Total synthesis of ningalin B utilizing a heterocyclic azadiene Diels-Alder reaction and discovery of a new class of potent multidrug resistant (MDR)reversal agents

A concise, efficient approach to the total synthesis of ningalin B (1) base d on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine -> 1,2 -diazine -> pyrrole) ideally suited for construction of the densely functio nalized pyrrole core found in the natural product is detailed. Examination of the natural product and a number of synthetic intermediates revealed tha t while lacking inherent cytotoxic activity, many reverse the multidrug-res istant (MDR) phenotype, resensitizing a human colon cancer cell line (HCT11 6/VM46) to vinblastine and doxorubicin at lower doses than the prototypical agent verapamil.