A series of hydroquinone 5-O-monoester analogues of renieramycin M were semisynthesized via bishydroquinonerenieramycin M (5) prepared from renieramycin M (1), a major cytotoxic bistetrahydroisoquinolinequinone alkaloid isolated from the Thai blue sponge Xestospongia sp. All 20 hydroquinone 5-O-monoester analogues possessed cytotoxicity with IC50 values in nanomolar concentrations against the H292 and H460 human non-small-cell lung cancer (NSCLC) cell lines. The improved cytotoxicity toward the NSCLC cell lines was observed from the 5-O-monoester analogues such as 5-O-acetyl ester 6a and 5-O-propanoyl ester 7e, which exhibited 8- and 10-fold increased cytotoxicity toward the H292 NSCLC cell line (IC50 3.0 and 2.3 nM, respectively), relative to 1 (IC50 24 nM). Thus, the hydroquinone 5-O-monoester analogues are a new generation of the renieramycins to be further developed as potential marine-derived drug candidates for lung cancer treatment.

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.

A three-step transformation of ecteinascidin 770 (1b) into 2′-N-indole-3-carbonyl derivative 3 via 18,6′-O-bisallyl-protected derivative 4a, which was shown to have higher cytotoxicity than 1b, is presented. In addition, a number of 2′-N amide derivatives of 1b have been prepared from 4a and their in vitro cytotoxicity were determined by measuring IC50 values against human cell lines HCT116, QG56, and DU145. Benzoyl amide derivatives 7a–c showed similar in vitro cytotoxicity to 1b, whereas the nitrogen-containing heterocyclic derivatives 7d–h and cinnamoyl derivatives 9a–b showed higher cytotoxicity than 1b. In contrast, the 18,6′-O-bisallyl protected derivatives 4a–c, 6a–h, and 8a–b showed dramatic decreases in cytotoxicity relative to 1b.Synthesis of 2′-N-amide analogues of ecteinascidin 770 (Et 770) via a three-step transformation employing an 18,6′-O-bisallyl protected derivative of Et 770 is presented along with in vitro cytotoxicity of the resulting amides.

A 25-step stereocontrolled total synthesis of (±)-renieramycin G (1g) from readily available 2-hydroxy-3-methyl-4,5-dimethoxybenzaldehyde (3) is described. This synthesis features the concise construction of the pentacyclic framework using the stereoselective Pictet–Spengler type cyclization reaction of lactam (14) with ethyl diethoxyacetate, followed by the base-catalyzed isomerization of the C-1 stereo center.A 25-step stereocontrolled total synthesis of (±)-renieramycin G from readily available 2-hydroxy-3-methyl-4,5-dimethoxy-benzaldehyde is described.

Twenty-four ester analogues of renieramycin M (1m) were prepared from jorunnamycin A (3a), which was easily transformed from marine natural 1m in three steps. These analogues, along with 1m itself, cyanojorumycin (2b), and jorunnamycins A (3a) and C (3b), were evaluated in vitro for cytotoxicity by measuring IC50 values through the 3-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay using human HCT116 colon carcinoma and MDA-MB-435 breast carcinoma cell lines. Nitrogen-containing heterocyclic ester derivatives 9a–f showed similar in vitro cytotoxicity to 1m, whereas the other derivatives were slightly less cytotoxic than 1m. 2′-Pyridinecarboxylic acid ester derivative (9c) exhibited a threefold increase in cytotoxicity relative to 1m.The synthesis of twenty-four ester analogues of renieramycin M, as well as their antitumor activities, is described. 9c exhibited a threefold increase in cytotoxicity relative to 1m.