ABSTRACT
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Subject(s)
Antineoplastic Agents/pharmacology , Isoindoles/pharmacology , Osteosarcoma/drug therapy , Protein Multimerization/drug effects , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Bone Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Stability , Female , Humans , Isoindoles/chemical synthesis , Isoindoles/metabolism , Macaca fascicularis , Male , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/metabolism , Molecular Structure , Protein Binding , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library.
Subject(s)
Oxazolidinones/chemical synthesis , Small Molecule Libraries/chemical synthesis , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Oxazolidinones/chemistry , Small Molecule Libraries/chemistryABSTRACT
The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library.
