No abstract

The synthesis of 13-membered polyamine alkaloid, (S)-dihydroperiphylline, was achieved by the condensation of a chiral β-lactam, (S)-4-phenyl-2-azetidinone, with a cyclic imino ether of a 9-membered lactam, followed by reductive ring expansion. Both of these reactions proceeded with retention of configuration around the chiral center to give the optical pure 13-membered alkaloids.

Abstract. In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G 2 /M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 -20 h, and then gradually decreased. Instead, QO-1 increased the sub-G 1 population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased timedependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization.

1,4-Naphthoquinone 1-oxime methyl ethers carrying an ester-substituted aryl pendant at 2-position were concisely prepared as seed compounds with structural flexibility for structure-activity relationship studies on antitumor activity. The key synthetic intermediate was a phthalide-tetralone spiro compound, which was provided by palladium-coupling reaction between 2-bromobenzoate and 1-tetralone followed by OsO 4 -NMO oxidation.

Synthesis of Polyamine Alkaloids by the Condensation of a Chiral β-Lactam with a Cyclic Imino Ether. (S)-Dihydroperiphylline and ItsDerivatives.-A facile route for the synthesis of (S)-dihydroperiphylline (Va) and its analogues (Vb) and (Vc) utilizing the condensation of chiral lactam (II) with a cyclic imino ether of a 9-membered lactam (III) and following reductive ring expansion as the key reactions is described. -(MATSUYAMA,