Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NF&#954;B Activity and Breast Cancer Stem Cells

Inflammation is a cancer hallmark that underlies cancer incidence and promotion, and eventually progression to metastasis. Therefore, adding an ...

University of Illinois at Chicago

The title compound, cis,fac-dichloridotetra-kis(dimethyl sulfoxide)-κ(3)S,κO-ruthenium(II), [RuCl(2)(C(2)H(6)OS)(4)], was obtained from newly synthesized ruthenium complexes of 3-amino-2-chloro-pyridine. The Ru atom has a distorted octa-hedral coordination with two cis-oriented chloride ligands and four dimethyl sulfoxide ligands. Three of the sulfoxide ligands are S-bonded in a fac configuration, while the fourth is O-bonded. The title compound represents a new, and fourth, polymorph of the complex. Two other monoclinic forms and an ortho-rhom-bic modification have been reported previously.

A new monoclinic polymorph of dichlorido-tetra-kis(dimethyl sulfoxide)-ruthenium(II).

The limiting solubility of fatty acids in micellar solutions of the anionic surfactant sodium laurylethersulfate (SLES) and the zwitterionic surfactant cocamidopropyl betaine (CAPB) is experimentally determined. Saturated straight-chain fatty acids with n=10, 12, 14, 16, and 18 carbon atoms were investigated at working temperatures of 25, 30, 35, and 40°C. The rise of the fatty acid molar fraction in the micelles is accompanied by an increase in the equilibrium concentration of acid monomers in the aqueous phase. Theoretically, the solubility limit is explained with the precipitation of fatty acid crystallites when the monomer concentration reaches the solubility limit of the acid in pure water. In agreement with theory, the experiment shows that the solubility limit is proportional to the surfactant concentration. For ideal mixtures, the plot of the log of solubility limit vs. the chainlength, n, must be a straight line, which is fulfilled for n=14, 16, and 18. For the fatty acids of shorter chains, n=10 and 12, a deviation from linearity is observed, which is interpreted as non-ideal mixing due to a mismatch between the chainlengths of the surfactant and acid. The data analysis yields the solubilization energy and the interaction parameter for the fatty acid molecules in surfactant micelles. By using the determined parameter values, phase diagrams of the investigated mixed solutions are constructed. The four inter-domain boundary lines intersect in a quadruple point, whose coordinates have been determined. The results can be applied for the interpretation and prediction of the solubility, and phase behavior of medium- and long-chain fatty acids and other amphiphiles that are solubilizable in micellar surfactant solutions, as well as for determining the critical micellization concentration (CMC) of the respective mixed solution.

Solubility limits and phase diagrams for fatty acids in anionic (SLES) and zwitterionic (CAPB) micellar surfactant solutions.

Here, we present a detailed theoretical model describing the growth of disclike surfactant micelles. The model is tested against light-scattering data for micellar solutions from mixed conventional surfactants and from fluorinated surfactants. Theoretical expressions are derived for the concentration dependencies of the number and mass average aggregation numbers. Central role in the theory is played by the difference between the chemical potentials of a surfactant molecule in cylindrical and discoidal micelles. This difference, scaled with the thermal energy kT, is denoted p. For p<0, the formation of cylindrical (rather than disclike) micelles is energetically favored. For p>0 disclike micelles are formed, but their growth is limited due to the rise of their positive peripheral energy. Because of that, disclike micelles can be observed in a relatively narrow interval, 0<p<0.1, and in a limited concentration range. Three sets of light-scattering data for different surfactants were processed. It is remarkable that in all cases the best fit gives small positive values of p, in agreement with the theoretical predictions. The model predicts that a strong increase in the viscosity of a surfactant solution should happen upon the transformation of disclike micelles into cylindrical ones at small variations in p. The model can be used for analyzing the shape and size of micelles in various surfactant solutions. The fact that typical disclike micelles form only in the special case 0<p<0.1 shows why such micelles represent a relatively rare form of stable surfactant self-assembly.

Disclike vs. cylindrical micelles: generalized model of micelle growth and data interpretation.

By analysis of experimental data, a quantitative theoretical interpretation of the solubility limit of medium- and long-chain fatty alcohols in micellar solutions of water-soluble surfactants is presented. A general picture of the phase behavior of the investigated systems is given in the form of phase diagrams. The limited solubility of the fatty alcohols in the micelles of conventional surfactants is explained with the precipitation of their monomers in the bulk, rather than with micelle phase separation. The long chain fatty alcohols (with n=14, 16 and 18 carbon atoms) exhibit an ideal mixing in the micelles of the anionic surfactant sodium laurylethersulfate (SLES) and the zwitterionic surfactant cocamidopropyl betaine (CAPB) at temperatures of 25, 30, 35 and 40 °C. Deviations from ideality are observed for the alcohols of shorter chain (n=10 and 12), which can be explained by a mismatch with the longer chains of the surfactant molecules. Using the determined thermodynamic parameters of the systems, their phase diagrams are constructed. Such a diagram consists of four domains, viz. mixed micelles; coexistent micelles and precipitate (dispersed crystallites or droplets); precipitate without micelles, and molecular solution. The four boundary lines intersect in a quadruple point, Q. For ionic surfactants (like SLES), a detailed theory for calculating the boundary lines of the phase diagrams is developed and verified against data for the positions of the kinks in surface tension isotherms. The theory takes into account the electrostatic interactions in the micellar solutions and the effect of counterion binding. The results can be useful for a quantitative interpretation and prediction of the phase behavior of mixed solutions of two (or more) surfactants, one of them being water soluble and forming micelles, whereas the other one has a limited water solubility, but readily forms mixed micelles with the former surfactant.

Solubility limits and phase diagrams for fatty alcohols in anionic (SLES) and zwitterionic (CAPB) micellar surfactant solutions.

In breast tumors, activation of the nuclear factor κB (NFκB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy--all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFκB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFκB pathway. We found that DMF effectively blocks NFκB activity in multiple breast cancer cell lines and abrogates NFκB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFκB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFκB activity. Also, the cell-permeable thiol N-acetyl l-cysteine, reverses DMF inhibition of the NFκB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFκB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.

Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.

The synergistic growth of giant wormlike micelles in ternary mixed solutions composed of an anionic surfactant (sodium laurylethersulfate, SLES), a zwitterionic surfactant (cocamidopropyl betaine, CAPB), and octanoic acid (HC8) is studied. Rheological data and their analysis in terms of Cole-Cole plots and micellar characteristic times are presented, and the micellar structures behind the observed rheological behavior are revealed by cryo-TEM micrographs. The surfactant composition is fixed near the maximal micelle size of the binary SLES + CAPB system, whereas the concentration of HC8 is varied. At a given HC8 concentration, the viscosity of the ternary micellar solutions exhibits a very high and sharp peak. Polarized-light optical microscopy indicates that all investigated solutions are isotropic rather than liquid-crystalline. The cryo-TEM imaging shows complex phase behavior: wormlike micelles to the left of the peak, giant entangled wormlike micelles at the peak, and long wormlike micelles coexisting with multiconnected micellar aggregates to the right of the peak. The formation of multiconnected micelles leads to a drop in viscosity at the higher concentrations. The results contribute to a better understanding of the structure-rheology relations in micellar surfactant solutions and could be useful for controlling the properties of formulations in personal-care and house-hold detergency.

Gergana Georgieva

College of Pharmacy

University of Illinois at Chicago

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

Gergana Georgieva

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University of Illinois at Chicago

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

College of Pharmacy