Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors.

Novel 4′-C-ethynyl isomeric dioxolane nucleoside analogues (β-D, α-D, β-L, and α-L, respectively) are successfully synthesized via a divergent strategy from the common starting material, (Z)-but-2-ene-1,4-diol, and are characterized and evaluated for their anti-HIV-1 and anti-HIV-2 activities. The β-D and β-L products display potent in vitro activities against HIV-1 (IIIB) with EC 50 values of 0.75 and 0.87 μM, respectively, and against HIV-2 (ROD) with EC 50 values of 0.75 and 0.35 μM, respectively, being better in comparison with 3TC [EC 50 , 5.27 μM (HIV-1) and 1.30 μM (HIV-2)]. The β-D and β-L nucleosides also potently inhibit different drug-resistant strains of the HIV-1 virus (L100I, K103N, Y181C, and V106A). The selectivity indices and cytotoxic profiles of the β-D and β-L nucleosides are much better than those of the standard drugs AZT and d4T.