- Title
- Focused library development of 2-phenylacrylamides as broad spectrum cytotoxic agents
- Creator
- Tarleton, Mark; Dyson, Lauren; Gilbert, Jayne; Sakoff, Jennette A.; McCluskey, Adam
- Relation
- ARC
- Relation
- Bioorganic & Medicinal Chemistry Vol. 21, Issue 1, p. 333-347
- Publisher Link
- http://dx.doi.org/10.1016/j.bmc.2012.10.003
- Publisher
- Elsevier BV
- Resource Type
- journal article
- Date
- 2013
- Description
- 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–Cdouble bond; length as m-dashC(CN)–Ar✠Ar–Cdouble bond; length as m-dashC(CN)–C(double bond; length as m-dashO)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.
- Subject
- focused library; acrylamides; cytotoxicity; synthesis
- Identifier
- http://hdl.handle.net/1959.13/1299783
- Identifier
- uon:19942
- Identifier
- ISSN:0968-0896
- Language
- eng
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