Renieramycins M (1m) and N (1n) were isolated from the Thai sponge Xestospongia sp., pretreated with potassium cyanide in methanolic buffer solution, and their structures and relative stereochemistries were elucidated on the basis of spectroscopic data. This strategy is the first example of the gram-scale preparation of this series of compounds and presents a potential solution for increasing the gram-scale supply of novel natural products from marine sources.

Four minor renieramycin-type derivatives, including renieramycins O (1o) and Q-S (1q-s), were isolated from the sponge Xestospongia sp. pretreated with potassium cyanide. Their structures were elucidated by comparison of spectral data with those of recently reported renieramycins M (1m) and N (1n). The results of transformation and cytotoxicity measurements are also described.

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Transcriptional activation of gene expression directed by the long terminal repeat (LTR) of HIV-1 requires both the transactivation response element (TAR) and Tat protein. HIV-1 mutants lacking a functional tat gene are not able to proliferate. Here we take a genetic approach to suppress HIV-1 replication based on Tat-dependent production of MazF, an ACA-specific endoribonuclease (mRNA interferase) from Escherichia coli. When induced, MazF is known to cause Bak- and NBK-dependent apoptotic cell death in mammalian cells. We first constructed a retroviral vector, in which the mazF (ACA-less) gene was inserted under the control of the HIV-1 LTR, which was then transduced into CD4+ T-lymphoid CEM-SS cells in such a way that, upon HIV-1 infection, the mazF gene is induced to destroy the infecting HIV-1 mRNA, preventing HIV-1 replication. Indeed, when the transduced cells were infected with HIV-1 IIIB, the viral replication was effectively inhibited, as HIV-1 IIIB p24 could not be detected in the culture medium. Consistently, not only cell growth but also the CD4 level was not affected by the infection. These results suggest that the HIV-1-LTR-regulated mazF gene was effectively induced upon HIV-1 IIIB infection, which is sufficient enough to destroy the viral mRNA from the infected HIV-1 IIIB to completely block viral proliferation in the cells, but not to affect normal cell growth. These results indicate that the T cells transduced with the HIV-1-LTR-regulated mazF gene acquire HIV-1 resistance, providing an intriguing potential for the use of the HIV-1-LTR-regulated mazF gene in anti-HIV gene therapy.

Eighteen 22-O-ester derivatives of jorunnamycin A (2) were prepared via 2, and their cytotoxicity against human non-small-cell lung cancer (NSCLC) cells was evaluated. Preliminary study of the structure-cytotoxicity relationship revealed that the ester part containing a nitrogen-heterocyclic ring elevated the cytotoxicity of the 22-O-ester derivatives. Among them, 22-O-(4-pyridinecarbonyl) ester 6a is the most potent compound (IC50 1.1 and 1.6 nM), exhibiting 21-fold and 5-fold increases in cytotoxicity against the H292 and H460 NSCLC cell lines, respectively, relative to renieramycin M (1), the major cytotoxic bistetrahydroisoquinolinequinone alkaloid of the Thai blue sponge Xestospongia sp.

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...

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