title: Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry.
abstract: 2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and four to six carbon bridge lengths (compounds 1-3) were synthesized as substrates for folate receptors (FRs) and the proton-coupled folate transporter (PCFT). Conversion of acetylene carboxylic acids to alpha-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FR alpha, reduced folate carrier (RFC), and PCFT. The analogs were selective for FR and PCFT over RFC. Glycinamide ribonucleotide formyltransferase was the principal cellular target. In SCID mice with KB tumors, 1 was highly active against both early (3.5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Christina
authors.initials: C
authors.lastname: Cherian
authors.forename: Sita Kugel
authors.initials: SK
authors.lastname: Desmoulin
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wu
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Hou
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.forename: Juiwanna
authors.initials: J
authors.lastname: Kushner
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058979:Proton-Coupled Folate Transporter; D011687:Purines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D026901:Membrane Transport Proteins; D058979:Proton-Coupled Folate Transporter; D011687:Purines; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C505058:SLC46A1 protein, human; C548700:Slc19a1 protein, mouse