title: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of TS and AICARFTase and as potential antitumor agents.
abstract: A new series of 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines, with an isosteric replacement of the side chain amide moiety to a sulfur atom, were designed and synthesized as multitargeted antifolates as well as potential antitumor agents. Starting from previously synthesized 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidin-6-yl-acetic acid, a reduction by lithium triethylborohydride and successive mesylation afforded the key mesylate. Nucleophilic substitution by mercaptoacetic or mercaptopropionic acid methyl esters, followed by hydrolysis and condensation with pyridinyl-methylamines provided the nonclassical compounds 1-6, whereas condensation with glutamic acid diethyl ester hydrochloride and saponification afforded the classical analogs 7-8. All target compounds exhibited inhibitory activities toward KB, SW620 and A549 tumor cell lines. The most potent compounds of this series, 7 and 8, are better inhibitors against A549 cells than methotrexate (MTX) and pemetrexed (PMX). Nucleoside protection assays establish compound 8 a dual inhibitor of thymidylate synthase (TS) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) targeting both de novo thymidylate and purine nucleotide biosynthesis, which is further verified by the molecular modeling studies. Analogous to PMX, target compound 8 alternates the cell cycle of SW620 cells with S-phase accumulation and induces apoptosis, leading to cell death.
authors.affiliation: Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Jiangsong
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Congying
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Huicai
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: hmuwanglei@hebmu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: ren-leiming@263.net.
authors.forename: Leiming
authors.initials: L
authors.lastname: Ren
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013940:Thymidylate Synthase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase
keywords: Antiproliferation; Drug discovery; Purine biosynthesis; Pyrrolo[2,3-d]pyrimidines; Thymidylate biosynthesis