Chalcones: Potential Chemotherapeutic Compounds and Educational Tools for Closing the Loop in STEM.

The study discussed herein describes the synthesis of halogenated chalcones as potential chemotherapeutics. The synthesis work was conducted by undergraduate students participating in an Organic Chemistry II laboratory course at Tuskegee University, while the biological assays were conducted by students enrolled in a Molecular Biology I laboratory course. Chalcones were synthesized via aldol condensation and purified from hot ethanol. The impetus for the work was the fact that Tuskegee University sits positioned within the Black Belt of Alabama which, in addition to being an area of fertile soil and excellent farmland, is also an area rife with health disparities that particularly affect African-Americans. Breast cancer, specifically triple-negative breast cancer, affects African-American women at a higher rate than any other ethnic group. The work described herein addresses a practical problem [teaching undergraduate students about the interface of synthetic techniques, synthesis of specific classes of compounds, functional groups, and their relation to biological activity], as well an existential problem [the prevalence of breast cancer among African-American women, and the need to develop targeted treatments]. One of the chief aims of this approach of integrating these ideas into our laboratory courses was to facilitate the understanding of translational science, i.e. taking chalcones from benchtop to potential therapies for breast cancer. Another aim of the current approach was to, in essence, create a research problem based course and concomitantly use the results of the experiments performed in the course as a way to address the dearth of research funding that HBCUs typically receive. The pharmacological activities of chalcones and their derivatives are well documented. They are an important class of natural products that occur in edible plant derivatives such as spices, teas, fruits and various vegetables. In vitro studies have shown that chalcones inhibit proliferation of breast cancer cells by inducing apoptosis and blocking cell progression. The synthesis of chalcones with aromatic substituents has been investigated, and electron rich chalcones, i.e., chalcones with donors attached to the aromatic rings, have been studied extensively. The effect that adding electron withdrawing groups to the chalcone structural motif has on the antiproliferation ability of chalcones had been only minimally investigated at the time that our studies were being conducted. We examined the introduction of chlorine to the aromatic system of the chalcone and how these electron withdrawing substituents affect the chalcone's antiproliferative ability. It was discovered that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one inhibited MDA-MB-231 cell progression in a dose dependent manner and outperformed the unsubstituted (E)-1,3-diphenyl-2-propen-1-one (1) at concentrations ranging from 0 µg/mL to 20 µg/mL. Cell death was determined by MTT assay.

In vitro activity of the interaction between taxifolin (dihydroquercetin) and pyrimethamine against Toxoplasma gondii.

Toxoplasmosis is one of the most neglected zoonotic foodborne parasitic diseases that cause public health and socioeconomic concern worldwide. The current drugs used for the treatment of toxoplasmosis have been identified to have clinical limitations. Hence, new drugs are urgently needed to eradicate T.gondii infections globally. Here, an in vitro anti-Toxoplasma gondii activity of taxifolin (dihydroquercetin) and dihydrofolate inhibitor (pyrimethamine) alone and in combination with a fixed concentration of pyrimethamine were investigated against the rapidly proliferating T.gondii RH strain at 48 hr using colorimetric assay. Pyrimethamine showed the highest anti-T. gondii activity with IC50P of 0.84 µg/ml (p > .05), respectively. The combination of pyrimethamine with dihydroquercetin gave a significant inhibitory activity against tachyzoites in in vitro with IC50p of 1.39 µg/ml (p < .05). The IC50p ranges obtained for the individual and the combination of taxifolin with pyrimethamine inhibition of parasite growth were not cytotoxic to the infected HFF and Hek-293 cell lines used. These compounds combination should be investigated further using in vivo model of toxoplasmosis.

Catalytic addition methods for the synthesis of functionalized diazoacetoacetates and application to the construction of highly substituted cyclobutanones.

[reaction: see text] Methyl 3-(trialkylsilanyloxy)-2-diazo-3-butenoate undergoes Lewis acid-catalyzed Mukaiyama aldol addition with aromatic and aliphatic aldehydes in the presence of low catalytic amounts of Lewis acids in nearly quantitative yields. Scandium(III) triflate is the preferred catalyst and, notably, addition proceeds without decomposition of the diazo moiety. Diazoacetoacetate products from reactions with aromatic aldehydes undergo rhodium(II)-catalyzed ring closure to cyclobutanones with high diastereocontrol. Examples of complimentary Mannich-type addition reactions with imines are reported.

Investigation of the rh-catalyzed asymmetric reductive aldol reaction. Expanded scope based on reaction analysis.

[reaction: see text] A series of experiments are described that suggest that the Rh-catalyzed reductive aldol reaction proceeds by addition of a Rh(I) hydride, generated in situ, to the reacting acrylate followed by a stereochemistry-controlling aldol addition reaction. On the basis of this hypothesis, reaction conditions are engineered that allow for increased substrate scope.

Divergence of carbonyl ylide reactions as a function of diazocarbonyl compound and aldehyde substituent: dioxolanes, dioxolenes, and epoxides.

The products from dirhodium(II) acetate-catalyzed reactions between diazocarbonyl compounds and a series of benzaldehydes demonstrate the extent of competition between intramolecular and intermolecular trapping of carbonyl ylide intermediates and the electronic effects that govern these transformations. With dimethyl diazomalonate, competition exists between dioxolane and epoxide formation so that with p-anisaldehyde only epoxide formation is observed and with p-nitrobenzaldehyde only 1,3-dioxolane products are formed. With methyl diazoacetoacetate, intramolecular trapping of the intermediate carbonyl ylide results in the sole production of dioxolenes. However, the vinyldiazoacetate analogue of methyl diazoacetoacetate, as its tert-butyldimethlsilyloxy derivative, only produces epoxides in its reactions with substituted benzaldehydes.