Macrophilones from the Marine Hydroid Macrorhynchia philippina Can Inhibit ERK Cascade Signaling

Abstract

Six new macrophilone-type pyrroloiminoquines were isolated and identified from an extract of the marine hydroid Macrorhynchia philippina. The proton-deficient and heteroatom-rich structures of macrophilones B-G (2-7) were elucidated by spectroscopic analysis and comparison of their data with those of the previously reported metabolite macrophilone A (1). Compounds 1-7 are the first pyrroloiminoquines to be reported from a hydroid. The macrophilones were shown to inhibit the enzymatic conjugation of SUMO to peptide substrates, and macrophilones A (1) and C (3) exhibit potent and selective cytotoxic properties in the NCI-60 anticancer screen. Bioinformatic analysis revealed a close association of the cytotoxicity profiles of 1 and 3 with two known B-Raf kinase inhibitory drugs. While compounds 1 and 3 showed no kinase inhibitory activity, they resulted in a dramatic decrease in cellular protein levels of selected components of the ERK signal cascade. As such, the chemical scaffold of the macrophilones could provide small-molecule therapeutic leads that target the ERK signal transduction pathway.

Marine Pyrrole Alkaloids

“…Oxidation by Fremy's salt yielded the iminoquinone, which, after the introduction of the thioether group by sodium methanethiolate, furnished the natural product 423 in just 4% yield over three steps (Scheme 26) [325]. Once more, the group of Gustafson and co-workers published the isolation of six further macrophilones B-G (424-429) from the same source one year later (Figure 59) [326]. Just as its related congener macrophilone A (423), compounds 424-429 showed moderate to weak inhibition effects of SUMO conjugation cascade (IC50 values ranging between 11.9 µM and >100 µM).…”

“…Just as its related congener macrophilone A (423), compounds 424-429 showed moderate to weak inhibition effects of SUMO conjugation cascade (IC50 values ranging between 11.9 µM and >100 µM). Furthermore, they exhibited significant toxicity against several cancer cell lines (no values given) [326]. To investigate their bioactivity potential, the first isolation of macrophilone A (423) was accompanied by its synthesis [325].…”

“…Furthermore, preparative olefin metathesis was used to localize the (E)-configured double bond [330]. Once more, the group of Gustafson and co-workers published the isolation of six further macrophilones B-G (424-429) from the same source one year later (Figure 59) [326]. Just as its related congener macrophilone A (423), compounds 424-429 showed moderate to weak inhibition effects of SUMO conjugation cascade (IC 50 values ranging between 11.9 µM and >100 µM).…”

Biochemical and Toxinological Characterization of Venom from Macrorhynchia philippina (Cnidaria, Hydrozoa)

“…Zlotkowski et al [ 37 ] showed that Macrophilone A increased intracellular reactive oxygen species levels and caused cytotoxicity in lung adenocarcinoma cells. Further studies showed that other Macrophilones caused cytotoxicity as well [ 38 ]. Lytophilippines were able to induce antibacterial, antiviral, and antitumor activities, besides displaying lethality in shrimps [ 39 ].…”

Synthesis of a Diastereomer of the Marine Macrolide Lytophilippine A

“…The stinging hydroid is widely distributed and sometimes considered invasive . However, its natural product chemistry has been only sparsely investigated …”