Total Synthesis of Nocarterphenyls A-B and 2-Dehydroxymethylnocarterphenyl A, Formal Synthesis of Nocarterphenyl D, and Biological Evaluation of Nocarterphenyls as α-Glucosidase Inhibitors

Abstract The divergent total synthesis of nocarterphenyls A-B and 2-dehydroxymethylnocarterphenyl A, as well as the formal synthesis of nocarterphenyl D, have been accomplished in five to six steps. The convergent route featured a novel one-step C–H functionalization of aniline to form the benzothiazole ring, a double Suzuki–Miyaura coupling to construct the thiazole-fused p-terphenyl core, and late-stage dehydrogenative couplings to afford nocarterphenyls divergently. Biological evaluation indicated that these natural products and their derivatives represent a new class of potent α-glucosidase inhibitors. Among all tested compounds, nocarterphenyl derivative 5 exhibited the strongest inhibitory effect, with an IC50 value of 9.82 ± 0.31 μM, which was markedly greater than that of the positive control acarbose (570 ± 4.40 μM). Enzyme kinetic assays demonstrated compound 5 to be a reversible, mixed-type α-glucosidase inhibitor. Circular dichroism (CD) spectroscopy further revealed that the binding of compound 5 induced pronounced conformational alterations and obvious changes in the microenvironment surrounding the secondary structure of α-glucosidase.