Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates

Requirements for novel bioconjugation reactions for the synthesis of antibody–drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies through a simple one‐pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next‐generation antibody therapeutics in terms of serum stability and in vivo antitumor activity.     

Hydrogels Incorporating GdDOTA: Towards Highly Efficient Dual T(1) /T(2) MRI Contrast Agents

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA?NPs) exhibited high relaxivity (r(1) =101.7?s(-1) mM(-1) per Gd(3+) ion at 37?°C and 20?MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1) /T(2) dual-mode contrast agent was studied in C6 cells.     

Turnover numbers, turnover frequencies, and overpotential in molecular catalysis of electrochemical reactions. Cyclic voltammetry and preparative-scale electrolysis

The search for efficient catalysts to face modern energy challenges requires evaluation and comparison through reliable methods. Catalytic current efficiencies may be the combination of many factors besides the intrinsic chemical properties of the catalyst. Defining turnover number and turnover frequency (TOF) as reflecting these intrinsic chemical properties, it is shown that catalysts are not characterized by their TOF and their overpotential (η) as separate parameters but rather that the parameters are linked together by a definite relationship. The log TOF-η relationship can often be linearized, giving rise to a Tafel law, which allows the characterization of the catalyst by the value of the TOF at zero overpotential (TOF(0)). Foot-of-the-wave analysis of the cyclic voltammetric catalytic responses allows the determination of the TOF, log TOF-η relationship, and TOF(0), regardless of the side-phenomena that interfere at high current densities, preventing the expected catalytic current plateau from being reached. Strategies for optimized preparative-scale electrolyses may then be devised on these bases. The validity of this methodology is established on theoretical grounds and checked experimentally with examples taken from the catalytic reduction of CO(2) by iron(0) porphyrins.     

New Applications of Ph 3 P=N--Li in Organic Synthesis and Heteroatom Chemistry

The lithium triphenylaminophosphonium azayldiide 1 proved again to be a very good tool in organic synthesis, allowing further synthesis of various compounds such as vinyl nitriles, aromatic or heteroaromatic nitriles, and mono-, bis-, and trisphosphinimines.     

Primary Amine‐Initiated Polymerizations of α–Amino Acid N‐Thiocarbonic Acid Anhydrosulfide

The N‐thiocarbonic acid anhydrosulfides NTAs of D,L‐leucine, D,L‐phenylalanine and sarcosine were polymerized in dioxane by addition of n‐hexylamine as initiator. Despite variation of the monomer‐initiator ratio (M/I) only low yields of oligopeptides were obtained from D,L‐Leu‐ and D,L‐Phe‐NTA. Both yields and molecular weights were almost twice as high for polymerizations of Sar‐NTA. MALDI‐TOF mass spectra confirmed that the isolated oligo‐and polypeptides possess the expected structure with one reactive amino end group. Therefore, it is surprising that the polymerizations stopped at low conversions. Two hypotheses explaining this phenomenon are discussed.     

Application Properties of Stimuli-Responsive Polyglycerol Hydrogels

Transient state swelling behavior and swelling kinetics of novel stimuli-responsive polyglycerol hydrogels were studied at 293, 310 and 333 K. Depending on temperature, Fickian or anomalous diffusion behavior was observed. Mechanical properties of the hydrogels in the swollen and dry states were investigated and the average molecular weight between crosslinks was calculated. To assess the potential for biodegradation of hydrogels, initial swelling behavior in phosphate buffered saline (PBS) solution and mass loss profiles as a function of degradation time were investigated over a period of 30 days. All swelling behavior, mechanical properties and degradations were clearly affected by the degree of cross-linking. The hydrophilicity and biodegradability of polyglycerol hydrogels make them suitable for pharmaceutical, biomedical and biotechnological applications. They could potentially serve as a substitute for common fossil-based hydrogels such as poly(ethylene glycol) and poly(vinyl alcohol) hydrogels.     

Poly(Urethane)-Crosslinked Poly(HEMA) Hydrogels

Abstract

Hydrogels have been prepared from 2-hydroxyethyl methacrylate polymerized in the presence of isocyanate-terminated poly(ethylene glycol) (PEG) crosslinking agents. PEGS of molecular weights 200, 400, and 1000 were investigated. The crosslinked nature of the hydrogels was demonstrated by their insolubility in solvents which normally dissolve poly(HEMA). Hexamethylene diisocyanate (HDI) was mainly used as the isocyanate. The molecular weight of the PEG and the crosslinker content significantly influenced the equilibrium water sorption and mechanical properties of the saturated networks. It was observed that as the molecular weight of the PEG increased, the water sorption increased and the nominal modulus decreased. However, for higher levels of cross-linker, water sorption decreased and modulus increased at low molecular weight PEG; for PEG 1000, water absorption increased as crosslinker content increased. These results are explained by the competing effects of flexibility, crosslink density, and hydrophobicity contributed by the various constituents of the hydrogels.     

Synthetic Applications of Phosphonium Diylides

Abstract

Phosphonium diylides 1 react with electrophiles leading to new monoylides which permit., by a Wittig reaction, the E stereoselective synthesis of various di- or tri-substituted α,β-unsaturated functionalized compounds.