Synthesis and DNA cleavage of phenyl and 2-naphthyl propargylic sulfones and study on axially chiral 2-substituted N,N-dialkyl-1-naphthamides
by Chow Chun Wo
xvi, 108 leaves : ill. ; 30 cm
In this thesis work, two classes of compounds are studied. They are the phenyl and 2-naphthyl propargylic sulfones used as DNA cleaving agents, and the axially chiral 2-substituted N,N-dialkyl-1-naphthamides....[ Read more ]
In this thesis work, two classes of compounds are studied. They are the phenyl and 2-naphthyl propargylic sulfones used as DNA cleaving agents, and the axially chiral 2-substituted N,N-dialkyl-1-naphthamides.
The first part of the thesis consists of two chapters. After a brief overview of the anticancer agents in Chapter One, Chapter Two deals with the synthesis and biological studies of novel propargylic sulfones. Propargylic sulfones are known to readily isomerize into allenic sulfones under mild basic conditions. The latter substances are highly electrophilic and react with nucleic bases to produce base-alkylated DNA, an event leading to DNA strand breakage and cell death. Mechanistic studies by other groups reveal that propargylic sulfones preferably attack at G residues and show clear sequence specificities. Recent reports from this group demonstrate that incorporation of DNA intercalators into the phenyl propargylic sulfone conjugates significantly enhances the DNA cleavage potency. In this thesis work, the author synthesized a series of phenyl propargylic sulfone conjugates possessing a short spacer group between the sulfone and the intercalator and observed the effect of the spacer group on the action of the conjugates. In parallel, a novel series of 2-naphthyl propargylic sulfones and conjugates were designed and synthesized in the hope that the 2-naphthyl group can serve for both DNA alkylation and intercalation. Experimental results confirmed that the 2-naphthyl propargylic sulfones with a free hydroxyl group are highly potent DNA cleavers that produce >80% net strand cut at 100 μM. The corresponding aromatic ester conjugates, however, showed a reduced DNA cleavage potency in contrast to the observation on the phenyl propargylic sulfones. Cytotoxicity of the 2-naphthyl propargylic sulfones against P388 mouse T cell leukemia was assayed and the conjugates possessing a short spacer group are more potent than the analogs having additional one or two methylene unit(s) in the spacer.
2-Substituted N,N-dialkyl-1-naphthamides are chiral due to the restricted rotation around the Ar-C(O)N single bond. Chapter Three of the thesis describes some preliminary results on the separation of these enantiomerically pure atropoisomers by HPLC over a chiral stationary phase (Chiralpak AD). Although the absolute stereochemistry of the separated axially chiral amides has not been determined, they were used as the chiral promoters in the catalytic enantioselective ethylation of benzaldehyde with diethylzinc. Asymmetric induction was observed to some extent, though it is not satisfactory compared with the existing available methodologies. Nevertheless, these preliminary results are of reference value for future development on this emerging topic of axially chiral molecules.