ABSTRACT
A facile, DAST-mediated intramolecular cyclization of 3-hydroxy-3-(2-((3-methoxybenzyl)oxy)phenyl)indolin-2-one derivatives for the synthesis of spirooxindoles fused with dibenzoxepine moieties is described. The success of this reaction is highly dependent on the choice of solvent (promoted by DCM and 1,2-DCE) and the electronic nature of the pendant aromatic ring, which is favored by the presence of electron-donating substituents. The reaction is believed to proceed through an intramolecular Friedel-Crafts-type reaction. Various dibenzoxepine-fused spirooxindoles were successfully synthesized in up to 98% yield. This methodology provides libraries of structurally diverse and medicinally important small molecules that could aid in the search for new bioactive molecules.
ABSTRACT
Uncialamycin is one of the structurally simpler and newer members of enediyne family of natural products. It exhibits highly potent activity against several types of bacteria and cancer cells. Described herein is a strategy for the targeted delivery of this cytotoxic agent to tumors using an antibody-drug conjugate (ADC) approach. Central to the design of ADC were the generation of potent and chemically stable uncialamycin analogues and attachment of protease cleavable linkers to newly realized phenolic handles to prepare linker-payloads. Conjugation of the linker-payloads to tumor targeting antibody, in vitro activity and in vivo evaluation are presented.
