Improved Methodology for the Synthesis of a Cathepsin B Cleavable Dipeptide Linker,Widely Used in Antibody-Drug Conjugate Research

Antibody-drug conjugates (ADCs) represent an emerging class of biopharmaceutical agents that deliver highly potent anticancer agents (payloads) selectively to tumors or components associated with the tumor microenvironment. The linker, responsible for the connection between the antibody and payload, is a crucial component of ADCs. In certain examples the linker is composed of a cleavable short peptide which imparts an additional aspect of selectivity. Especially prevalent is the cathepsin B cleavable Mc-Val-Cit-PABOH linker utilized in many pre-clinical ADC candidates, as well as the FDA approved ADC ADCETRIS^® (brentuximab vedotin). An alternative route for the synthesis of the cathepsin B cleavable Mc-Val-Cit-PABOH linker is reported herein that involved six steps from l-Citrulline and proceeded with a 50% overall yield. In this modified route, the spacer (a para-aminobenzyl alcohol moiety) was incorporated via HATU coupling followed by dipeptide formation. Importantly, this route avoided undesirable epimerization and proceeded with improved overall yield. Utilizing this methodology, a drug-linker construct incorporating a potent small-molecule inhibitor of tubulin polymerization (referred to as KGP05), was synthesized as a representative example.     

Oxidation of organic compounds by hydrogen peroxide using polymer-anchored azo-metal catalysts

Polymer-anchored azo complexes of Cu(II) and Ni(II) were synthesized by the reaction of chloromethylated polystyrene, 3-aminophenol, and 1-nitroso-2-naphthol with the metal chlorides. The catalytic activities of these complexes were studied in the oxidation of various organic substrates including alkenes, alcohols, alkanes, and sulfides with 30 % aqueous hydrogen peroxide. The structures of both catalysts have been investigated by physiochemical methods. Both catalysts proved to be very stable and could be reused more than five times without significant loss of activity. Furthermore, these catalysts require very mild reaction conditions.     

Effect of residual Doppler averaging on the probe absorption in cascade type system: A comparative study

Effect of residual Doppler averaging on the probe absorption in an alkali vapor medium in the presence of a coherent pump beam is studied analytically for the Ξ type system. A coherent probe field is assumed to connect the ground level with the intermediate level whereas a coherent control beam is supposed to act between the intermediate energy level and the uppermost level. Optical Bloch equations(OBE) for a three-level Ξ type system and a four-level Ξ type system are derived by using density matrix formalism. These equations are solved by an analytic method to determine the probe response, which not only depends on the wavelength difference between the control(pump) field and the probe field but shows substantially different features depending on whether the wavelength of the control field is greater than that of the probe field or the reverse. The effect of temperature on probe response is also shown. Enhancement in probe absorption and additional features are noticed under a strong probe limit at room temperature. The four-level Ξ type system has two ground levels and this leads to substantial modification in the simulated probe absorption as compared to the three-level system.     

Use of a recyclable poly(<Emphasis Type="Italic">N</Emphasis>-vinyl carbazole) palladium(II) complex catalyst: Heck cross-coupling reaction under phosphine-free and aerobic conditions

A poly(3,6-dibenzaldimino N-vinyl carbazole) Pd(II) complex has been synthesized and characterized by physicochemical and spectroscopic techniques. The complex was found to be highly active toward hydrogenation reactions of various organic substrates under atmospheric pressure at ambient temperature. A tentative reaction mechanism is proposed on the basis of kinetic studies and isolation of reactive intermediates. The catalyst shows good conversion rates, thermal stability and recyclability.     

A quick accelerating microwave-assisted sustainable technique: permutated spiro-casing for imaging experiment

Molecular Diversity - A quick access tool for the one-pot, chromatography-free synthesis of the diversified dihydrospiro[indeno[1,2-b]pyridine-4,3′-indoline or...     

Synthesis and Functionalization of Allenes by Direct Pd-Catalyzed Organolithium Cross-Coupling

A palladium-catalyzed cross-coupling between in situ generated allenyl/propargyl-lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri- and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.     

Chaos and order in librating quantum planar elastic pendulum

Nonlinear Dynamics - We investigate, numerically and analytically, the quantum mechanics of planar elastic pendulum in libration. The classical phase space of the system consists of both regular...     

Ligandless heterogeneous palladium: an efficient and recyclable catalyst for Suzuki‐type cross‐coupling reaction

A mild and efficient ligand‐free Suzuki‐type cross‐coupling reaction of benzoyl chlorides and arylboronic acids catalyzed by heterogeneous Pd/C was developed. Benzoyl chlorides undergo cross‐coupling with electronically diverse arylboronic acids to give biaryl ketones in excellent yield, under aqueous media and optimum temperature. The application of 3 mol% of 10 wt% Pd/C to the cross‐coupling delivers utmost efficiency, and could be reused up to many consecutive cycles without any loss in activity. This method proceeds under aqueous media and a recyclable catalytic system, offering an environmentally benign alternative to the existing protocols. Copyright © 2014 John Wiley & Sons, Ltd.