Synthesis and evaluation of antitumor, anti-inflammatory and analgesic activity of novel deoxycholic acid derivatives bearing aryl- or hetarylsulfanyl moieties at the C-3 position

•Formation of C-3β-epoxy derivatives of DCA with high stereoselectivity.•Synthesis of new DCA derivatives via an epoxide ring opening reaction with S-nucleophiles.•Sensitivity of tumor cell lines to synthesised compounds was HuTu-80 > KB-3-1 > HepG2 > MH-22a.•Epoxide moiety at the C-3 position was key for high anti-proliferative and anti-NO activities.•All tested compounds exhibited bioactivity in different edema models.

Novel deoxycholic acid (DCA) derivatives were stereoselectively synthesised with -OH and -CH2SR moieties at the C-3 position, where R was a substituted aryl [2-aminophenyl (8) or 4-chlorophenyl (9)] or hetaryl [1-methylimidazolyl (5), 1,2,4-triazolyl (6), 5-amino-1,3,4-thiadiazolyl (7), pyridinyl (10) or pyrimidinyl (11)]. These compounds were prepared in good yields from the C-3β-epoxy derivative 2 in the epoxide ring-opening reaction by S-nucleophiles. These derivatives were evaluated for their in vitro anti-proliferation activity in a panel of tumor cell lines. Data showed that: (i) heterocycle-containing derivatives displayed higher cytotoxicity profiles than the parent molecule; (ii) heterocyclic substituents were more preferable than aryl moieties for enhancing anti-proliferation activity; (iii) the sensitivity of tumor cell lines to analysed compounds decreased in the following order: HuTu-80 (duodenal carcinoma) > KB-3-1 (cervical carcinoma) > HepG2 (hepatocellular carcinoma) > MH-22a (hepatoma); (iv) compounds 5, 6 and 11 exhibited a high cytotoxic selectivity index (HuTu-80: SI > 7.7, 38.5 and 12.0, respectively). Compounds 2 and 6-8 markedly inhibited NO synthesis by interferon γ-induced macrophages. Screening for anti-inflammatory activity of these derivatives in vivo showed their high potency on histamine- (5, 10) and formalin- (2, 10, 11) induced paw edema models.

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