I) Synthesis of small molecules as potential antibiotic and anticancer candidates

Abstract

The first part of this work involved the synthesis of chemical probes to the inhibition of the BfrB/Bfd protein interaction limiting the bioavailability of Fe3+ in Pseudomonas aeruginosa as potential antibiotic candidates Previously, our group synthesized substituted 4-aminoisoindoline-1,3-diones which exhibited promising enzymatic inhibition of the BfrB/Bfd protein interaction in the micromolar range. One of the primary goals of this project was to synthesize analogs in the nanomolar range. To achieve this, we synthesized 1- and 3-carbon linked analogs of substituted 4-aminoisoindoline-1,3-diones.

• Incorporation of new substituted benzaldehydes: This can be achieved by starting with relatively inexpensive materials. Based on molecular modeling, we previously predicted that the incorporation of these functionalities in analogs of 4-aminoisoindoline-1,3-dione would increase the protein inhibitory effect. We subsequently designed and synthesized a new series of 10 compounds incorporating various substituents on the benzaldehyde component. For the purpose of this study, the 1° and 3-carbon linkers were not altered in the synthesis.

• Altering the carbon linker BfrB/Bfd chemical probes: Other modifications to 4-aminoisoindoline-1,3-dione were also made by decreasing the 3-atom carbon linker to a 1-atom linker and incorporating a phenoxyethoxy linker. We were interested in comparing the activity data of the 1-carbon, with 3-carbon and phenoxyethoxy linked 4-aminoisoindoline-1,3-diones using similar substitution patterns in substituted benzaldehydes.

This work also involved the synthesis of anti-cancer agents. Flexible Heteroarotinoids (Flex-Hets) are a class of substituted di-aryl compounds that exhibit potent anti-cancer activity without toxicity. Previously, our group developed a sulfur containing heteroarotinoid SHetA2 (NSC 721689), which exhibited promising activity against 62 different cancer cell lines at micromolar concentration with excellent differentiation between normal and cancer cells. This work focused on modifying the linker unit of the SHetA2 compound.

• This study also focused on the synthesis of various analogs of SHetA2 and their evaluation against ovarian cancer cell line A2780. Structural modifications were made to the linker unit and Ring B of SHetA2 in order to improve aqueous solubility, potency and efficacy. The second part of this work involved devising new methods for preparing bioactive heterocyclic scaffolds. These methods are summarized below.

• Synthesis of naphthoates, dihydroquinolines, and naphthyridine carboxylates was accomplished via the Morita-Bayliss-Hillman reaction.

• A four-step synthesis to 2-fluoro-5-nitronicontinaldehyde was facilitated by reduction of an ester by DIBAL-H.

• An efficient tandem reaction was designed to synthesize 4-chromanone using 20 mol% of bismuth(III) triflate.