ABSTRACT
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC50) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Protein-Lysine 6-Oxidase/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Mice , Neoplasm Metastasis/drug therapy , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Thiophenes/therapeutic useABSTRACT
1,2-Amino alcohols are high-value, versatile functional groups that are found in scores of biologically active molecules and other interesting synthetic targets such as ligands and auxiliaries. Given their prominent position within organic compounds of import, it is no surprise to note that many routes have been developed to access this motif and there are many different starting points from which a synthetic chemist might embark on a synthesis. However, one particular approach stands out from the others, and this is the direct conversion of an alkene to a vicinal amino alcohol derivative (oxyamination). Research in this field has been particularly active in recent years and many interesting new methodologies have been reported. The purpose of this review is to give the reader a tour of the methods that have emerged in the last few years so one can appreciate the myriad of different metals and reagents that can accomplish the oxyamination of alkenes. There are still many challenges to be overcome and, herein, we also outline the areas that are ripe for further development and which bode well for the future.
Subject(s)
Alkenes/chemistry , Amino Alcohols/chemical synthesis , Chemistry, Organic/methods , Amino Alcohols/chemistry , Catalysis , Molecular StructureABSTRACT
A novel osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendant vinyl silane affords THFs that contain silicon functionality at the ring junction. When the cyclisation occurs onto a vinyl benzyldimethylsilyl group, the resulting silyl group can act as a masked hydroxyl group and undergo a Fleming-Tamao type oxidation at a later stage to form the corresponding lactol. The scope of this reaction can also be extended beyond 1,2-diols and applied to the cyclisation of α-hydroxy-sulfonamides and α-hydroxy-amides.
Subject(s)
Silanes/chemistry , Cyclization , Oxidation-ReductionABSTRACT
Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated by its application to the tetrasubstituted pyrrole subunit of Atorvastatin.
ABSTRACT
The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes is an effective method for the construction of pyrrolidines, utilizing a novel reoxidant (4-nitropyridine N-oxide = NPNO). The cyclization of enantiopure syn- and anti-amino alcohols gives rise to enantiopure cis- and trans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of bis-homoallylic amines bearing an exocyclic chelating group is shown to be a complementary method for trans-pyrrolidine formation.
Subject(s)
Osmium/chemistry , Catalysis , Cyclization , Models, Molecular , Molecular Conformation , Oxidation-ReductionABSTRACT
The first examples of amide-tethered aminohydroxylation reactions, catalyzed by osmium, showing that the use of N-O-based reoxidants are essential for success, are reported. The system that is described is compatible with a variety of different alkene substitution patterns and ring sizes and works with low loadings in both cyclic and acyclic systems. The levels of diastereoselectivity that were observed for substituents at both the allylic and homallylic position bode well for the use of stereoselective TA reactions in organic synthesis.
