Eight new cytotoxic metabolites closely related to onnamide A from two marine sponges of the genus Theonella

✍ Scribed by Shigeki Matsunaga; Nobuhiro Fusetani; Youichi Nakao

• Publisher: Elsevier Science
• Year: 1992
• Tongue: French
• Weight: 600 KB
• Volume: 48
• Category: Article
• ISSN: 0040-4020
• DOI: 10.1016/s0040-4020(01)86585-6

✦ Synopsis

New cytotoxic compounds l-7 were isolated along with onnamide A (9) from a marine sponge Theonellu sp. collected at Hachijo Island, whereas another Theonelka sponge yielded 8. The structures of these compounds were determined by interpretation of the NMR spectral data as well as by comparison of spectral data with those of 9. Six compounds (l-6) were highly cytotoxic against the P388 cell line.

Marine sponges of the genus Theonella have proved to contain a diverse array of secondary metabolites possessing various biological activities; e. g. swinholides.* bistheonellides,3 theonellamide F,4 and theonellapeptolides.5 We have already reported cyclotheonamides,6 orbiculamide A,7 aurantosides.8 and theopederins9 from a Theo&la sponge yellowish inside collected off Hachijo Island. Further examination of the water soluble portion of the EtOH extract led to the isolation of eight cytotoxic metabolites which include onnamide AIO and closely related compounds.

The EtQH extract of the sponge was partitioned between water and ether, and the aqueous phase was extracted with n-BuOH. The MeOH soluble portion of the n-BuOH extract was fractionated by Sephadex LH-20 and ODS chromatographies to afford l-7 along with onnamide A (9). Similarly, another species of a Theonella sponge, which was also collected off Hachijo Island, gave rise to pseudoomtamide A (Sk1 * also related to onnamide A. Compounds, l-6 and 9 were highly cytotoxic against the P388 cell line with JCsO values of 0.15, 0.04, 0.13, 0.10.0.07, 0.02, and 0.01 pg/mL, respectively.

13-Des-O-methyl-onnamide A (1). the most polar of the 9 metabolites, had a molecular formula of C3gH6lNSQI2, which was one CH2 unit smaller than omramide A. The 1~ and 13C NMR spectra (Tables I andII) were almost superimposable on those of omtamide A, except for signals assignable to the Cl30-methyl group, which were missing in 1. In addition, the Cl3 signal in 1 was shifted upfield (6 69.8 vs. 8 80.6 in 9). while the HI3 signal was shifted downfield (6 4.01 vs. 8 3.62 in 9). This indicated that the C130-methyl group in onnamide A was replaced by a hydrogen atom in 1. Interestingly, 13C NMR signals for 14-Me and Cl 1 and lH NMR signal for H13, which were broad in onnamide A and related compounds described in this paper, were sharp in l.'* Dihydroonnamide A (2) displayed an HPLC peak with the longest retention time among the nine metabolites. A molecular formula of C39H65N5012 was deduced from high resolution FAB mass spectroscopy, indicating that one of double bonds in onnamide A had been reduced. This deduction was also supported by the IH and 13C NMR spectra and by the UV spectrum (hmax 260 nm), which revealed the presence of a conjugated diene system instead of a conjugated triene in 9. Interpretation of the COSY, HMQC,13 and HMBC13 spectra showed that 01 to C17, C23 to C27, and arginyl amide portions of 2 were identical with those of onnamide A. The remaining five methylenes could be placed between Cl7 and C23. Though connectivities H17/H218 and H221/H222 were readily secured by COSY spectrum, the assignment of other methylene signals was hampered due to a severe overlapping of the signals, which was overcome by a relayed-COSY experiment,14 which showed correlation peaks between HI7 and H219 and between H222 and H22O. Therefore structure 2 was secured for dihydroonnamide A.

Onnamide B (3) was smaller than onnamide A by a C2H2 unit. The UV spectrum (hmax 260 nm) indicated the presence of an a. p, 7, &unsaturated carbonyl chromophore as in 2. Interpretation of the COSY and HMQC spectra revealed that onnamide B was a derivative of onnamide A with one less double bond.