One-pot sugar conversion to N-aryl pyrrole-2-carbaldehydes for the synthesis and cytotoxic evaluation of lamellarin R analogues.

We report a modular synthetic approach to lamellarin R derivatives based on ribose conversion with substituted anilines, enabling rapid access to N-arylated pyrrole-2-carbaldehyde scaffolds. Subsequent Pinnick oxidation, bromination, halogen migration, and Suzuki-Miyaura coupling afforded a series of 3,4- and 4,5-diarylpyrrole-2-carboxylates as lamellarin R analogues bearing diverse aryl substituents. The synthesized compounds were evaluated for cytotoxicity against SW480 colorectal cancer and EJ-1 bladder cancer cell lines. Structure-activity relationship studies revealed that a 4-(4-hydroxyphenyl) substituent on the pyrrole ring is essential for cytotoxic activity, whereas N-(4-methoxyphenyl) substitution conferred the highest cytotoxic potency. Selectivity index (SI) analyses showed that natural lamellarin R (1) exhibited the highest selectivity toward SW480 cells, whereas compound 3a was the most selective toward EJ-1 cells. Overall, this study demonstrates that the ribose conversion strategy provides an efficient and versatile platform for the synthesis and SAR exploration of lamellarin R derivatives.