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

Computational screening of fatty acid synthase inhibitors against thioesterase domain

<p>Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein–ligand interactions and binding free energies using MM-PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design.</p

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