The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.

We report the cancer stem cell (CSC) potency of a novel series of copper(ii)-phenanthroline complexes bearing nonsteriodial anti-inflammatory drugs: naproxen, tolfenamic acid, and indomethacin (2a-3c). Two of the complexes, 2a and 3c, kill breast CSC-enriched HMLER-shEcad cells (grown in both monolayer and three-dimensional cell cultures) to a significantly better extent than salinomycin, a well-established CSC toxin. The most potent complex in the series, 3c induces its cytotoxic effect by generating intracellular reactive oxygen species (ROS) and inhibiting cyclooxgenase-2 (COX-2) activity. Encapsulation of 3c using biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactic-co-glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 3c NP) enhances breast CSC uptake and reduces overall toxicity. The nanoparticle formulation, 3c NP selectively kills breast CSCs over bulk breast cancer cells, and evokes a similar cellular response to the payload, 3c. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver CSC-potent metal complexes into CSCs.

The breast cancer stem cell (CSC) potency of aseries of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4,s electivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells.F urthermore, 4 reduces the formation, size,a nd viability of mammospheres, to ag reater extent than salinomycin, ap otassium ionophore knowntoselectively inhibit CSCs.Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs.T he former induces DNAd amage, activates JNK and p38 pathways, and leads to apoptosis.

not follow the anti-Markovnikov rule. We proceed to show that in addition to the polarity of the double bonds within a molecule, in this case, the conjugation with the allyl double bond and the specific geometric features of the cyclohexane ring were key stabilizing factors for the unexpected transition state preference, resulting in a regioselectivity that is in quantitative agreement with previous experimental data. Our results further indicated that Re-face attacks and steric factors due to substituents of the substrate influenced mainly the stereoselective outcome of the reaction, also affecting the pathways available to proceed through to complete the hydroboration process.

(2016). Deviation from the anti-Markovnikov rule: a computational study of the regio-and stereoselectivity of diene hydroboration reactions. DOI: 10.1007DOI: 10. /s00214-015-1768 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. We proceed to show that in addition to the polarity of the double bonds within a molecule, in this case, the conjugation with the allyl double bond and the specific geometric features of the cyclohexane ring were key stabilizing factors for the unexpected transition state preference, resulting in a regioselectivity that is in quantitative agreement with previous experimental data. Our results further indicated that Re-face attacks and steric factors due to substituents of the substrate influenced mainly the stereoselective outcome of the reaction, also affecting the pathways available to proceed through to complete the hydroboration process.