A New Tetracyclic Bromopyrrole-Imidazole Derivative through Direct Chemical Diversification of Substances Present in Natural Product Extract from Marine Sponge Petrosia (Strongylophora) sp.

Chemical diversification of substances present in natural product extracts can lead to a number of natural product-like compounds with a better chance of desirable bioactivities. The aim of this work was to discover unprecedented chemical conversion and produce new compounds through a one-step reaction of substances present in the extracts of marine sponges. In this report, a new unnatural tetracyclic bromopyrrole-imidazole derivative, rac-6-OEt-cylindradine A (1), was created from a chemically diversified extract of the sponge Petrosia (Strongylophora) sp. We also confirmed that 1 originated from naturally occurring (-)-cylindradine A (2) via a new reaction pattern. Moreover, (-)-dibromophakellin (3) and 4,5-dibromopyrrole-2-carboxylic acid (4), as well as 2, were reported herein for the first time in this genus. Studies on the possible reaction mechanism and bioactivities were also conducted. The results indicate that the direct chemical diversification of substances present in natural product extracts can be a speedy and useful strategy for the discovery of new compounds

Asymmetric Synthesis and Cytotoxicity Evaluation of Right-Half Models of Antitumor Renieramycin Marine Natural Products

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)

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

Two new series of synthetic renieramycins including 22-O-amino ester and hydroquinone 5-O-amino ester derivatives of renieramycin M were semi-synthesized and evaluated for their cytotoxicity against the metastatic non-small-cell lung cancer H292 and H460 cell lines. Interestingly, the series of 22-O-amino ester derivatives displayed a potent cytotoxic activity greater than the hydroquinone derivatives. The most cytotoxic derivative of the series was the 22-O-(N-Boc-l-glycine) ester of renieramycin M (5a: IC50 3.56 nM), which showed 7-fold higher potency than renieramycin M (IC50 24.56 nM) and 61-fold more than jorunnamycin A (IC50 217.43 nM) against H292 cells. In addition, 5a exhibited a significantly higher cytotoxic activity than doxorubicin (ca. 100 times). The new semi-synthetic renieramycin derivatives will be further studied and developed as potential cytotoxic agents for non-small-cell lung cancer treatment

Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5‑<i>O</i>‑Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells

A series of hydroquinone 5-<i>O</i>-monoester analogues of renieramycin M were semisynthesized via bishydroquinonerenieramycin M (<b>5</b>) prepared from renieramycin M (<b>1</b>), a major cytotoxic bistetrahydro­isoquinolinequinone alkaloid isolated from the Thai blue sponge <i>Xestospongia</i> sp. All 20 hydroquinone 5-<i>O</i>-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-<i>O</i>-monoester analogues such as 5-<i>O</i>-acetyl ester <b>6a</b> and 5-<i>O</i>-propanoyl ester <b>7e</b>, which exhibited 8- and 10-fold increased cytotoxicity toward the H292 NSCLC cell line (IC₅₀ 3.0 and 2.3 nM, respectively), relative to <b>1</b> (IC₅₀ 24 nM). Thus, the hydroquinone 5-<i>O</i>-monoester analogues are a new generation of the renieramycins to be further developed as potential marine-derived drug candidates for lung cancer treatment

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

Eighteen 22-<i>O</i>-ester derivatives of jorunnamycin A (<b>2</b>) were prepared via <b>2</b>, 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-<i>O</i>-ester derivatives. Among them, 22-<i>O</i>-(4-pyridinecarbonyl) ester <b>6a</b> 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 (<b>1</b>), the major cytotoxic bistetrahydro­isoquinolinequinone alkaloid of the Thai blue sponge <i>Xestospongia</i> sp

Replacement of a Quinone by a 5‑<i>O</i>‑Acetylhydroquinone Abolishes the Accidental Necrosis Inducing Effect while Preserving the Apoptosis-Inducing Effect of Renieramycin M on Lung Cancer Cells

Renieramycin M (<b>1</b>), a bistetrahydroisoquinolinequinone alkaloid isolated from the marine sponge <i>Xestospongia</i> sp., has been reported to possess promising anticancer effects. However, its accidental necrosis inducing effect has limited further development due to concerns of unwanted toxicity. The presence of two quinone moieties in its structure was demonstrated to induce accidental necrosis and increase reactive oxygen species (ROS) levels. Therefore, one quinone of <b>1</b> was modified to produce the 5-<i>O</i>-acetylated hydroquinone derivative (<b>2</b>), and <b>2</b> dramatically reduced the accidental necrosis inducing effect while preserving the apoptosis-inducing effect of parent <b>1</b> on lung cancer H23 cells. Addition of the antioxidant <i>N</i>-acetylcysteine suppressed the accidental necrosis mediated by <b>1</b>, suggesting that its accidental necrosis inducing effect was ROS-dependent. The fluorescent probe dihydroethidium revealed that the accidental necrosis mediated by <b>1</b> was due to its ability to generate intracellular superoxide anions. Interestingly, the remaining quinone in <b>2</b> was required for its cytotoxicity, as the 5,8,15,18-<i>O</i>-tetraacetylated bishydroquinone derivative (<b>3</b>) exhibited weak cytotoxicity compared to <b>1</b> and <b>2</b>. The present study demonstrates a simple way to eliminate the undesired accidental necrosis inducing effect of substances that may be developed as improved anticancer drug candidates