Cooperativity in the Aldol Condensation Using Bifunctional Mesoporous Silica-Poly(styrene) MCM-41 Organic/Inorganic Hybrid Catalysts.

This work explores the efficacy of silica/organic hybrid catalysts, where the organic component is built from linear aminopolymers appended to the silica support within the support mesopores. Specifically, the role of molecular weight and polymer chain composition in amine-bearing atom transfer radical polymerization-synthesized poly(styrene-co-2-(4-vinylbenzyl)isoindoline-1,3-dione) copolymers is probed in the aldol condensation of 4-nitrobenzaldehyde and acetone. Controlled polymerization produces protected amine-containing poly(styrene) chains of controlled molecular weight and dispersity, and a grafting-to thiol-ene coupling approach followed by a phthalimide deprotection step are used to covalently tether and activate the polymer hybrid catalysts prior to the catalytic reactions. Site-normalized batch kinetics are used to assess the role of polymer molecular weight and chain composition in the cooperative catalysis. Lower-molecular-weight copolymers are demonstrated to be more active than catalysts built from only molecular organic components or from higher-molecular-weight chains. Molecular dynamics simulations are used to probe the role of polymer flexibility and morphology, whereby it is determined that higher-molecular-weight hybrid structures result in congested pores that inhibit active site cooperativity and the diffusivity of reagents, thus resulting in lower rates during the reaction.

Compartmentalisation of molecular catalysts for nonorthogonal tandem catalysis.

The development of nonorthogonal tandem catalysis enables the use of a combination of arbitrary catalysts to rapidly synthesize complex products in a substainable, efficient, and timely manner. The key is to compartmentalise the molecular catalysts, thereby overcoming inherent incompatibilities between individual catalysts or reaction conditions. This tutorial review analyses the development of the past two decades in the field of nonorthogonal tandem catalysis with an emphasis on compartmentalisation strategies. We highlight design principles of functional materials for compartmentalisation and suggest future directions in the field of nonorthogonal tandem catalysis.

Novel Small Molecule Fibroblast Growth Factor 23 Inhibitors Increase Serum Phosphate and Improve Skeletal Abnormalities in Hyp Mice.

Excess fibroblast growth factor (FGF) 23 causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the fibroblast growth factor receptor/α-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design, we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23. Additional structure-activity studies developed a series of ZINC13407541 analogs with enhanced drug-like properties. In this study, we tested in a preclinical Hyp mouse homolog of XLH a direct connect analog [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] (8n), which exhibited the greatest stability in microsomal assays, and [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] (13a), which exhibited increased in vitro potency. Using cryo-electron microscopy structure and computational docking, we identified a key binding residue (Q156) of the FGF23 antagonists, ZINC13407541, and its analogs (8n and 13a) in the N-terminal domain of FGF23 protein. Site-directed mutagenesis and bimolecular fluorescence complementation-fluorescence resonance energy transfer assay confirmed the binding site of these three antagonists. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and increased serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound had greater therapeutic effects in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat excess FGF23-mediated disorders. SIGNIFICANCE STATEMENT: This study used structure-based drug design and medicinal chemistry approaches to identify and optimize small molecules with different stability and potency, which antagonize excessive actions of fibroblast growth factor 23 (FGF23) in hereditary hypophosphatemic rickets. The findings confirmed that these antagonists bind to the N-terminus of FGF23 to inhibit its binding to and activation of the fibroblast growth factor receptors/α-Klotho signaling complex. Administration of these lead compounds improved phosphate homeostasis and abnormal skeletal phenotypes in a preclinical Hyp mouse model.

Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.

Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area. Current outcomes described in this work highlight efforts related to lead identification and modification using organic synthesis of strategic analogues to probe structure-activity relationships and preliminarily define the pharmacophore of a computationally derived hit obtained from virtual high-throughput screening. Synthetic strategies for the initial hit and analogue preparation, as well as preliminary cellular in vitro assay results highlighting sub micromolar inhibition of the FGF-23 signaling sequence at a concentration well below cytotoxicity are reported herein.