The structure-based design, synthesis, biological evaluation, and X-ray structural studies of fluorine-containing HIV-1 protease inhibitors are described. The synthesis of both enantiomers of the gem-difluoro-bis-THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl) carbamate (3) and (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-aminophenyl)sulfonamido)phenylbutan-2-yl) carbamate (4), exhibited HIV-1 protease inhibitory K_i values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC₅₀ values of 0.8 and 3.1 nM against the laboratory strain HIV-1_LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high-resolution X-ray structure of inhibitor 4 in complex with HIV-1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV-1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis-THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.

β-Secretase continues to be an attractive drug discovery target for the therapeutic intervention of Alzheimer’s disease (AD). This enzyme plays a critical role in the production of neurotoxic β-amyloid (Aβ) peptides in the brain. Over the years, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Many small-molecule, peptidomimetic, and nonpeptide β-secretase inhibitors have now overcome the key challenging development hurdles such as selectivity and brain penetration. A number of inhibitors have also shown further promise in reducing brain Aβ and rescuing cognitive decline in animal models. Recently, several β-secretase inhibitors have entered into preclinical and phase I studies, and at least one of these inhibitors has advanced to phase II/III human trials. The outlook on β-secretase inhibitor drugs for the treatment of AD patients is discussed herein.

A convergent synthesis of carbocyclic sinefungin (2), its C-5 epimer 3a, and adenine-modified derivative 3b is described. The key features of our approach include the use of commercially available L-methionine and readily available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate as starting materials, a cross-metathesis reaction, an enzymatic kinetic resolution, and a Staudinger reduction. The current synthesis is flexible and, therefore, provides convenient access to the synthesis of various carbocyclic sinefungin analogues for biological evaluation.

A detailed account of the enantioselective total synthesis of (–)-zampanolide, a macrolide marine natural product with high anticancer activity, is described. For the synthesis of the 4-methylenetetrahydropyran unit of (–)-zampanolide, we initially relied upon an oxidative C–H activation of an alkenyl ether and intramolecular cyclization to provide the substituted tetrahydropyran ring. However, this strategy was unsuccessful. Subsequently, we found that a cinnamyl ether is critical for the successful oxidative intramolecular cyclization reaction. The synthesis also features a cross-metathesis reaction for the construction of a trisubstituted olefin, a ring-closing metathesis to form a highly functionalized macrolactone, and a chiral phosphoric acid promoted formation of an N-acyl aminal to furnish (–)-zampanolide stereoselectively and in good yield. The synthetic (–)-zampanolide had effects on cultured cells and on tubulin assembly consistent with the properties reported for the natural product.

Die Entstehung von Arzneimittelresistenzen ist eines der grundlegenden Probleme der Medizin. Dass sich bei HIV/AIDS so schnell resistente HIV-1-Varianten einstellen, ist ein großes Hindernis für die modernen Therapien. Wichtige Zielmoleküle der derzeitigen antiretroviralen Therapien sind Inhibitoren der HIV-1-Protease. Das Virus entwickelt Resistenzen, wenn Mutationen die Inhibitorbindung des Enzyms verändern und somit die Effizienz mindern. Um diese Resistenzbildung zu vermeiden, haben wir Inhibitoren erforscht, die am aktiven Zentrum der Protease Wasserstoffbrücken zum Proteinrückgrat bilden. Weil sich die Geometrie am katalytischen Zentrum ohne Funktionsverlust nicht ändern kann, schränken solche Wechselwirkungen die Möglichkeiten der Protease zur Resistenzbildung erheblich ein. Hier diskutieren wir das enzymatische Strukturprinzip, auf dem unser Konzept der Rückgratbindung beruht. Besonderes Augenmerk richten wir auf die Anwendung des Konzepts in unseren jüngeren Arbeiten zu antiviralen Inhibitoren der HIV-1-Protease.

The evolution of drug resistance is one of the most fundamental problems in medicine. In HIV/AIDS, the rapid emergence of drug-resistant HIV-1 variants is a major obstacle to current treatments. HIV-1 protease inhibitors are essential components of present antiretroviral therapies. However, with these protease inhibitors, resistance occurs through viral mutations that alter inhibitor binding, resulting in a loss of efficacy. This loss of potency has raised serious questions with regard to effective long-term antiretroviral therapy for HIV/AIDS. In this context, our research has focused on designing inhibitors that form extensive hydrogen-bonding interactions with the enzyme’s backbone in the active site. In doing so, we limit the protease’s ability to acquire drug resistance as the geometry of the catalytic site must be conserved to maintain functionality. In this Review, we examine the underlying principles of enzyme structure that support our backbone-binding concept as an effective means to combat drug resistance and highlight their application in our recent work on antiviral HIV-1 protease inhibitors.

A detailed account of the enantioselective total synthesis of (−)-lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α-alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero-Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.