Pentathiepins are an understudied molecular prism of biological activities.

The pentathiepin core was first synthesized in 1971, and while synthetic techniques have progressed over subsequent decades, the biological applications of this heterocycle have received less attention and are only now becoming more apparent. The first natural product, varacin, was identified in 1991, showing cytotoxicity toward a human colon cancer cell line. More recently, the pentathiepin has acted as a surrogate to replace elemental sulfur, that was discovered as a hit in neurodegenerative animal models. A variety of other medicinal chemistry applications have recently been disclosed. Here, we summarize these indications and highlight the main synthetic pathways to access the pentathiepin core. We offer a concise summary and future perspective of this unique sulfur isosteric replacement.