Chiral Alkyl Halides: Underexplored Motifs in Medicine.
While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.
Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA. bgal@stanford.edu.
Bálint
B
Gál
Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA. cbucher@stanford.edu.
Cyril
C
Bucher
Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA. nburns@stanford.edu.
Noah Z
NZ
Burns
D000818:Animals; D001688:Biological Products; D054879:Halogenation; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
D001688:Biological Products; D006846:Hydrocarbons, Halogenated
alkyl halide; anesthetic; astins; clindamycin; corticosteroid; forazoline; halomon; lapachone; lipophilicity; pimecrolimus; stereochemistry; sucralose