Design and Synthesis of New Antitumor Agents Using Marine Natural Product Lamellarin as A Structural Motif

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A marine natural product lamellarin D exhibits potent cytotoxicity against a wide range of cancer cell lines. This compound is also effective for multidrug resistant (MDR)cancer cell lines. We have developed two different types of synthetic routes to lamellarine-class natural products. We have also performed structure-activity relationship studies using synthetic analogues and revealed structural requirements for cytotoxicity. Recently, Bailly and co-workers have reported that the major mechanism of action of lamellarin D is the inhibition of topoisomerase I which is known to be the molecular targent of approved camptotecin-type antitumor agents. We performed collaboration with Bailly group to propose topoisomerase I-DNA-lamellarin D ternary complex model. Based upon this model, we designed 1-dearyllammelarin D and 1-substituted 1-dearyllamellarin D as effective lamellarin D analogues. In the present research project, we planned to develop efficient synthetic routes to these analogues … More and evaluate their antitumor activity.Thus, we have achieved the synthesis of 1-dearyllamellarin D in eight steps using regioselective lithiation of N-benzenesulfony1-3-bromopyrrole as a key reaction. Electrophilic substitutions of the O-protected (by isopropyl group)1-dearyllamellarin D proceeded at the 1-position selectively to give a variety of 1-substituted O-protected 1-dearyllamellarin D s. O-protected 1-bromo-1-dearyllamellarin D underwent palladium-catalyzed cross-coupling (Suzuki-Miyaura coupling)with boronic acids in the presence of CsF-Ag_2O to give the other types of 1-substituted O-protected 1-dearyllamellarin D s in good yields. Deprotection of the isopropyl group of these compounds by boron trichloride gave 1-substituted 1-dearyllamellarin D analogues.The bioassay of these new analogues against a wide range of cancer cell lines is under investigation. A preliminary result indicated 1-dearyllamellarin D exhibited potent cytotoxicity against Hela cells in the level similar to lamellarin D. Less