Corrigendum: Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III.

This corrects the article DOI: 10.1038/srep42957.

Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy.

Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitochondria, it induced the release of apoptogenic factors. The natural compound piperlongumine has been shown to target the stress response to reactive oxygen species in cancer cells. We explored the combinatorial potential of two small molecules (SVTH-6 and piperlongumine) that target these vulnerabilities in cancer cells. Interestingly, when combined with the PST analog, SVTH-6, an increase in mitochondrial dysfunction was observed, leading to an enhanced cytotoxic effect against several human cancer cell types. Additionally, this combination treatment was effective in reducing cancer cell growth in physiologically more relevant 3-dimensional spheroid cell cultures. This enhanced effect was found to be dependent on reactive oxygen species generation because an antioxidant could rescue cancer cells from this combination treatment. Importantly, noncancerous cells were markedly less sensitive to this combination treatment. Thus, targeting mitochondrial and oxidative stress vulnerabilities of cancer cells could be an effective strategy for cancer therapy.-Ma, D., Gilbert, T., Pignanelli, C., Tarade, D., Noel, M., Mansour, F., Gupta, M., Ma, S., Ropat, J., Curran, C., Vshyvenko, S., Hudlicky, T., Pandey. S. Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy.

Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III.

Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.

Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore.

Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention as a new pharmacophore on account of their unique structural and physicochemical properties and their ability to interact selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectroscopy, in mixed aqueous-organic solvent, to confirm the strong preference for the closed form of benzoxaborole and its six- and seven-membered homologues over the open boronic acid form. Only with the eight-membered homologue does the cyclic form become unfavorable. Using dynamic VT-NMR studies with designed probe compound 20, we demonstrate that the oxaborole ring undergoes rapid hydrolytic ring closing-opening at ambient temperature at a rate of >100 Hz via a mechanism featuring rate-limiting proton-transfer steps. This knowledge can help provide a better understanding of the behavior of benzoxaboroles in biological systems.

Self-Healing and Injectable Shear Thinning Hydrogels Based on Dynamic Oxaborole-Diol Covalent Cross-Linking.

Hydrogels containing sugar and oxaborole residues with remarkable self-healing properties were synthesized by free-radical polymerization in a facile and one pot process. The strong covalent interactions between the oxaborole residues and free adjacent hydroxyl groups of the pendent sugar residues of the glycopolymer allowed the in situ formation of hydrogels achievable under either neutral or alkaline conditions. These hydrogels showed excellent self-healing and injectability behaviors in aqueous conditions and were found to be responsive to both pH and the presence of free sugars (such as glucose) in solution. Furthermore, these hydrogels can easily be reconstructed from their lyophilized powder into any desired three-dimensional scaffold. Additionally, the hydrogels can be designed to have very low cytotoxicity and hence can be used as a scaffold for cell encapsulation. With these unique properties, these biocompatible, biodegradable, rebuildable, and self-healable hydrogels offer great potential in many biomedical applications.

Synthesis and biological evaluation of unnatural derivatives of narciclasine: 7-aza-nornarciclasine and its N-oxide.

Several unnatural derivatives of narciclasine were prepared in which the C-7 carbon was replaced with nitrogen. The 7-aza derivative and its N-oxide were prepared by the coupling of iodopicolinic acid with a conduramine unit derived chemoenzymatically from bromobenzene. Intramolecular Heck reaction was used to construct the isocarbostyryl ring system. The compounds were submitted to biological screening against cancer cell lines. Full experimental and spectra data are provided for all new compounds.

Unnatural C-1 homologues of pancratistatin - Synthesis and promising biological activities.

Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.

On a réalisé la synthèse de plusieurs homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine en faisant appel à une stratégie de recyclisation oxydante phenantrène­phénathridone. Les étapes clés impliquent la dihydroxylation du bromobenzène, l'addition d'une arylalane à une époxyaziridine, une ouverture intramoléculaire d'aziridine sur gel de silice en phase solide et la stratégie de recyclisation mentionnée plus haut. Les données expérimentales et spectrales sont rapportées pour tous les nouveaux produits. Tous les homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine ont été évalués pour leur activité à contrer la prolifération dans un éventail de lignées de cellules cancéreuses humaines. Tel que prévu, les composés 7-hydroxy sont les plus puissants alors que l'activité de l'analogue C-1 benzoxyméthyle est supérieure à celle de la narciclasine qui a été utilisée comme contrôle positif.

Synthesis of C-1 homologues of pancratistatin and their preliminary biological evaluation.

The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.