Synthesis and Biological Activity of 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Inhibitors of de Novo Purine Biosynthesis with Selectivity for Cellular Uptake by High Affin
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- 作者：Lei Wang ; Christina Cherian ; Sita Kugel Desmoulin ; Shermaine Mitchell-Ryan ; Zhanjun Hou ; Larry H. Matherly ; Aleem Gangjee
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：February 23, 2012
- 年：2012
- 卷：55
- 期：4
- 页码：1758-1770
- 全文大小：453K
- 年卷期：v.55,no.4(February 23, 2012)
- ISSN：1520-4804
文摘
We previously 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 three- (3a) and four-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 the 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 four-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 FR伪 and PCFT over RFC.