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With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3b enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents. [ABSTRACT FROM AUTHOR]

Starting from 3,5-dimethoxybenzaldehyde, some functionalized 2,3,4-trisubstituted tricyclic 4,5-cycloalkyl-fused and 6-modified chromans could be prepared via ortho-quinone methides ( o-QMs)/hetero-Diels-Alder (HDA) reactions of the appropriate precursors. The bromide at C6 served as a handle for introducing other substituents through palladium-catalyzed cross-coupling reactions and other functional-group transformations. Moderate to high yields (up to 80 %) and diastereoselectivities (up to >99:1) could be obtained under [PtCl4] catalysis. The preferred endo transition state during the cycloaddition reaction played an important role in governing the stereochemical outcomes at C2C3C4. The configurationally fixed E geometry of the bicyclic o-QMs influenced the cycloaddition reactions to favor the C2C4 cis relationship. [ABSTRACT FROM AUTHOR]