Palladium-catalyzed cyclization of drug candidates

Abstract

Ovarian cancer is both difficult to detect and difficult to treat, therefore the discovery of new therapies is important. Retinoids (retinoic acid derivatives) are known to induce cellular apoptosis in various cancers, especially in ovarian cancer. Retinoids are also highly cytotoxic to healthy cells, however. SHetA2 leads a class of retinoids known as Flexible Heteroarotinoids (Flex-Hets) that have low toxicity to healthy cells while retaining anti-cancer activity. Rigorous studies of the structure-activity relationship of retinoids and heteroarotinoids have determined that 5-membered heterocyclic Ring A systems in SHetA2 analogs might exhibit anti-cancer activity as well as improved water solubility. The synthetic challenge in preparing these molecules led to the investigation of a new synthetic route for preparing SHetA2 analogs. This new route involves cyclizing tethered alkenes via a reductive Heck reaction using the Jeffery conditions. This reaction is known to prepare heterocycles that contain structural characteristics essential to SHetA2 analog anti-cancer activity. This study synthesized a new class of heteroarotinoids using this method, then explored other ways in which the method could be applied to the greater project. The method was also employed to synthesize a previously known heterarotinoid, OHet72, as well as a new analog of that compound. In addition, the synthesis of bacterioferritin-inhibiting antibiotics was explored, including the preparation of a specific substrate designed to provide insight into a problem observed in the synthesis of previous analogs. This substrate required a new synthetic approach, and was designed to eliminate the possibility of various side reactions occurring. This study explored the preparation of 4-((5-chloro-2-hydroxybenzyl)amino)isoindolin-1-one and whether similar side reactions were observed.