文摘
A new series of 6-substituted straight side chain pyrrolo[2,3-d]pyrimidines 3a鈥?b>d with varying chain lengths (n = 5鈥?) was designed and synthesized as part of our program to provide targeted antitumor agents with folate receptor (FR) cellular uptake specificity and glycinamide ribonucleotide formyltransferase (GARFTase) inhibition. Carboxylic acids 4a鈥?b>d were converted to the acid chlorides and reacted with diazomethane, followed by 48% HBr to generate the 伪-bromomethylketones 5a鈥?b>d. Condensation of 2,4-diamino-6-hydroxypyrimidine 6 with 5a鈥?b>d afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 7a鈥?b>d. Hydrolysis and subsequent coupling with diethyl l-glutamate and saponification afforded target compounds 3a鈥?b>d. Compounds 3b鈥?b>d showed selective cellular uptake via FR伪 and -尾, associated with high affinity binding and inhibition of de novo purine nucleotide biosynthesis via GARFTase, resulting in potent inhibition against FR-expressing Chinese hamster cells and human KB tumor cells in culture. Our studies establish, for the first time, that a side chain benzoyl group is not essential for tumor-selective drug uptake by FR伪.