Natural Pyranoacridones from Citrus and Sarcomelicope Species as Models for the Conception of New Antitumor Agents

Abstract

The pyranoacridone alkaloid acronycine, first isolated from Sarcomelicope simplicifolia, was shown to exhibit a promising activity against a broad spectrum of solid tumors. Clinical trials only gave poor results, probably due to the moderate potency and low water solubility of this alkaloid. Early studies on structure-activity relationships in the series concluded that the 1,2-double bond was an essential structural requierement to observe cytotoxic activity. It is the reason why the isolation of the unstable acronycine epoxide from several Sarcomelicope species led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane in vivo. Consequently, there was interest in the search for stable acronycine derivatives modified in the pyran ring and having improved stability, but a similar reactivity toward nucleophilic agents as acronycine epoxide. A series of cis- and trans-1,2-dihydroxy-1,2-dihydroacronycine diesters exhibited interesting antitumor properties with a broadened spectrum of activity and an increased potency when compared with acronycine. The demonstration that acronycine should interact with DNA led to develop benzo[b]acronycine analogs possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. When tested against a panel of cancer cell lines in vitro, cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters exhibited cytotoxic activities within the same range of potency as the most active drugs currently used in cancer chemotherapy. In vivo, cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine, selected for further preclinical development, demonstrated a marked antitumor activity in several models of human orthotopic cancers xenografted in nude mice.