Xiongyu Wu

Synthesis, X-Ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors.

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a Ki of 2.1 nM and an EC50 of 0.64 μM. Further optimization by decoration of the P1′ side chain furnished an even more potent HIV-1 protease inhibitor (Ki = 0.8 nM, EC50 = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

Fast, acid-free, and selective lactamization of lactones in ionic liquids.

A fast and acid-free one-pot 0.2-30 mmol microwave methodology for direct ionic liquid-mediated preparation of lactams from lactones and primary amines has been developed. The protocol was investigated with a wide range of primary amines and a handful of lactones, including substrates with acid-sensitive substituents. Both gamma-lactams and delta-lactams were, despite the complete absence of a Brønsted acid, obtained in useful to excellent yields after only 35 min of microwave processing.

HIV-1 protease inhibitors with a tertiary alcohol containing transition-state mimic and various P2 and P1′ substituents

Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as the transition-state mimic have been synthesised and evaluated. Replacement of the previously used, but metabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moieties provided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 μM, respectively). The P1′ subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing the corresponding inhibitors with retained activity. Permeability and stability studies showed examples in the same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme co-complexes (9a and 9d) supplied detailed structural information. The binding modes were compared to those of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novel inhibitors with an elongated P1′ side chain enabled a previously unexploited edge-on interaction with Phe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3 side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 A shift of the Arg8/108 in comparison to 14, indicating the flexibility of the protease active site.