Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands.

Introduction: The progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.

Methods: By combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.

Synthesis of a stable and orally bioavailable englerin analogue.

Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.

Application of silver N-heterocyclic carbene complexes in O-glycosidation reactions.

We report the efficient O-glycosidation of glycosyl bromides with therapeutically relevant acceptors facilitated by silver N-heterocyclic carbene (Ag-NHC) complexes. A set of four Ag-NHC complexes was synthesized and evaluated as promoters for glycosidation reactions. Two new bis-Ag-NHC complexes derived from ionic liquids 1-benzyl-3-methyl-1H-imidazolium chloride and 1-(2-methoxyethyl)-3-methylimidazolium chloride were found to efficiently promote glycosidation, whereas known mono-Ag complexes of 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride and 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride failed to facilitate the reaction.

O-Glycosidation reactions promoted by in situ generated silver N-heterocyclic carbenes in ionic liquids.

We herein report O-glycosidation reactions promoted via silver N-heterocyclic carbene complexes formed in situ in ionic liquids. Seven different room temperature ionic liquids were screened for the glycosidation reaction of 4-nitrophenol with tetra-O-acetyl-α-d-galactopyranosyl bromide. Good to excellent yields were obtained using Ag-NHC complexes derived from imidazolium halide salts to promote the glycosidation reaction, whereas yields considered moderate to low were obtained without use of the silver carbene complex.

Carbohydrate-based drugs in the treatment of epilepsy, depression and other affective disorders.

Mental illness affects a quarter of the US population. Recently, it has been shown that new, carbohydrate-based drugs hold promise in the treatment of central nervous system (CNS) disorders. A variety of ways in which drugs of this sort may reduce the symptoms of epilepsy, depression and other affective disorders have been proposed, including: targeting the immune system, disrupting glycolysis, acting at different sites in the hypothalamic-pituitary-adrenal (HPA) axis, and targeting specific biochemical pathways such as the inositol pathway.

Amino substituted analogs of 1-phenyl-3-phenylimino-2-indolones with potent galanin Gal3 receptor binding affinity and improved solubility.

A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthesized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, Ki=5 nM) shows good selectivity and solubility of 48 microg/mL at pH 7.4.