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) based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine-->1,2,-diazine-->pyrrole) ideally suited for construction of the densely functionalized pyrrole core found in the natural product is detailed. Examination of the natural product and a number of synthetic intermediates revealed that while lacking inherent cytotoxic activity, many reverse the multidrug-resistant (MDR) phenotype, resensitizing a human colon cancer cell line (HCT116/VM46) to vinblastine and doxorubicin at lower doses than the prototypical agent verapamil.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, California 92037, USA.
Soenen
D R
DR
Boyce
C W
CW
Hedrick
M P
MP
Jin
Q
Q
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis*; D006801:Humans; D051379:Mice; D014407:Tumor Cells, Cultured; D014561:Urochordata / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C409782:ningalin B; D004317:Doxorubicin