Synthesis and biological activity of 6-substituted pyrrolo23-dpyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier

摘要

We reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a 3- (>3a) and 4-carbon (>3b) bridge. Compound >3a was more potent than >3b against tumor cells; While >3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over reduced folate carrier (RFC), >3a was not. To determine if decreasing the distance between the bicyclic scaffold and L-glutamate in >3b would preserve transport selectivity and potency against human tumor cells, >3b regioisomers with [1,3] (>7 and >8) and [1,2] (>4, 5 and >6) substitutions on the thienoyl ring, and with acetylenic insertions in the 4-atom bridge, were synthesized and evaluated. Compounds >7 and >8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC.