Antitumor agents 292. Design, synthesis and pharmacological study of S- and O-substituted 7-mercapto- or hydroxy-coumarins and chromones as potent cytotoxic agents

Thirty-five S- and O-substituted 7-mercaptocoumarin (9–23) and 7-hydroxy- or 7-mercapto-chromone (24–43) analogs were designed, synthesized and evaluated in vitro against four human tumor cell lines [KB (nasopharyngeal), KB-vin (vincristine-resistant subline), A549 (lung) and DU145 (prostate)] with paclitaxel as the positive control. Many of the synthesized compounds exhibited potent cytotoxic activity. Among them, compounds 10 and 18 showed broad spectrum activity with GI50 values ranging from 0.92 to 2.11 μM and 2.06–14.07 μM, respectively. However, 33, a 3-brominated compound, displayed significant and selective inhibition against MDR KB-vin with a GI50 of 5.84 μM. Regardless of the size of the 7-alkoxy group, 2-α-bromoethyl-8-bromomethyl compounds (40–43) exhibited increased cytotoxicity compared with 2-ethyl-8-bromomethyl compounds (36–39). Moreover, in a preliminary pharmacological study, 10 not only remarkably increased cellular apoptosis in a concentration-dependent manner, but also clearly induced A549 cell cycle arrest at the G2/M phase. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism(s). Compound 10 induced apoptosis in A549 cells. Condensed and fragmented nuclei with bright staining were considered as apoptotic cells. [Display omitted] ► Cytotoxic substituted 7-mercaptocoumarins and 7-hydroxychromones were synthesized. ► 7-(Chloropyridinylthio) analog 10 showed broad spectrum activity (GI50 0.92–2.11 μM). ► Analog 10 increased cellular apoptosis and induced A549 cell cycle arrest. ► 3-Bromo-7-isopropoxy substituted chromenone 33 was selective against MDR KB-vin.