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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
It is noteworthy that thalidomide is synthesized, purified, and administered as a racemic mixture. However, the individual (R)- and (S)-enantiomers differ from the racemate, each having higher water solubility by a factor of approximately three. There is also indirect evidence that enantiomerically pure thalidomide is absorbed more readily and undergoes faster hydrolytic cleavage. Another interesting aspect of the stereochemistry is that the (R)-enantiomer is responsible for the sedative effect, whereas the (S)-isomer is teratogenic. However, both in vitro and in vivo studies have shown that, under physiological conditions, there is very rapid racemization, so whichever enantiomer is administered, a similar equilibrium mixture will quickly be established.
Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Stereochemistry is an important consideration when designing drugs, as chirality can have important implications for drug metabolism. Metabolic enzymes can often distinguish between two enantiomers, such that each can undergo different reactions. This means that testing each enantiomer separately during screening is necessary and may mean that the design of a drug may need an asymmetric synthesis.
Chemistry of Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
The synthesis of l-menthol (94) provides an interesting example of different routes operating in economic balance. The three production routes in current use are shown in Figure 6.40. The oldest and simplest route is extraction from plants of the Mentha genus and M. arvensis (corn mint) in particular. This is achieved by freezing the oil to force the l-menthol to crystallize out. Diethylamine can be added to myrcene (70) in the presence of base and rearrangement of the resultant allyl amine (224) using the optically active catalyst ruthenium (S)-BINAP perchlorate gives the homochiral enamine (225). This can then be hydrolyzed to d-citronellol (209). The chiral center in this molecule ensures that, on acid-catalyzed cyclization, the two new stereocenters formed possess the correct stereochemistry for conversion, by hydrogenation, to give l-menthol as the final product. Starting from the petrochemically sourced m-cresol (226), propenylation gives thymol (97), which can be hydrogenated to give a mixture of all eight stereoisomers of menthol (227). Fractional distillation of this mixture gives racemic menthol. Resolution was originally carried out by fractional crystallization, but recent advances include methods for the enzymic resolution of the racemate to give l-menthol.
How do we further enhance 2D fingerprint similarity searching for novel drug discovery?
Published in Expert Opinion on Drug Discovery, 2022
Although more complex and information-rich molecular representations such as 3D fingerprints exist, they rarely outperform 2D fingerprints [5]. 3D fingerprints allow for encoding molecular features that are mostly inaccessible to 2D methods, such as describing non-bonding atoms close in space but topologically distant, stereochemistry, and conformational ensemble characteristics. These 3D features can add important additional molecular information and therefore have the potential to provide better similarity prediction performance. However, the often difficult identification and weighting of relevant conformations adds noise and complexity, often without performance gain. Comparing directly related extended 3D circular fingerprints (E3FP) and 2D circular fingerprints (E2FP) demonstrated better performance of the 3D method in bioactivity predictions; however, this example is a rare exception in 3D fingerprint superiority [6]. 2D fingerprints remain largely popular due to their low sensitivity to feature noise and their proven success in finding diverse compounds with desired properties and activities. Of note are alternative molecular fingerprint representations such as biological or affinity fingerprints consisting of compound potencies against a panel of protein targets in combination with QSAR training that have generated promising results in scaffold hopping and virtual screening [7].
A patent review of adenosine A2B receptor antagonists (2016-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Beatrice Francucci, Diego Dal Ben, Catia Lambertucci, Andrea Spinaci, Rosaria Volpini, Gabriella Marucci, Michela Buccioni
Two patents (A and B) reported, in 2020, several substituted amino triazolopyrimidines and amino triazolopyrazines as adenosine receptor antagonists, pharmaceutical composition, and their use in the treatment of various diseases that are mediated by the A2A and/or A2BARs [96]. The biological evaluation was performed by binding assay and the values were expressed as IC50. All compounds were selective for A2AAR and showed, at the same time, good A2BAR antagonist activity. Representative compounds (patents A and B) are reported in Table 4. All the compounds present in patent A are sterically cluttered and they show only small structure differences. The stereochemistry of the carbon atoms of methyl-piperidine, linked to the amino triazolo-pyrimidine, is important for the activity. In fact, compounds 2–3, 4–5, which are enantiomers, showed a different activity toward the A2A/A2BARs. Compounds 2 and 4, which have carbons in the configurations (2s, 5r) and (3r, 6s) respectively, have a better affinity for both receptor subtypes than their respective enantiomers. Compounds reported in patent B have the central core identical to the compounds synthesized in the precedent patent but differ from the substituent in the 1 position of triazole. This modification is significant, since it switches affinity and selectivity toward A2BAR.
Harnessing the power of foot-and-mouth-disease virus for targeting integrin alpha-v beta-6 for the therapy of cancer
Published in Expert Opinion on Drug Discovery, 2021
Most interactions of cells with their environment, be it with extracellular matrix, other cells or pathogens are usually through protein-protein interactions. This means for every receptor there is a definable amino-acid sequence arranged in a specific stereochemistry that provides a specific binding site on a ligand. A20FMDV2 is special example of one of these defined amino-acid sequences in that within just 20 amino-acids it provides two separate receptor-binding sites (RGD and hydrophobic LXXL/I sites) and a shape stabilizing α-helix. Its ability as an unstructured linear peptide to assume a 3D shape when bound to αvβ6 that closely matches the FMDV virus protein from which it was derived is critical in its specificity and activity. Its remarkable activity (<1 nM) and specificity for αvβ6 are rare among peptide inhibitors of integrins and almost certainly unique as a linear integrin-inhibiting peptide.