Titanium-alkoxide based reductive coupling and medicinal chemistry for treatment of porphyromonas gingivalis-induced oral diseases

• Main Author: Cai, Bin
• Other Authors: Panek, James S.
• Language: en_US
• Published: 2019
• Subjects: Chemistry
• Online Access: https://hdl.handle.net/2144/33251

Both enantiomers of highly enantioenriched chiral allenylsilanes were prepared in high yields through a scalable synthetic sequence, employing a modified copper-mediated SN2’ reaction. These reagents were utilized in the asymmetric three-component propargylation reactions to produce enantioenriched homopropargylic ethers. The generated ethers were then subjected to titanium alkoxide-mediated reductive coupling with acetylenic esters to produce (E,E)-dienes bearing α,β,γ,δ-unsaturated esters. NFAT-68, a natural product isolated from the broth and mycelia of two Streptomyces sp. Fermentations, displayed potent in vitro immunosuppressive activity with an IC50 concentration <1 μg/ mL and no cytotoxicity observed at that concentration. The sequential use of the two methodologies facilitated the convergent synthesis of the both enantiomers of NFAT-68 in five steps and allowed a quick access to its analogues for future SAR studies. Stereodefined, highly functionalized (E,E)-dienes are common structural moiety embedded in natural products and pharmaceutically important agents. A titanium alkoxide-based alkyne-alkyne reductive coupling mediated by in situ generated arylamidate was developed. Complete regioselectivity was achieved in 39 (out of 40) examples, where (E,E)-dienes were formed exclusively in preference to other regioisomers. Mechanistic studies pointed to the directing effects of arylacetamide and –carbamate. Muramyl dipeptide (MDP) and its analogues exhibit potent anti-inflammatory effect. To aid the biochemical evaluation of the role of MDP in porphyromonas gingivalis (P.g.)-induced TNF-α production, a convergent and scalable solution-phase synthesis of diastereomerically and enantiomerically pure MDP analogues was developed. The developed method allowed fast production of MDP analogues in useful quantities that ultimately led to the discovery of one analogue that further improved MDP function and inhibition of P.g.-induced pro-inflammatory activities. Periodontal disease caused by bacterial accumulations or dental plaque on the teeth is highly prevalent in the United States. Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The benzoates showed promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis. === 2020-12-11T00:00:00Z