Tracing Binding Modes in Hit‐to‐Lead Optimization: Chameleon‐Like Poses of Aspartic Protease Inhibitors

Successful lead optimization in structure‐based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision‐making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)‐validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X‐ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well‐established surrogate for e.g. renin and β‐secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.     

Direct arylation of benzene with aryl bromides using high-temperature/high-pressure process windows: expanding the scope of C-H activation chemistry

A detailed investigation on the direct arylation of benzene with aryl bromides by using first-row transition metals under high-temperature/high-pressure (high-T/p) conditions is described. By employing a parallel reactor platform for rapid reaction screening and discovery at elevated temperatures, various metal/ligand/base combinations were evaluated for their ability to enable biaryl formation through C-H activation. The combination of cobalt(III) acetylacetonate and lithium bis(trimethylsilyl)amide was subjected to further process intensification at 200?°C (15?bar), allowing a significant reduction of the catalyst/base loading and a dramatic increase in catalytic efficiency (turnover frequency) by a factor of 1000 compared to traditional protocols. The high-throughput screening additionally identified novel nickel- and copper-based metal/ligand combinations that favored an amination pathway competing with C-H activation, with the addition of ligands, such as 1,10-phenanthroline, having a profound influence on the selectivity. In addition to metal-based catalysts, high-T/p process windows were also successfully applied to transition-metal-free systems, utilizing 1,10-phenanthroline as organocatalyst.     

A Fluorinated Detergent for Membrane‐Protein Applications

Surfactants carrying fluorocarbon chains hold great promise as gentle alternatives to conventional hydrocarbon‐based detergents for the solubilization and handling of integral membrane proteins. However, their inertness towards lipid bilayer membranes has limited the usefulness of fluorinated surfactants in situations where detergent‐like activity is required. We demonstrate that fluorination does not necessarily preclude detergency, as exemplified by a fluorinated octyl maltoside derivative termed F₆OM. This nonionic compound readily interacts with and completely solubilizes phospholipid vesicles in a manner reminiscent of conventional detergents without, however, compromising membrane order at subsolubilizing concentrations. Owing to this mild and unusual mode of detergency, F₆OM outperforms a lipophobic fluorinated surfactant in chaperoning the functional refolding of an integral membrane enzyme by promoting bilayer insertion in the absence of micelles.     

Phase synchronization from noisy univariate signals

We present methods for detecting phase synchronization of two unidirectionally coupled, self-sustained noisy oscillators from a signal of the driven oscillator alone. One method detects soft phase locking; another hard phase locking. Both are applied to the problem of detecting phase synchronization in von Kármán vortex flow meters.     

Catalytic Properties of High Nitrogen Content Carbonaceous Materials

The influence of structural modifications on the catalytic activity of carbon materials is poorly understood. A collection of carbonaceous materials with different pore networks and high nitrogen content was characterized and used to catalyze four reactions to deduce structure–activity relationships. The CO₂ cycloaddition and Knoevenagel reaction depend on Lewis basic sites (electron-rich nitrogen species). The absence of large conjugated carbon domains resulting from the introduction of large amounts of nitrogen in the carbon network is responsible for poor redox activity, as observed through the catalytic reduction of nitrobenzene with hydrazine and the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine using hydroperoxide. The material with the highest activity towards Lewis acid catalysis (in the hydrolysis of (dimethoxymethyl)benzene to benzaldehyde) is the most effective for small molecule activation and presents the highest concentration of electron-poor nitrogen species.     

Chelation versus Binucleation: Metal Complex Formation with the Hexadentate all‐cis‐N1,N2‐Bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine

The hexadentate ligand all‐cis‐N¹,N²‐bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine (L^e) was synthesized in five steps with an overall yield of 39 % by using [Ni(taci)₂]SO₄?4 H₂O as starting material (taci=1,3,5‐triamino‐1,3,5‐trideoxy‐cis‐inositol). Crystal structures of [Na_0.5(H₆L^e)](BiCl₆)₂Cl_0.5?4 H₂O ( 1 ), [Ni(L^e)]‐ Cl₂?5 H₂O ( 2 ), [Cu(L^e)](ClO₄)₂?H₂O ( 3 ), [Zn(L^e)]CO₃?7 H₂O ( 4 ), [Co(L^e)](ClO₄)₃ ( 5 c ), and [Ga(H_?2L^e)]‐ NO₃?2 H₂O ( 6 ) are reported. The Na complex 1 exhibited a chain structure with the Na⁺ cations bonded to three hydroxy groups of one taci subunit of the fully protonated H₆(L^e)⁶⁺ ligand. In 2 , 3 , 4 , and 5 c , a mononuclear hexaamine coordination was found. In the Ga complex 6 , a mononuclear hexadentate coordination was also observed, but the metal binding occurred through four amino groups and two alkoxo groups of the doubly deprotonated H_?2(L^e)^2?. The steric strain within the molecular framework of various M(L^e) isomers was analyzed by means of molecular mechanics calculations. The formation of complexes of L^e with Mn^II, Cu^II, Zn^II, and Cd^II was investigated in aqueous solution by using potentiometric and spectrophotometric titration experiments. Extended equilibrium systems comprising a large number of species were observed, such as [M(L^e)]²⁺, protonated complexes [MH_z(L^e)]^2+z and oligonuclear aggregates. The pK_a values of H₆(L^e)⁶⁺ (25 °C, μ=0.10 m ) were found to be 2.99, 5.63, 6.72, 7.38, 8.37, and 9.07, and the determined formation constants (log β) of [M(L^e)]²⁺ were 6.13(3) (Mn^II), 20.11(2) (Cu^II), 13.60(2) (Zn^II), and 10.43(2) (Cd^II). The redox potentials (vs. NHE) of the [M(L^e)]^3+/2+ couples were elucidated for Co (?0.38 V) and Ni (+0.90 V) by cyclic voltammetry.     

Direct Arylation of Benzene with Aryl Bromides using High‐Temperature/High‐Pressure Process Windows: Expanding the Scope of C?H Activation Chemistry

A detailed investigation on the direct arylation of benzene with aryl bromides by using first‐row transition metals under high‐temperature/high‐pressure (high‐T/p) conditions is described. By employing a parallel reactor platform for rapid reaction screening and discovery at elevated temperatures, various metal/ligand/base combinations were evaluated for their ability to enable biaryl formation through C? H activation. The combination of cobalt(III) acetylacetonate and lithium bis(trimethylsilyl)amide was subjected to further process intensification at 200 °C (15 bar), allowing a significant reduction of the catalyst/base loading and a dramatic increase in catalytic efficiency (turnover frequency) by a factor of 1000 compared to traditional protocols. The high‐throughput screening additionally identified novel nickel‐ and copper‐based metal/ligand combinations that favored an amination pathway competing with C? H activation, with the addition of ligands, such as 1,10‐phenanthroline, having a profound influence on the selectivity. In addition to metal‐based catalysts, high‐T/p process windows were also successfully applied to transition‐metal‐free systems, utilizing 1,10‐phenanthroline as organocatalyst.