Synthesis and Anticancer Activity of Agelastatin Alkaloids

Technology

The inventors have synthesized all six (–)-agelastatin alkaloids, as well as nine structurally-related alkaloids and advanced intermediates, to study the SAR of this class of naturally occurring products and determine the potency of their anticancer activity. Agelastatins exhibit a unique tetracyclic framework with four contiguous stereogenic centers on the carbocyclic C-ring. A synthesis process involving late-stage C-ring formation allowed for the creation of nine synthetic (–)-agelastatin alkaloids for a comparative study of all known (–)-agelastatins in their ability to induce cell death in U-937 (lymphoma), HeLa (cervical carcinoma), A549 (non-small cell lung carcinoma), BT549 (breast carcinoma) and IMR90 (immortalized lung fibroblasts) human cell lines. Overall, the compounds demonstrate selectivity for cancer cells, induce apoptotic cell death and arrest cell growth in the G2/M phase. These compounds are particularly active against white blood cancer cell lines, and the selectivity for these cells over normal cells suggests considerable potential as anticancer agents.  

Problem Addressed

(–)-Agelastatin alkaloids are a class of natural products that have been shown to have potent anticancer activity. Until now, there has not been a comparative study of the structure-activity relationship (SAR) of all natural and synthetic (–)-Agelastatin alkaloids as it pertains to the alkaloids’ activity against cancer cell lines in culture.  

Advantages 

• Concise and effective synthetic access to a range of compounds
• Side-by-side testing of all known agelastatin alkaloids for anticancer potency
• Potent induction of apoptotic cell death and cell cycle arrest
• Activity against a wide range of cancer types, particularly white blood cancer cell lines