A general protocol for the asymmetric synthesis of 3-N-arylmethylated right-half model compounds of renieramycins was developed, which enabled structure-activity relationship (SAR) study of several 3-N-arylmethyl derivatives. 

The most active compound (6a) showed significant cytotoxic activity against human prostate cancer DU145 and colorectal cancer HCT116 cell lines (IC50 = 11.9, and 12.5 nM, respectively).

Natural products belonging to the bis-1,2,3,4-tetrahydroisoquinoline family, such as renieramycins, saframycins, and ecteinascidins, have attracted considerable attention due to their potent biological activities, structural diversity, and meager availability in nature.

Thai blue sponge Xestospongia 

The researchers have discovered a number of renieramycin marine natural products having extraordinary structures from blue sponges collected in Thailand and the Philippines. For example, renieramycin M (1m) isolated from the Thai blue sponge Xestospongia sp. has p-quinones in both terminal rings.

3-N-benzyl derivative (±)-6a exhibited approximately five and nine times more potent cytotoxic activity against HCT116 and QG56, respectively than 3-N-methylated derivative (±)-5, indicating the importance of the substituent at 3-nitrogen.

In contrast, renieramycins T (1t) and U (1u) share a common A-ring with ecteinascidin 743 (ET-743, 2), which has already been approved as an anticancer agent. In addition, the A-ring of renieramycin Y (1y) has the same substituent pattern as the E-ring of 2.

These renieramycins have similar structures to 2 and are expected to have similar potent antitumor activity. However, the amount obtainable from nature is scarce, and this has set back the implementation of detailed biological tests.

A single-cell suspension of each cell line (2 × 103 cells/well) was added to the serially diluted test compounds in a 96-well microplate and cultured for 4 days. Cell viability was measured with Cell Counting Kit-8 (Dojindo Laboratories, Kumamoto, Japan). IC50 was expressed as the concentration at which cell growth was inhibited by 50% compared with the untreated control.

The synthesized model compounds were screened for their cytotoxic activity against DU145 and HCT116. Compounds 6aand 21 bearing benzyl group at 3-nitrogen showed very strong activity with IC50 at nanomolar concentrations. It was also found that chirality had no effect on the cytotoxic activities of the model compounds.