Chemistry of Renieramycins. 15. Synthesis of 22-O-Ester Derivatives of Jorunnamycin A and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cells

Abstract

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.

Cytotoxic Alkaloids Derived from Marine Sponges: A Comprehensive Review

“…Other renieramycin-type alkaloids, such as jorunnamycin A (223), were purified from the sponge-eating nudibranch Jorunnaf unebris, 222-223 were also reported from the Thai blue sponge Xestospongia sp., collected off Sichang island, the Gulf of Thailand. Compounds 222-223 revealed outstanding cytotoxic activity versus H292 cell line with IC 50 (23 ± 4 and 220 ± 20 nM, respectively) and H460 cell line with IC 50 8.3 ± 0.6 and 160 ± 10 nM, respectively [94]. Renieramycin J (224), which has been reported from Neopetrosia sp., collected off Kuchinoerabu-jima island also showed outstanding cytotoxicity on 3Y1, HeLa, and P388 cells with IC 50 values 5.3, 12.3, and 0.53 nM, respectively [95].…”

Apoptosis-inducing Effect of Hydroquinone 5-O-Cinnamoyl Ester Analog of Renieramycin M on Non-small Cell Lung Cancer Cells

“…As part of our continuing searching for novel cytotoxic natural products, we isolated and modified a series of renieramycin (RM) alkaloids from blue sponge Xestospongia sp. (12,13,15,18). RMs are a group of bistetrahydro-isoquinoline quinone alkaloids possessing potent cytotoxicity against several human cancer cell lines (15)(16)(17)(18)(28)(29).…”

“…(12,13,15,18). RMs are a group of bistetrahydro-isoquinoline quinone alkaloids possessing potent cytotoxicity against several human cancer cell lines (15)(16)(17)(18)(28)(29). In addition, RM was shown to have antimetastasis potential and suppress cancer stem cells in lung cancer (16,17,28).…”

“…Successful synthesis of 22-O-acyl and hydroquinone 5-Oacyl ester analogs of RM has led to several more potent compounds for anticancer approaches (15,18,19). Interestingly, our previous work of RM derivatives showed that the hydroquinone 5-O-acetyl ester analog of RM was the first analog possessing selective apoptotic induction while reduce its necrosis-inducing effect by reducing oxidative stress (30).…”

Chemistry of Renieramycins. Part 19: Semi-Syntheses of 22-O-Amino Ester and Hydroquinone 5-O-Amino Ester Derivatives of Renieramycin M and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cell Lines

“…Interestingly, 1 and its semi-synthetic derivatives, replacing the angelate ester at various new ester side chains at C-22, exhibited a moderate to high potency of cytotoxicity in the nanomolar range against several human cancer cell lines such as colon, lung, and breast carcinomas [ 16 ]. In the past several years, the prominent structure–activity relationship studies of 1 and its semi-synthetic derivatives featuring various linear and aromatic ester side chains at C-22 and C-5 have been continuously explored and evaluated for their cytotoxic activity against non-small-cell lung cancer cell lines [ 17 , 18 ], which have been listed as one of the world’s leading causes of death [ 19 , 20 ]. Based on the current findings, the chemically modified ester side chains at C-22 and C-5 displayed a key structure-cytotoxicity relationship.…”