- Benzofurazanyl- and benzofuroxanyl-1,4-dihydlropyridines : Synthesis, structure and calcium entry blocker activity
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The synthesis, structural characterization and calcium blocking activity of a series of benzofurazanyl-1,4-dihydropyridines (18 and 19) and benzofuroxanyl analogues (20 and 21) are reported. 1H-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. The predominant tautomeric form in solution of the derivative 20 (dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-benzofuroxanyl)-3,5-pyridinedicarboxylate) is also the one preferred in the solid state as shown by X-ray analysis. The conformation in the solid state of the benzofurazanyl analogue is also reported. Calcium entry blocker activity of the dihydropyridine derivatives 18-21 has been evaluated in isolated rabbit basilar artery as relaxation of calcium-induced contractions in high K+-depolarizing solution. All the compounds displayed high potency. The activity of benzofurazan derivatives was not changed by the N-oxidation. The two most active compounds 18 and 20 were as potent as Nifedipine.
- Gasco,Ermondi,Fruttero,Gasco
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- Identification, synthesis and evaluation of substituted benzofurazans as inhibitors of CREB-mediated gene transcription
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Cyclic-AMP response-element binding protein (CREB) is a stimulus-activated transcription factor. Its transcription activity requires its binding with CREB-binding protein (CBP) after CREB is phosphorylated at Ser133. The domains involved for CREB-CBP interaction are kinase-inducible domain (KID) from CREB and KID-interacting domain (KIX) from CBP. Recent studies suggest that CREB is an attractive target for novel cancer therapeutics. To identify novel chemotypes as inhibitors of KIX-KID interaction, we screened the NCI-diversity set of compounds using a split renilla luciferase assay and identified 2-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio]pyridine 1-oxide (compound 1, NSC228155) as a potent inhibitor of KIX-KID interaction. However, compound 1 was not particularly selective against CREB-mediated gene transcription in living HEK 293T cells. Further structure-activityrelationship studies identified 4-aniline substituted nitrobenzofurazans with improved selectivity.
- Xie, Fuchun,Li, Bingbing X.,Broussard, Candice,Xiao, Xiangshu
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p. 5371 - 5375
(2013/09/23)
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