Focused library development of 2-phenylacrylamides as broad spectrum cytotoxic agents
| Autor: | Mark Tarleton, Adam McCluskey, Lauren Dyson, Jennette A. Sakoff, Jayne Gilbert |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Neoplasms Furan Drug Discovery Humans Potency Moiety Cytotoxicity Molecular Biology Cell Proliferation Acrylamides Cytotoxins Organic Chemistry chemistry Acrylamide Molecular Medicine Drug Screening Assays Antitumor Growth inhibition Acrylonitrile Lead compound |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:333-347 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.10.003 |
| Popis: | With our lead compound (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (1) inducing 50% growth inhibition of 11 cancer cell lines at 27–61 μM, potency enhancements were rapidly established through the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised. Each library allowed the identification of a new lead compound, viz Library A identified (E)-3-(pentafluorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (11) and (E)-3-(1H-indol-3-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (13) as inhibitors with improved cytotoxicity. Synthesis of discrete libraries of amidoacrylamide analogues (Ar–C C(CN)–Ar✠Ar–C C(CN)–C( O)NH)–Ar) resulted in a series of analogues significantly more potent that the lead, 1. Three furan three analogues: (E)-3-(5-chlorofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (33), (E)-3-(5-bromofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (34) and (E)-2-cyano-3-(furan-3-yl)-N-(4-methoxybenzyl)acrylamide (37) returned broad spectrum growth inhibition (GI50 values of 5–16 μM). Replacement of the furan moiety with simple aromatics gave an additional three analogues: (E)-2-cyano-N-(4-methoxybenzyl)-3-phenylacrylamide (39), (E)-3-(4-chlorophenyl)-2-cyano-N-(4-methoxybenzyl)acrylamide (41) and (E)-2-cyano-N-(4-methoxyphenyl)-3-(naphthalen-1-yl)acrylamide (45) with GI50 values of 7–24 μM. The final library retained the aromatic substituents but introduced a 3,4-dichlorbenzylamine moiety to afford the 1-naphthyl substituted 52, which was the most potent broad spectrum cytotoxic analogue produced here in with an average GI50 = 8.6 μM. This represents a fivefold potency enhancement relative to 1 and a new cytotoxic scaffold suitable for further development. |
| Databáze: | OpenAIRE |
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