Light-Mediated Transformation of Renieramycins and Semisynthesis of 4'-Pyridinecarbonyl-Substituted Renieramycin-Type Derivatives as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells.

The semisynthesis of renieramycin-type derivatives was achieved under mild and facile conditions by attaching a 1,3-dioxole-bridged phenolic moiety onto ring A of the renieramycin structure and adding a 4'-pyridinecarbonyl ester substituent at its C-5 or C-22 position. These were accomplished through a light-induced intramolecular photoredox reaction using blue light (4 W) and Steglich esterification, respectively. Renieramycin M (4), a bis-tetrahydroisoquinolinequinone compound isolated from the Thai blue sponge (Xestospongia sp.), served as the starting material. The cytotoxicity of the 10 natural and semisynthesized renieramycins against non-small-cell lung cancer (NSCLC) cell lines was evaluated. The 5-O-(4'-pyridinecarbonyl) renieramycin T (11) compound exhibited high cytotoxicity with half-maximal inhibitory concentration (IC50) values of 35.27 ± 1.09 and 34.77 ± 2.19 nM against H290 and H460 cells, respectively. Notably, the potency of compound 11 was 2-fold more than that of renieramycin T (7) and equal to those of 4 and doxorubicin. Interestingly, the renieramycin-type derivatives with a hydroxyl group at C-5 and C-22 exhibited weak cytotoxicity. In silico molecular docking and dynamics studies confirmed that the mitogen-activated proteins, kinase 1 and 3 (MAPK1 and MAPK3), are suitable targets for 11. Thus, the structure-cytotoxicity study of renieramycins was extended to facilitate the development of potential anticancer agents for NSCLC cells.

An Efficient DNA Extraction for a Blue Xestospongia sp. Sponge and Its Associated Microorganisms Containing Cytotoxic Substances.

Extraction of high quantity and quality DNAs from marine sponges, which contain diverse and abundant microbial communities, is important to molecular biology techniques for the analysis of nucleic acids. Several marine sponges and their associated microorganisms have been known to produce cytotoxic natural products on several cancer cell lines via DNA damage mechanisms. These marine cytotoxic substances might be one of the factors that cause the low quantity and quality of DNAs during the DNA extraction from its living origin. Therefore, the extraction of DNA of a Thai blue marine sponge Xestospongia sp. with sufficient purity and quantity for molecular study can be challenging. In this study, we developed an efficient extraction method to prepare DNAs from a Thai blue marine sponge Xestospongia sp. which accumulated a highly potent cytotoxic alkaloid with DNA-damaging activity, named Renieramycin M (RM), as a major constituent in high quantity. We demonstrated that removal of RM from the sponge samples by a simple methanolic extraction before DNA extraction dramatically increased the yield and purity of DNAs compared to the RM-unremoved sponge samples. High molecular weight (HMW) genomic DNA was obtained from sponge samples with 8 times of RM elimination by using modified NaOAc salting-out extraction method. The quantity and quality of the prepared DNAs were comparatively determined via spectrophotometry, electrophoresis, and 16S rRNA gene amplification. Our result suggests that the removal of DNA-damaging constituents from the samples is a crucial step and must be seriously taken as the necessary consideration for the practical protocol of DNA extraction.

Renieramycin-type alkaloids from marine-derived organisms: Synthetic chemistry, biological activity and structural modification.

Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.