ABSTRACT
An imidazolone â triazolone replacement addressed the limited passive permeability of a series of protein arginine methyl transferase 5 (PRMT5) inhibitors. This increase in passive permeability was unexpected given the increase in the hydrogen bond acceptor (HBA) count and topological polar surface area (TPSA), two descriptors that are typically inversely correlated with permeability. Quantum mechanics (QM) calculations revealed that this unusual effect was due to an electronically driven disconnect between TPSA and 3D-PSA, which manifests in a reduction in overall HBA strength as indicated by the HBA moment descriptor from COSMO-RS (conductor-like screening model for real solvation). HBA moment was subsequently deployed as a design parameter leading to the discovery of inhibitors with not only improved passive permeability but also reduced P-glycoprotein (P-gp) transport. Our case study suggests that hidden polarity as quantified by TPSA-3DPSA can be rationally designed through QM calculations.
Subject(s)
Arginine , Prostate-Specific Antigen , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Humans , Male , Permeability , Prostate-Specific Antigen/metabolism , Protein-Arginine N-Methyltransferases/metabolism , Transferases/metabolismABSTRACT
A practical synthesis of porphobilinogen based on the biosynthetic mechanism is described. The crossed Mukayiama aldol reaction is the key step creating the central carbon-carbon bond between the two protected forms of 5-aminolevulinic acids. The optimized sequence gives a crystalline, storable precursor, which can be transformed in high yield into porphobilinogen and bioconjugates thereof. The enzymatic hydrolysis of the precursor produces porphobilinogen in quantitative yield.
