Peloruside B, A Potent Antitumor Macrolide from the New Zealand Marine Sponge Mycale hentscheli: Isolation, Structure, Total Synthesis, and Bioactivity

Abstract

Peloruside B (2), a natural congener of peloruside A (1), was isolated in sub-milligram quantities from the New Zealand marine sponge Mycale hentscheli. Peloruside B promotes microtubule polymerization and arrests cells in the G2M phase of mitosis similar to paclitaxel, and its bioactivity was comparable to that of peloruside A. NMR-directed isolation, structure elucidation, structure confirmation by total synthesis and bioactivity of peloruside B are described in this article. The synthesis features Sharpless dihydroxylation, Brown's asymmetric allylboration reaction, reductive aldol coupling, Yamaguchi macrolactonization and selective methylation.

Chemical and Biological Aspects of Marine Sponges from the Family Mycalidae

“…The 5-alkylpyrrole-2-carboxaldehydes 16,17,35,36,43,49,60, and 61 were again reisolated from a member of the Mycalidae family, this time from an unidentified M. (Carmia) sp. from Palau together with twelve new mycalenitriles 4-14 (65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75), and seven new mycalazals 14-20 (76-82) [29]. Finally, in 2013, an unidentified Mycale sp.…”

“…Pelorusides share some structural similarity to the geminal dimethyls and polyhydroxylation observed in mycalamides (next section) and the macrolide ring of pateamine (2), however, they are not biochemically related [7]. Peloruside A (3) was active against P388 murine leukaemia cells at approximately 18 nM [7] and peloruside B (107) was active (IC 50 value of 71 nM) against human ovarian carcinoma (1A9 cells) [74]. Pelorusides A-D (3, 107-109) were active against human myeloid leukaemia (HL-60 cells) with IC 50 values of 10 nM, 33 nM, 221 nM, and 2 µM, respectively [71,74].…”

“…The natural congener peloruside B (107, l " Fig. 8) was characterised from a New Zealand specimen of M. (Carmia) hentscheli [74]. Peloruside A (3) was reisolated from another New Zealand specimen of M. (Carmia) hentscheli together with the two new structures peloruside C (108) and D (109) [71].…”

“…Peloruside A (3) was active against P388 murine leukaemia cells at approximately 18 nM [7] and peloruside B (107) was active (IC 50 value of 71 nM) against human ovarian carcinoma (1A9 cells) [74]. Pelorusides A-D (3, 107-109) were active against human myeloid leukaemia (HL-60 cells) with IC 50 values of 10 nM, 33 nM, 221 nM, and 2 µM, respectively [71,74]. Pelorusides have also been shown to arrest cells in the G 2 /M phase of the cell cycle, suggesting that the mitotic microtubules are the target for observed cytotoxicity [71,74,75].…”

Marine Pharmaceuticals: A New Wave of Anti-angiogenic Drugs

“…Peloruside A is a polyketide isolated from New Zealand marine sponge Mycale hentscheli [23]. Previous studies have shown that Peloruside A causes hyper-stabilization of microtubules by binding to a site on β-tubulin in a manner similar to that of Paclitaxel.…”