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On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andreas Sebastian Klein, Thomas Classen, Jörg Pietruszka
Enzymes are often associated with the term “green chemistry” because they are natural, biological degradable and so on. However, it must be considered that enzymes are usually used in aqueous solutions causing downstream challenges: energy consuming evaporation or salt/solvent contaminated wastewater. These drawbacks may be taken into account if the synthesis profits from an enzyme’s selectivity, which is in many cases much higher than the selectivity of competing chemical catalysts. Enzymes may install chemical moieties by their chemoselectivity and may bypass step-intensive protective strategies. Stereogenic centers might be installed with high selectivity by means of asymmetric synthesis or the enantiomeric excess can be increased to pharmaceutical relevance by means of kinetic resolution.
The problem of racemization in drug discovery and tools to predict it
Published in Expert Opinion on Drug Discovery, 2019
Andrew Ballard, Stefania Narduolo, Hiwa O. Ahmad, David A. Cosgrove, Andrew G. Leach, Niklaas J. Buurma
The impact of chirality on drug discovery has been reviewed previously and here we focus primarily on work that includes specific studies of the process of racemization. Relevant reviews include general surveys of chiral drugs, as well as those that describe the impact of chirality on toxicity and on synthesis [1–5]. Some studies of racemization have also been reviewed elsewhere [6,7]. In the context of dynamic kinetic resolution (DKR) for the preparation of highly enantio-enriched materials, a rapid racemization is often desirable [8]. Where an enzyme is the chiral catalyst in DKR, racemization must occur in conditions that are compatible with the enzyme. These conditions are likely to be similar to those in biological systems in general, and therefore also to be relevant to drug discovery.
Brain slice viability determined under normoxic and oxidative stress conditions: involvement of slice quantity in the medium
Published in Neurological Research, 2020
Zulfiye Gul, M. Cagatay Buyukuysal, R. Levent Buyukuysal
In vitro acute adult brain slice models offer a rapid instrument for examining the electrophysiological and metabolic properties without contaminating by intrinsic regulatory substances, relaxants, or anesthetics. Moreover, these models largely preserve the tissue architecture of the brain regions that they originated from and maintain neuronal activities with intact functional local synaptic circuitry unlike cultures or cell homogenates [1,4]. Additionally, brain slices, as other in vitro methods, have many advantages of permitting greater control of the surrounding environment such as temperature, pH, O2 concentration, and finer kinetic resolution of pharmacological experiments.
Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients
Published in Expert Opinion on Drug Discovery, 2023
Other important targets, of note, are Sumitomo Chemical Co’s key building block for the anti-AIDS drug darunavir that used a Jørgensen-Hayashi diphenylprolinol (3 mol% loading) catalyzed multi-gram aldol reaction step [46], Abbott’s dipeptidyl peptidase IV inhibitor and type 2 diabetes candidate ABT-341 that involved a prolinol 6 catalyzed Michael addition [47], as well as the use of the isothiourea; levamisole, in a key alcohol kinetic resolution step for BMS-986001, a nucleoside RT inhibitor (NRTI) used for the treatment of AIDS (in fact this organocatalyzed route proved better than various biocatalytic processes [48]).