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
| Autor: | Lei Wang, Meng Li, Hongying Zhang, Leiming Ren, Yumin Du, Congying Zhang, Jiangsong Yuan, Huicai Guo, Kai Zhang, Lijuan Zhao, Yi Liu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Ribonucleotide Lithium triethylborohydride Hydrochloride Stereochemistry Antineoplastic Agents Thymidylate synthase Phosphoribosylaminoimidazolecarboxamide Formyltransferase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Amide Drug Discovery Humans Pyrroles Enzyme Inhibitors Purine metabolism Pharmacology Phosphoribosylaminoimidazolecarboxamide formyltransferase biology Organic Chemistry Thymidylate Synthase General Medicine Pyrimidines 030104 developmental biology chemistry Drug Design 030220 oncology & carcinogenesis biology.protein Nucleoside |
| Zdroj: | European Journal of Medicinal Chemistry. 115:245-256 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect