The Synthesis of Prodigiosene-Based Anticancer Reagents and Development of Reactions for Dipyrrin-Based Molecules
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Prodigiosenes, dipyrrins and F-BODIPYs are related pyrrolic compounds that share a common, conjugated backbone structure composed of an adhered pyrrole and azafulvene unit. Prodigiosenes are tripyrrolic compounds isolated from the Serrantia and Streptomyces genus of bacteria. In addition to possessing an array of immunosuppressive activities, they also exhibit the capacity for the induction of apoptosis in malignant cells. Dipyrrins are a main component of a variety of porphyrin-based, biologically relevant molecules, including many precursors along the pathway to molecules such as heme and vitamin- B12. They are themselves very strong chromophores, and have historically been utilized as dyes. F-BODIPYs are boron complexes of dipyrrins, and possess highly fluorescent character. These molecules are significantly more stable than their dipyrrin precursors, enabling their use in a vast quantity of important active fields of research. The first project investigated involves the synthesis of several prodigiosenes containing short-chain, ester-substituted moieties. The anticancer properties of these molecules were determined utilizing the NCI 60-cell line screen. One molecule containing a pentyl-ester chain showed promise as an anticancer agent, and was further tested in a toxicity assay as well as using a hollow-fibre assay. The cross-membrane ion transport properties of this compound were also examined using an egg-yolk 1-phosphatidylcholine model, and these results validated via competitive protonation of a native prodigiosin analogue. In addition to the synthesis of these prodigiosenes, preliminary work examining the use of decarboxylative coupling as a replacement for the low-yielding Suzuki-coupling step is also reported. The second project investigated focuses on the synthesis and characterization of compounds arising from 1-methylated dipyrrins. Microwave heating under pressurized conditions facilitates deuterium labelling of the 1-methyl group using protic, deuterated solvents. This reactivity is deactivated by the presence of acyl-substitution at the adjacent 2-position. Conjugate addition with N-phenylmaleimide has generated a new class of dipyrrins bearing 2,5-dioxo-1-phenylpyrrolidin-3-yl pendant groups at the 1-methyl position. Moreover, the first isolation of a 1-(methylenedipyrromethane)-dipyrrin, an unstable intermediate in the formation of 1-(vinylpyrrolyl)-dipyrrins, is also described. The final project investigated describes syntheses pertaining to of F-BODIPYs. The first portion of the report focuses on substitution reactions at the boron atom of the simplest, unsubstituted F-BODIPY. Attempted alkylation, alkoxylation and arylation reactions of this framework are reported. Chlorination to form the Cl-BODIPY is described, as is decomplexation from this form to generate the stable salt of the otherwise unstable unsubstituted dipyrrin core. The second portion of this project focuses on sulfination reactions of Knorr-type 1-ester pyrroles. Crystal structures of thiono-ester pyrroles are discussed, as is the first reported 1,3,2-thiazaphosphole derived from pyrrole. The generation of F-BODIPY products from alkyl-substituted, Knorr-type 1-ester pyrroles under microwave heating conditions is also reported. This reaction represents a four-step, one-pot process (averaging approximately 65% yield per step) to form high-value F-BODIPY products from simple starting materials.