ABSTRACT
The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.
Subject(s)
Neoplasms , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Humans , Mice , Animals , Signal Transduction , Receptor Protein-Tyrosine Kinases/metabolism , Allosteric SiteABSTRACT
The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the ß-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric ß-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric ß-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the ß-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.
Subject(s)
Alkaloids/chemical synthesis , Carboxylic Acids/chemistry , Diketopiperazines/chemical synthesis , Piperazines/chemical synthesis , Alkaloids/chemistry , Diketopiperazines/chemistry , Molecular Structure , Piperazine , Piperazines/chemistry , StereoisomerismABSTRACT
The first total synthesis of an epidithiodiketopiperazine alkaloid, (+)-MPC1001B, was accomplished. This synthesis features a tetra-n-butylammonium fluoride mediated intramolecular aldol reaction for forming the 15-membered macrolactone ring, and the construction of an epidithiodiketopiperazine substructure through a stepwise sulfenylation reaction involving a novel trityl trisulfide (TrSSS)-group transfer.
Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Alkaloids/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , StereoisomerismABSTRACT
A benzyne-mediated synthesis of substituted indolines and carbazoles was developed. The reaction includes generation of benzyne using Mg(TMP)2·2LiCl as a base, cyclization, and trapping the resulting organomagnesium intermediate with an electrophile to provide a series of substituted indolines and carbazoles in a regiospecific manner. This was applied to a concise five-pot total synthesis of heptaphylline.
Subject(s)
Benzene Derivatives/chemistry , Carbazoles/chemical synthesis , Indoles/chemical synthesis , Carbazoles/chemistry , Combinatorial Chemistry Techniques , Cyclization , Indoles/chemistry , Molecular StructureABSTRACT
The key step in this total synthesis of (-)-acetylaranotin is the efficient formation of the characteristic dihydrooxepine ring from cyclohexenone through an unusual vinylogous Rubottom oxidation and a regioselective Baeyer-Villiger oxidation. (-)-Acetylaranotin is obtained in 22 steps from commercially available L-Cbz-tyrosine (Cbz=benzyloxycarbonyl).
Subject(s)
Oxepins/chemical synthesis , Cyclohexenes/chemistry , Oxepins/chemistry , Oxidation-Reduction , Piperazine , Piperazines/chemistry , StereoisomerismABSTRACT
A highly efficient total synthesis of dictyodendrins A-E was accomplished. The synthesis features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. Peripheral substituents were introduced onto this intermediate in a modular fashion to complete the total synthesis of dictyodendrins A-E.
