Abstract
A series of the newly substituted thienopyrimidine derivatives 2-13 were synthesized by using 3-amino-6-(4-chlorophenyl)-4-(4-isopropylphenyl) thieno[2,3-b]pyridine-2-carbohydrazide 1 as starting material. Reaction of compound 1 with p-nitrobenzaldehyde in refluxing ethanol afforded the corresponding Shiff base 2, which was cyclized with triethyl orthoformate to give thienopyrimidine derivative 3. Compound 1 was treated with formic acid or acetic anhydride to afford the corresponding thienopyrimidines 4 and 5, respectively. Treatment of 1 with acetylacetone afforded pyrazolothienopyrimidine 6. Treatment of 1 with triethyl orthoformate, carbon disulfide, dimethylformamide and ethyl acetoacetate or diethyl malonate gave compounds 7-11, respectively. Cyclization of 1 with m-nitrophthalic anhydride or formaldehyde afforded thienopyrimidines 12 and 13, respectively. The newly synthesized compounds were found to be potent selective and orally bioavailable CHK1 inhibitors. This elucidated and confirmed via determination of checkpoint abrogation, antiproliferative activity and potentiation of genotoxic drug efficacy in cancer cell lines and also determination of compound concentrations in vivo at selected time points following i.v. and oral dosing.