A novel and short synthesis of (1,4/2)-cyclohex-5-ene-triol and its conversion to (+/-)-proto-quercitol

(1,4/2)-cyclohex-5-ene-triol was synthesized starting from cyclohexa-1,4-diene with two different approaches. Photooxygenation of cyclohexa-1,4-diene and epoxy-cyclohexene afforded anti-2,3-dioxabicyclo[2.2.2]oct-7-en-5-yl hydroperoxide and anti-7-oxabicyclo[4.1.0]hept-4-en-3-yl hydroperoxide, respectively. Hydroperoxy endoperoxide was reduced with aqueous sodium bisulfite; hydroperoxy-epoxide with dimethylsulfide-titanium tetraisopropoxide to give 7-oxabicyclo[4.1.0]hept-4-en-3-ol. Acidic hydrolysis of the epoxy-alcohol gave the (1,4/2)-cyclohex-3-ene-triol. Oxidation of the double bond with KMnO4 resulted in the formation of (+/-)-proto-quercitol.     

Impaired activation of caspase cascade during cell death induced by newly synthesized singlet oxygen generator, 1-buthylnaphthalene-4-propionate endoperoxide

Endoperoxides of naphthalene derivatives generate singlet oxygen under physiological conditions. Here we have synthesized a new endoperoxide of a naphthalene derivative, 1-buthylnaphthalene-4-propionate endoperoxide (BNPE), and studied its cytotoxic properties on HepG2 and HaCaT cells. BNPE induced cell death at much lower concentration than 1-methylnaphthalene-4-propionate endoperoxide (MNPE) and naphthalene dipropionate endoperoxide (NDPE). A positive correlation exists between the amount of endoperoxide incorporated into cells and its cytotoxic ability. The cytotoxic effect of BNPE was attenuated by alpha-tocopherol but not by sodium azide. In contrast, the effects of MNPE and NDPE were attenuated by both alpha-tocopherol and sodium azide. The caspase cascade in cells treated with endoperoxide was impaired. Caspase activity in a soluble protein fraction were inhibited similarly by the above three endoperoxides. These results suggest an abortive apoptotic pathway due to the suppression of caspase activation is a general feature of cell death induced by singlet oxygen.     

Novel conjugates of endoperoxide and 4-anilinoquinazoline as potential anticancer agents

In the present study, endoperoxide and 4-anilinoqnazoline were conjugated to obtain a series of compounds. These conjugates exhibited high antiproliferative potency against a number of cancer cell lines, including the epidermal growth factor receptor (EGFR) L858R/T790M mutant cell. Compound 5 was selected as a representative for mechanistic study. Further experiments revealed the conjugate’s reactive oxygen species (ROS) generating ability, apoptosis inducing activity and involvement in EGFR downstream signaling pathways.