ABSTRACT
Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 µM and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators.
Subject(s)
Benzamides/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Purines/pharmacology , Aminophenols/pharmacology , Benzamides/chemical synthesis , Benzamides/metabolism , Binding Sites , Cystic Fibrosis Transmembrane Conductance Regulator/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Synergism , HeLa Cells , Humans , Molecular Docking Simulation , Mutation , Protein Binding , Purines/chemical synthesis , Purines/metabolism , Quinolones/pharmacologyABSTRACT
Micelle-forming amphiphilic drug conjugates were synthesized starting from a biologically active epipodophyllotoxin derivative which was covalently inserted in between a hydrophilic targeting spermine unit, and a hydrophobic stearyl chain. The amphiphilic drug conjugates were further assembled into the corresponding micelles and evaluated in vitro for the active targeting of tumor cells overexpressing the polyamine transport system.
Subject(s)
Micelles , Nanostructures , Podophyllotoxin/chemistry , Polyamines/metabolism , Biological Transport , Drug Delivery Systems , Hydrophobic and Hydrophilic InteractionsABSTRACT
Micelle-forming amphiphilic drug conjugates were synthesized starting from a biologically active epipodophyllotoxin derivative which was covalently inserted in between a hydrophilic PEG unit and a hydrophobic stearyl chain. The epipodophyllotoxin-containing amphiphiles were assembled into the corresponding micelles which were evaluated in vivo for their tumor targeting properties.
Subject(s)
Drug Carriers , Micelles , Nanoparticles/chemistry , Podophyllotoxin/chemistry , Animals , Cell Line, Tumor , Humans , Mice , Mice, Nude , Neoplasms/diagnostic imaging , Polyethylene Glycols/chemistry , Spectroscopy, Near-Infrared , Transplantation, HeterologousABSTRACT
Highly substituted purines were synthesized in good to high yields through a one-pot straightforward metal-free scalable method, using the Traube synthesis adapted to Vilsmeier-type reagents. From 5-amino-4-chloropyrimidines, new 9-aryl-substituted chloropurines and intermediates for peptide nucleic acid synthesis were prepared. Variant procedures allowing a rapid synthesis of ribonucleosides and 7-benzylpurine from 5-amidino-6-aminopyrimidines are also reported to illustrate the high potential of this versatile toolbox. This route appears to be particularly interesting in the field of nucleic acids for a direct and rapid access to various new 8-alkylpurine nucleosides.
ABSTRACT
Macrocarpals A and C are structurally related compounds that have been extracted from different Eucalyptus species. Although macrocarpal C is of biological interest, its isolation in pure form is difficult to achieve. We report herein an efficient method for the semisynthesis of macrocarpal C by selective exo-dehydration of another member of the macrocarpal family, macrocarpal A. We also report the semisynthesis of three new macrocarpal structures derived from either macrocarpal A or B.
Subject(s)
Phloroglucinol/analogs & derivatives , Sesquiterpenes/chemical synthesis , Eucalyptus/chemistry , Molecular Structure , Phloroglucinol/chemical synthesis , Phloroglucinol/chemistry , Sesquiterpenes/chemistryABSTRACT
A novel approach for the asymmetric synthesis of the active (1S,2R)-enantiomer of the antidepressant milnacipran is reported. The two stereogenic centers borne by the cyclopropane ring were sequentially installed starting from phenylacetic acid.
Subject(s)
Antidepressive Agents/chemical synthesis , Cyclopropanes/chemistry , Cyclopropanes/chemical synthesis , Antidepressive Agents/chemistry , Milnacipran , Phenylacetates/chemical synthesis , Phenylacetates/chemistry , StereoisomerismABSTRACT
A palladium-catalyzed C-H functionalization reaction for the synthesis of highly substituted aromatic nitriles is reported. The modularity of the reaction is demonstrated by the broad range of aryl iodides which can be coupled with metal cyanides and alkyl halides or aryl bromides.
