Diazinane and aryl moieties with vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti-glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used as an advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: C log P, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229 tumor cell death at 1 µg/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB.Download high-res image (100KB)Download full-size image

Efficient synthetic procedures for the preparation of acid hydrazines and hydrazides were developed by converting the corresponding carboxylic acid into the methyl ester catalyzed by Amberlyst-15, followed by a reaction with hydrazine monohydrate. Sulfohydrazides were prepared from the corresponding sulfonyl chlorides and hydrazine monohydrate. Both of these group of compounds were condensed with substituted salicylaldehydes using gradient concentration methods that generated a large library of hydrazone, hydrazide and sulfohydrazide analogs. Antifungal activity of the prepared analogs showed that salicylaldehyde hydrazones and hydrazides are potent inhibitors of fungal growth with little to no mammalian cell toxicity, making these analogs promising new targets for future therapeutic development.

•Direct foramidation procedure of electron rich aromatic halides was developed.•Aryl amination was performed on open air without copper ligand.•Economical approach to aryl C–N bond formation.•Copper(II) sulfate mediated reactions.A simple synthetic procedure for direct formamidation and amination of aryl halides mediated by copper(II) salts was developed in open air, without an external ligand in formamide with potassium carbonate as a base. This approach is particularly efficient when electron active aryl halides are used as substrates. In these cases almost quantitative formamidation was observed.

•Mild reaction conditions for the preparation of substituted semicarbazides.•The preparation method applicable to structurally diverse semicarbazides.•Building semicarbazide library from amines, hydrazines, and phenyl chloroformate.A simple synthetic procedure for the conversion of amines and hydrazines into substituted semicarbazides was developed. The initial condensation between the desired amine and phenyl chloroformate into phenyl carbamate is followed by the addition of hydrazine under basic conditions. The reaction is tolerable to a variety of functional groups, with mild conditions and high percent yields.

A simple, efficient, and rapid method was developed for high-yielding regioselective monobromination of activated aromatic compounds using NBS in combination with ionic liquid 1-butyl-1-methylimidazolium bromide ([Bmim]Br) or dioxane. The ionic liquid is recyclable and can be reused with minimal loss in the catalytic efficiency if the ionic liquid is rapidly microwaved prior to reactions.

Microwave-assisted preparation of several cyclic imides was performed with four different cyclic anhydrides. All the reactions are significantly faster and the isolated yields are significantly higher compared to conventionally heated reactions. Furthermore, many of these reactions can be performed with a minimal amount of solvent, thereby enabling the synthetic chemist to obtain high quantities of pure cyclic imides in a matter of hours.Microwave-assisted preparation of cyclic imides is superior with respect to isolated yield and length of reaction time when compared to conventional methods of preparation of imides.

Electrospray-ionization mass spectrometric (ESIMS) studies of several A007 prodrugs in aqueous cyclomaltohexaose (α-cyclodextrin, α-CD), cyclomaltoheptaose (β-cyclodextrin, β-CD), and cyclomaltooctaose (γ-cyclodextrin, γ-CD) were performed. The acetic acid derivative of A007 should metabolize in vivo before becoming the A007 prodrug, while on the other hand, the glycine-modified A007 prodrug has surfactant-like physical properties and slowly hydrolyzed in the aqueous cyclodextrins by releasing free A007. ESIMS studies give insight into the process of prodrug hydrolysis in the presence of cyclodextrins and, hence, the influence of cyclodextrins on the timely release of the A007 prodrug. Formation of various molecular aggregates and cyclodextrin inclusion complexes of A007 prodrugs and their hydrolyzed products was demonstrated by ESIMS.