Synthesis and Biological Screening of Structurally Modified Phaeosphaeride Analogues

Phaeosphaeride A and its analogues have been extensively explored for their potential pharmacological applications, particularly in the development of anticancer agents. In this study, the synthesis of structurally modified phaeosphaeride analogues is reported. The structures of the synthesized analogues bearing the tetrahydro- and hexahydro-2H-furo[3,2-b]pyran-2-one and hexahydropyrano[3,2-b]pyrrol-2(1H)-one moieties were assessed and the new compounds were evaluated for their antiproliferative activity against two cancer cell lines. Despite successful synthesis and structural modification, the majority of the phaeosphaeride analogues exhibited limited bioactivity. Structure-activity relationship studies suggested that specific modifications did not enhance anticancer potency. The hydroxy groups and the alkyl moiety in cyclic or non-cyclic phaeosphaeride analogues contribute to the activity, as shown by the activity of compounds 24 and 25. The presence of double bonds and oxygen or nitrogen heteroatoms in furopyranones or pyranopyrrolones 9, 28, 29 and 33a, does not significantly impact cytotoxic activity. These findings highlight the challenges in optimizing phaeosphaerides for anticancer applications and provide insights into future structural modifications to improve their therapeutic potential. Moreover, our studies open a synthetic route for the development of new phaeosphaeride analogues.