Total Synthesis and Biological Evaluation of Mutolide and Analogues

Abstract

The convergent total syntheses of three 14membered macrolide natural products, mutolide, nigrosporolide and (4S,7S,13S)-4,7-dihydroxy-13-tetradeca-2,5,8-trienolide have been achieved. The key synthetic features include Shiina macrolactonization to assemble the 14-membered macrocyclic core, Wittig or Still-Gennari olefination and selective reduction of propargylic alcohol to construct the Eor Z-olefins. Cross metathesis was also highlighted as an efficient tool to forge the formation of E-olefin. The three synthetic macrolides were evaluated for their cytotoxic activity against three human cancer cell lines as well as for inhibitory effect on CFTR-mediated chloride secretion in human intestinal epithelial (T84) cells. Mutolide displayed significant cytotoxic activity against HCT116 colon cancer cells with an IC 50 of ~12 μM as well as a potent CTFR inhibitory effect with an IC 50 value of ~1 μM.

Total Synthesis and Biological Evaluation of Seiricuprolide and Pestalotioprolide B

“…Our group has also recently disclosed the CFTR inhibitory activity of synthetic macrolide 7-9, in which mutolide (9) showed stronger inhibition (~70 % inhibition) compared to analogues 7 (40 % inhibition) and 8 (30 % inhibition) at the same concentration of 5 μM. [9] Disappointingly, synthetic 4 and 5 were found to show no effects on CFTR-mediated chloride secretion in T84 cells stimulated by forskolin (a cAMP donor) at both 5 and 10 μM compared to a positive control, CFTR(inh)-172 (Figure S77 in the Supporting Information). Therefore, the β-epoxide moiety of macrolides 4 and 5 apparently suppressed the CFTR inhibitory activity compared to compounds 7 and 8, which are their C5À C6 Zolefin counterparts.…”

“…Our research group has recently reported the in vitro cytotoxic activity of synthetic analogues of 4 and 5 , i.e. nigrosporolide ( 7 ), (4 S ,7 S ,13 S )‐4,7‐dihydroxy‐13‐tetradeca‐2,5,8‐trienolide ( 8 ) and mutolide ( 9 ) against three human cancer cell lines including HCT116 colorectal carcinoma, MCF‐7 breast adenocarcinoma and Calu‐3 lung adenocarcinoma using the MTT assay [9] . It was discovered that synthetic mutolide ( 9 ) was significantly active against the HCT116 colon cancer cells (IC 50 =12 μM) and was essentially inactive against the other two cell lines (IC 50 >50 μM), whereas macrolactone analogues 7 and 8 showed no cytotoxic effects on all three cancer cell lines tested.…”

“…CFTR Inhibition Assay : inhibitory effect on CFTR in human intestinal epithelial (T84) cells of 4 and 5 was measured using short‐circuit current analysis following the procedure previously described by our research group (for CFTR inhibition of 7 – 9 [9] or a fungal metabolite zearalenone [25] ).…”

“…Pestalotioprolide B ( 5 ) is structurally nearly identical to 4 except for the configuration of double bond at C8−C9, which also makes 5 a β‐epoxide analogue of previously reported (4 S ,7 S ,13 S )‐4,7‐dihydroxy‐13‐tetradeca‐2,5,8‐trienolide ( 8 , Figure 1C). [9] Although macrolactones 4 and 5 were reported to have no cytotoxicity against the L5178Y murine lymphoma and the A2780 human ovarian cancer cell lines by the Liu and Proksch group, their novel structures and unprecedented chemical syntheses sparked our interest. As part of our ongoing program on total syntheses and anticancer drug discovery of 14‐membered macrolides, we report herein the first total syntheses of seiricuprolide ( 4 ) and pestalotioprolide B ( 5 ) as well as evaluation of their cytotoxic activity against the HCT116 colon cancer cells and inhibitory activity against cystic fibrosis transmembrane regulator (CFTR).…”

“…The structure and the absolute configurations of 4 were later confirmed by singlecrystal X-ray diffraction analysis by the Lamba group in 1992, [8] rendering 4 a β-epoxide analogue of nigrosporolide (7,Figure 1C), a known 14-membered macrolactone of which the first total synthesis was disclosed by our research group. [9] Pestalotioprolide B (5), the other known macrolactone of this subclass, was first discovered as a diacetate derivative 6 from mangrovederived endophytic fungus Pestalotiopsis sp. PSU-MA119 by Rukachaisirikul et al in 2012.…”