- Discovery of iminobenzimidazole derivatives as novel cytotoxic agents
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In our quest to identify inhibitors of the eukaryotic translation initiation factor 4F (eIF4F), we serendipitously discovered a novel cytotoxic agent. Even though this compound did not inhibit translation, we explored the structural requirements for its cytotoxicity due to its structural originality. A series of 1,3-disubstituted iminobenzimidazoles was synthesized and evaluated for their in vitro cytotoxicity. The structure-activity relationship studies demonstrate that hydrophobic substituent is essential for activity. The most active compounds displayed a cytotoxicity in KB, HL60 and HCT116 human cancer cells with an IC50 of about 1μM. These first-in-class series of low molecular weight synthetic molecules may provide the basis for the development of new anticancer drugs.
- Chouha, Nora,Hammoud, Hassan,Brogi, Simone,Campiani, Giuseppe,Welsch, Caroline,Robert, Caroline,Vagner, Stéphan,Cresteil, Thierry,Bentouhami, Embarek,Désaubry, Laurent
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- Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase
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In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg2+ ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.
- Gritzalis, Dimitrios,Park, Jaeok,Chiu, Wei,Cho, Hyungjun,Lin, Yih-Shyan,De Schutter, Joris W.,Lacbay, Cyrus M.,Zielinski, Michal,Berghuis, Albert M.,Tsantrizos, Youla S.
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supporting information
p. 1117 - 1123
(2015/02/19)
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- Synthesis and mutagenic potency of structural isomers of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
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(Chemical Equation Presented) Synthesis of 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), three structural isomers, and two desphenyl PhIP congeners has been carried out. Mutagenic potency was evaluated using S. typhimurium strain TA98 in the Ames test. Mutagenic potency increased in relation to structural features in these heterocyclic amines that allow extended resonance between the phenyl and imidazo[4,5-b]pyridine N2-amino substituents. By contrast, PhIP isomers, whose substitution disallows involvement of the phenyl group in their ammoimidazo resonance hybrids, and desphenyl congeners were from 86- to 234-fold less mutagenic than PhIP.
- Chrisman,Knize,Tanga
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experimental part
p. 1641 - 1649
(2009/08/09)
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