Synthesis and conversion of primary and secondary 2-aminoestradiols into A-ring-integrated benzoxazolone hybrids and theirin vitroanticancer activity

Abstract

Hybrid systems are often endowed with completely different and improved properties compared to their parent compounds. In order to extend the chemical space toward sterane-based molecular hybrids, a number of estradiol-derived benzoxazol-2-ones with combined aromatic rings were synthesizedviathe corresponding 2-aminophenol intermediates. 2-Aminoestradiol was first prepared from estrone by a two-step nitration/reduction sequence under mild reaction conditions. Subsequent reductive aminations with different arylaldehydes furnished secondary 2-aminoestradiol derivatives in good yields. The proton dissociation processes of the aminoestradiols were investigated in aqueous solution by UV-visible spectrophotometric titrations to reveal their actual chemical forms at physiological pH. The determined pK1and pK2values are attributed to the+NH3or+NH2R and OH moieties, and both varied by the different R substituents of the amino group. Primary and secondary 2-aminoestradiols were next reacted with carbonyldiimidazole as a phosgene equivalent to introduce a carbonyl group with simultaneous ring-closure to give A-ring-fused oxazolone derivatives in high yields. The novel aminoestradiols and benzoxazolones were subjected toin vitrocytotoxicity analysis and were found to exert cancer cell specific activity.