Abstract
The molecular design and chemical synthesis of novel and artificial enediyne classes of DNA cleaving molecules 14, and their chemical and DNA cleaving profiles are described. The enediyne sulfides 1aI were synthesized via the coupling of the vinyl iodide 8 and the protected propargyl alcohol 9, and the intramolecular cyclization of the dibromide 17. 1b was found to cycloaromatize by 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) in 1, 4-cyclohexadiene through radical pathways and by a hydroxy anion in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer through a polar pathway. 1aI cleaved DNA under weakly alkaline conditions, and 1e, 1k and 1l, all of which have a DNA intercalatable moiety, exhibited strong DNA cleaving activities with the identical high purine base (G>A) selectivity. The enediyne triols 2ac were prepared from xylitol (19) via the conversion of the keto-aldehyde 24 into the keto-enediyne 25 by an intramolecular aldol reaction. 2a was also cycloaromatized in a manner similar to that for the enediyne sulfide, and 2ac showed guanine-specific DNA cleavages under weakly alkaline conditions. The enynallene sulfones 3af were obtained by m-CPBA oxidation of the corresponding enediyne sulfides. 3c was cycloaromatized by DBU through both radical and polar pathways. 3af cleaved DNA at any DNA-base site under weakly alkaline conditions, and 3df possessing a hydrophilic moiety exhibited stronger DNA cleavages. The dienediynes 4ac were synthesized from 25. 4c possessing acetoxy groups at the propargylic positions was cycloaromatized by methyl thioglycolate through radical pathways, and cleaved DNA at any pH with guanine-base selectivity. Furthermore, the DNA cleaving activity of 4c significantly increased in the presence of methyl thioglycolate.
