Free–Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity

Abstract

Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free–Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry

“…The University of Nottingham (UoN) has been hosting drug discovery activities analogous to those undertaken in pharmaceutical companies for 10 years as part of both its teaching and learning (T&L) activities − and also as part of its R&D portfolio. − As of September 2019, the GSK Carbon Neutral Laboratory for Sustainable Chemistry, University of Nottingham project laboratory (which hosts 16 organic and medicinal research chemists and graduate and undergraduate students when at full capacity) has ceased its use of chlorinated solvents for all chromatographic applications except for rare cases involving solubility issues. On average, 20–25 flash chromatographic separations are conducted each week using a Biotage SP4 to purify new investigational medicinal chemistry drug molecules, synthetic natural products, and their intermediates.…”

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma

“… For instance, Idelalisib is a type of propeller-shaped inhibitor that is core-structured with quinazolin-4­(3 H )-one, and until now, there has been extensive medicinal chemistry exploration of chemotypes that give propeller-shaped structures for differential therapies. − Despite these advances, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy remains continuous interesting and important. During the course of our efforts in drug discovery and HCC therapy, − we started our exploration for PI3Kδ inhibitors by looking for a novel propeller-shaped chemotype via a scaffold-hopping strategy to replace quinazolin-4­(3 H )-one of Idelalisib. − Hence, we identified indazole as a new and suitable core to be potent, propeller-shaped, and selective PI3Kδ inhibitor . A total of 26 novel indazoles were designed and prepared to identify compound 9x , which exhibits good isoform selectivity, pharmaceutical profile, and a notably superior efficacy toward HCC compared to Idelalisib and Sorafenib.…”

Synthesis of Quinolone Antibiotic Analogues: A Multistep Synthetic Chemistry Experiment for Undergraduates

“…This multistep experiment allows for a more challenging synthetic organic chemistry experience for undergraduate students and allows them to carry out organic transformations typically used in the pharmaceutical industry and that are taught in the organic chemistry curriculum, which includes the preparation of acyl chlorides, 1,4-conjugate addition–elimination, heterocycle synthesis, nucleophilic aromatic substitution, and ester hydrolysis. This experiment provides a guided-inquiry based project that is closely aligned with industrial pharmaceutical chemistry and research and contributes to our ongoing work in training “industry-ready” graduates in medicinal chemistry. − …”