Caulibugulones A−F, Novel Cytotoxic Isoquinoline Quinones and Iminoquinones from the Marine Bryozoan Caulibugula intermis

Abstract

An extract of the marine bryozoan Caulibugula intermis, collected in the Indo-Pacific off Palau, produced a distinct pattern of differential cytotoxicity in the National Cancer Institute's 60 cell line antitumor screen. Bioactivity-directed fractionation of the extract provided six new compounds, caulibugulones A-F (1-6). The structures of these novel metabolites were determined by spectrochemical analyses including LC-MS, HRFABMS, 1-D and 2-D NMR experiments, and by comparison with related compounds. The structures of compounds 2 and 3 were confirmed by chemical interconversion. The isolated compounds exhibited IC(50)'s of 0.03-1.67 microg/mL against murine tumor cells in an in vitro cytotoxicity assay.

Independent Mechanistic Inhibition of Cdc25 Phosphatases by a Natural Product Caulibugulone

“…The caulibugulone natural products represent a unique class of cytotoxic marine-derived compounds with an unknown mechanism of action (Milanowski et al, 2004). The specificity of the caulibugulones for inhibition of Cdc25 phos- (Table 1) stimulated interest in examining the mechanism responsible for mammalian growth inhibition.…”

“…The isoquinoline quinones caulibugulones A, B, and C and the isoquinoline iminoquinones caulibugulones E and F caused growth arrest of murine IC-2 WT cells with IC 50 values ranging from 0.03 to 1.67 g/ml (Milanowski et al, 2004). We previously reported the total syntheses for these naturally occurring compounds and their ability to inhibit Cdc25B in vitro (Alagille et al, 2004;.…”

“…Caulibugulones A to F are novel secondary metabolites originally extracted from the marine bryozoan Caulibugula intermis (Milanowski et al, 2004). The isoquinoline quinones caulibugulones A, B, and C and the isoquinoline iminoquinones caulibugulones E and F caused growth arrest of murine IC-2 WT cells with IC 50 values ranging from 0.03 to 1.67 g/ml (Milanowski et al, 2004).…”

Antiproliferative Activity of New 6-Bromine Derivatives of 7-Anilino-1-Arylisoquinolinequinones

“…Caulibugulones A-D, evaluated for antitumor activity against the murine IC-2WT cell line exhibit high potency. In these assays, the A-C members displayed significant cytotoxicity againts the tested cell line (IC50: 0.22 to 0.34 µg/mL) [8]. These data indicate that the insertion of nitrogen and halogen atoms in the quinone nucleus moiety have influence on the cytotoxicity of the isoquinoline-5,8-quinone scaffold.…”

“…The isoquinoline-5,8-quinone scaffold appears in a number of naturally occurring cytotoxic compounds such as caulibugulones A-D and mansouramysin A-D (Figure 1) [5][6][7][8][9][10]. Caulibugulones A-D, evaluated for antitumor activity against the murine IC-2WT cell line exhibit high potency.…”