malignant tumors [17], and our previous work has demonstrated that the introductions of α-aminophosphonate, dipeptide, and thiourea on DHAA could lead to improved antitumor activity. Reagents and conditions: (a) phthalic anhydride, CH3COOH, 50 °C; (b) oxalyl chloride, CH2Cl2, r.t.;. (e) oxalyl chloride, CH2Cl2, r.t.; (f) C6H5CH3, KSCN 110 °C; (g) CH2Cl2, r.t
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