New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells.

Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC50). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models.

A novel 4'-brominated derivative of fisetin induces cell cycle arrest and apoptosis and inhibits EGFR/ERK1/2/STAT3 pathways in non-small-cell lung cancer without any adverse effects in mice.

The therapeutic toxicity and resistance to currently available treatment options are major clinical challenges for the management of lung cancer. As a novel strategy, we synthesized analogues of a known flavonol, fisetin, which has shown anti-tumorigenic potential against cancer in cell culture with no adverse effects in animal models. We studied the synthetic analogues of fisetin for their anti-cancer potential against lung cancer cells, toxicity in mice and efficacy in a xenograft model. Brominated fisetin analogues were screened for their effects on the viability of A549 and H1299 lung cancer cells, and three analogues (3a, 3b, 3c), showed improved activity compared to fisetin. These analogues were more effective in restricting lung cancer cell proliferation, inducing G2 M phase cell cycle arrest and apoptosis. The fisetin analogues also downregulated EGFR/ERK1/2/STAT3 pathways. Fisetin analogue-induced apoptosis was accompanied by a higher Bax to Bcl-2 expression ratio. Based on the in vitro studies, the most effective fisetin analogue 3b was evaluated for in vivo toxicity, wherein it did not show any hepatotoxicity or adverse health effects in mice. Furthermore, analogue 3b showed greater antitumor efficacy (p < .001) as compared to its parent compound fisetin in a human lung cancer cell xenograft study in athymic mice. Together, our data suggest that the novel fisetin analogue 3b is more effective in restricting lung cancer cell growth, both in vitro as well as in vivo, without any apparent toxicity, supporting its further development as a novel anti-lung cancer agent.

Cocrystallization-Induced Spontaneous Deracemization: A General Thermodynamic Approach to Deracemization.

Processes leading to enantiomerically pure compounds are of utmost importance, in particular for the pharmaceutical industry. Starting from a racemic mixture, crystallization-induced diastereomeric transformation allows in theory for 100 % transformation of the desired enantiomer. However, this method has the inherent limiting requirement for the organic compound to form a salt. Herein, this limitation is lifted by introducing cocrystallization in the context of thermodynamic deracemization, with the process applied to a model chiral fungicide. We report a new general single thermodynamic deracemization process based on cocrystallization for the deracemization of (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one. This study demonstrates the feasibility of this novel approach and paves the way to further development of such processes.