Jorunnamycins A-C, New Stabilized Renieramycin-Type Bistetrahydroisoquinolines Isolated from the Thai Nudibranch Jorunna funebris

Abstract

The nudibranch Jorunna funebris (Mollusca: Gastropoda: Opisthobranchia: Nudibranchia: Kentrodorididae) is one of the marine, slug-like invertebrates belonging to phylum Mollusca that lacks a protective hard shell.1) This nudibranch and other dorid nudibranchs can accumulate secondary metabolites that are derived from dietary organisms in order to protect themselves from predators.2-4) J. funebris is carnivorous and feeds mainly on sponges such as Xestospongia sp., Haliclona sp., Euplacella cf. australis, 5) and Oceanapia sp. 6) In 1988, de Silva and Gulavita isolated several simple isoquinolinequinones including renierol acetate (4a), renierol propionate (4b), N-formyl-1,2-dihydrorenierol acetate (5a), and Nformyl-1,2-dihydrorenierol propionate (5b) from Xestospongia sp. and its associated nudibranch J. funebris, but no bistetrahydroisoquinolines.7-9) An in-depth chemical analysis of the mantle and mucus of the Pacific nudibranch J. funebris by Fontana et al. resulted in the isolation of the bistetrahydroisoquinoline jorumycin (6), the primary assay of which revealed cytotoxicity against NIH 3T3 fibroblast cells and against some tumor cell lines, such as P388 mouse lymphoma, A549 human lung carcinoma, HT29 human colon carcinoma, and MEL28 human melanoma, at very low concentrations. 10) Compound 6 shows the promising antitumor properties: however, it is available only in very minute quantities, because 6 has relatively an unstable carbinolamine functional group that may be decomposed during isolation procedure. To obtain sufficient quantities of more stable derivatives with retention of bioactivity, we reported that ecteinascidin 770 was isolated from the Thai tunicate Ecteinascidia thurstoni pretreated with KCN in methanolic buffer solution.11) Furthermore, we have recently succeeded the isolation and structure elucidation of renieramycin M (2m) with gram-scale supply from a Thai sponge Xestospongia sp. that was also pretreated with KCN.12) As series of our search for new metabolites via the isolation and characterization of biologically active compounds from Thai marine animals, we found the Thai nudibranch J. funebris feeding on the blue sponge Xestospongia sp., growing around Sichang Island in the Gulf of Thailand. In this paper, we present the isolation, structure elucidation, and cytotoxicity of three stabilized bistetrahydroisoquinolines jorunnamycins A-C (1a-c) from the KCN-pretreated J. funebris. The preparation of a carbinolamine analog 1d from 1c and its chemical stability are also reported. Results and DiscussionJ. funebris (20 animals; 500 g, wet weight) was collected in the vicinity of Sichang Island at the depth of 3-5 m in March 2004 and its egg ribbons (23.2 g, wet weight) were separately obtained in November 2004. The animals were carefully dissected into two parts, the mantles and the visceral organs (the combined digestive glands and gonads). Then, the three parts were separately homogenized with phosphate buffer (pH 7). Aqueous KCN solution was added to each suspension, the mixture was macera...

Chemistry of renieramycins. Part 7: Renieramycins T and U, novel renieramycin–ecteinascidin hybrid marine natural products from Thai sponge Xestospongia sp.

“…2 In our ongoing search for new anticancer metabolites in Thai marine animals, we were able to identify several biologically active compounds from the tunicate Ecteinascidia thurstoni, 3 the blue sponge Xestospongia sp., 1,4,5 and the nudibranch Jorunna funebris. 6 However, all of our target natural products were isolable in only trace amounts and were relatively unstable, decomposing during extraction and isolation. We solved this problem by converting original natural products having a very unstable amino alcohol functionality at C-21 into stable a-aminonitrile compounds by pretreatment with KCN.…”

Microarray-Based Transcriptional Profiling of Renieramycin M and Jorunnamycin C, Isolated from Thai Marine Organisms

“…We realized the gram-scale supply of renieramycin-type compounds using our procedure, and recently reported significant results gained from the extension of our initial investigation and the results of cytotoxicity evaluation of C-22 ester analogues and a very promising compound, the 2′-pyridinecarboxylic acid ester derivative [19] (Figure 2). We also reported the isolation of jorunnamycins A–C from the mantles, visceral organs, and egg ribbons of the Thai nudibranch Jorunna funebris, following the same procedure that used potassium cyanide [20]. …”

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

“…In 2007, studies on Thai J. funebris (Fig. H) specimens led to the isolation from the mantle, viscera, and egg‐ribbons novel tetrahydroisoquinoline alkaloids, jorunnamycins A–C, along with several renieramycins . It is interesting to note that certain renieramycins have also been isolated from the Thai sponge Xestospongia sp .…”

“…Indeed, J. funebris is carnivorous and feeds mainly on sponges such a Xestospongia sp., Haliclona sp., Euplacella cf. australis , and Oceanapia sp . Jorunnamycin C ( 85; Fig.…”