Synthesis and Anticancer Activity of the (R,S)-Benzofused 1,5-Oxathiepine Moiety Tethered to Purines through Alkylidenoxy Linkers

Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)‐9‐[2‐ or 3‐(3,4‐dihydro‐2H‐1,5‐benzoxathiepine‐3‐yloxy)alkyl]‐9H‐purines. Derivatives with propylenoxy‐linked 2′,6′‐dichloro‐ and 6′‐bromopurines are more active than their respective ethylenoxy‐linked purine conjugates. On the other hand, the compound with a propylenoxy‐linked 6′‐chloropurine is nearly equipotent to the corresponding ethylenoxy‐linked conjugate. Our results show that bromo‐ and chloropurine‐conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF‐7 breast cancer cells, indicating that the activation of eIF2α, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF‐7 cell line; apoptosis was induced in a p53‐independent manner. Tethered to fight cancer: 3,4‐Dihydro‐2H‐1,5‐benzoxathiepines linked to substituted 9H‐purines through 2‐ethylenoxy or 3‐propylenoxy spacers were synthesized and screened for anticancer activity toward the MCF‐7 breast cancer cell line. Inhibition of eIF2α phosphorylation and of the PI3 kinase pathway are the molecular targets for the most active compounds.