Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity.

Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 in vitro to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.

Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes.

Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.

We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.

General methods for flash chromatography using disposable columns.

As technology has evolved available guidelines for normal-phase flash chromatography have become less relevant. Years of experience performing chromatography with disposable columns have been condensed into simple guidelines useful for translating TLC results into either isocratic- or gradient-flash chromatography. The described studies should provide researchers with a means of selecting adequate columns and guidelines to reduce the waste of solvents, silica, time, and money.

Inside or outside a ligand cleft? Synthetic, structural, and kinetic inertness studies of zinc, cadmium, and mercury complexes of cross-bridged cyclam and cyclen.

Ethylene cross-bridging of the popular tetraazamacrocyclic ligand cyclam has led to metal complexes with enhanced kinetic inertness. The synthesis and spectral characterization of zinc(II), cadmium(II), and mercury(II) complexes of cross-bridged cyclam (L1) as well as cross-bridged cyclen (L2) are reported along with the details of our synthetic route to L2. X-ray structural studies revealed that all Zn(II) and Cd(II) cations are fully kappa(4)N-coordinated inside the respective ligand's molecular cleft with L1 providing the better fit for Zn(II). While Hg(II) is similarly coordinated to L2, it has been found to complex L1 outside the ligand cleft in a novel exo-kappa(2)N-mode. Solution NMR data of the kappa(4)N complexes are consistent with the presence of only a single cis-folded isomer in each case. Ligand (1)H and (13)C coupling to both (111,113)Cd and (199)Hg in their complexes can be clearly discerned. The relative kinetic inertness of representative cross-bridged complexes in acidic aqueous solution has been assessed and found to be in the following order: Zn(II) > Cd(II)[dbl greater-than] Hg(II). The data also reaffirm that cross-bridged cyclam ligand L1 forms a substantially more inert complex with zinc(II) than either the smaller cyclen analogue L2 or the unbridged 1,4,8,11-tetramethyl-cyclam L3.

Synthesis of Lipophilic Paramagnetic Contrast Agents.

The facile, high-yielding synthesis of a series of macrocycles 7a-k in 75-100% yield is reported. The transformation of these compounds to their carboxymethylated analogues 8a-k in 75-90% yield and subsequent gadolinium complexes 9a-k provides a series of homologous neutral paramagnetic contrast agents (PCAs) with tunable lipophilicity. Alkylated cationic intermediates 6a-k are prepared in yields of 72-94% from glyoxal adduct of cyclen (5) and slight excesses of alkyl iodides. The methodology is selective for monoalkylation and amenable to large-scale synthesis.