title: 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 affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier.
abstract: 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 FRα and PCFT over RFC.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Christina
authors.initials: C
authors.lastname: Cherian
authors.forename: Sita
authors.initials: S
authors.lastname: Kugel Desmoulin
authors.forename: Shermaine
authors.initials: S
authors.lastname: Mitchell-Ryan
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Hou
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004354:Drug Screening Assays, Antitumor; D058975:Folate Receptor 1 / Q000378:metabolism*; D006801:Humans; D058979:Proton-Coupled Folate Transporter / Q000378:metabolism*; D011687:Purines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058978:Reduced Folate Carrier Protein / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D058975:Folate Receptor 1; D058979:Proton-Coupled Folate Transporter; D011687:Purines; D011743:Pyrimidines; D011758:Pyrroles; D058978:Reduced Folate Carrier Protein; D013876:Thiophenes; C030985:purine