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Galectin proteins have been targets of interest in numerous therapeutic areas for some time. Galectin-3 has been identified as a target of particular interest because of its unique structural characteristics and physiological profile. Recent literature indicates Gal-3 inhibition can decrease myofibroblast activation and procollagen expression with the potential to affect the progression of fibrosis in the lung, liver and kidney. Potential π-stacking interactions between one monosaccharide ligand bound to the carbohydrate recognition domain of a galectin-3 protein and a second ligand bound to a different galectin-3 protein molecule were observed in the extended crystalline lattice in an X-ray crystal structure obtained while studying the monosaccharide structure-activity relationship. The direct interaction between the ligands suggests a potential for dimeric galectin-3 inhibitors which bind to two galectin-3 molecules simultaneously. This work describes the exploration of dimers designed to further probe these observations and explore the potential of binding to dimeric or higher order multimeric galectin-3 assemblies.

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC

Electrophilic substitution protocols useful for functionalizations at C7 of 4-hydroxy-6-methyl-2-pyrone, or triacetic acid, are described here. This method was applied to the synthesis of annularin E.

[reaction: see text] An enantioselective total synthesis of (-)-cylindricine C is described, featuring a diastereoselective intramolecular aza-[3 + 3] annulation strategy and an interesting halohydrin formation of the C4-5 olefin for construction of C4-ketone. This work provides a unique approach to this family of natural products.

[reaction: see text] Details of problems and solutions encountered during the development of an enantioselective total synthesis of (+)-cylindricine C are described here. The total synthesis itself was accomplished in 8 steps, featuring an N-acyliminium cyclization strategy, the seldom-used Wharton rearrangement, and a key epimerization at C5.

Azaheterocyclic compounds are interesting and medicinally relevant targets. Herein we disclose an improved synthesis into the oxazepine and thiazepine ring systems. The key step in the synthesis exploits recent advancements in the palladium-catalyzed amination reaction, which was utilized to form the seven-membered rings. General conditions for this reaction were Pd2dba3, P(t-Bu)3, NaO-t-Bu alone or with K2CO3, in toluene. The scope of the reaction was investigated, and has been shown to be effective on a variety of substrates as illustrated.

[reaction: see text] A Lewis acid-catalyzed formal cycloaddition of alpha,beta-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters is described here.

A Lewis acid-catalyzed formal cycloaddition of α,β-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters is described here.

Efforts in achieving an enantioselective total synthesis of (-)-cylindricine C along with the syntheses of putative lepadiformine, epi-lepadiformines, (-)-4-deoxo-cylindricine C, and (-)-2-epi-cylindricine C are described here in details. These syntheses feature a stereoselective intramolecular aw-[3+ 3] annulation as a unified strategy, and specifically, the total synthesis of (-)-cylindricine C was accomplished in 22 steps with a 4.5% overall yield from L-serine. In addition, we developed an interesting halohydrin formation for the construction of the C4-ketone of cylindricines.