Highlights d Specific compounds against P. falciparum Plasmepsin IX and X were identified d PMIX and PMX are modulators of parasite proteins for egress, invasion, and development d Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium d One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites

Born August 22, 1953, Dale L. Boger (seated) received his B.Sc. in chemistry from the University of Kansas (1975) and Ph.D. in chemistry from Harvard University (1980). Immediately following graduate school, he returned to the University of Kansas as a member of the faculty in the Department of Medicinal Chemistry (1979Chemistry ( −1985, moved to the Department of Chemistry at Purdue University (1985University ( −1991, and joined the faculty at The Scripps Research Institute (1991 to present) as the Richard and Alice Cramer Professor of Chemistry. His research interests span the fields of organic and bioorganic chemistry and include the development of synthetic methodology, the total synthesis of natural products, heterocyclic chemistry, bioorganic chemistry, medicinal chemistry, the study of DNA−agent and protein−ligand interactions, and antitumor agents.Christopher W. Boyce (standing left) was born January 30, 1972, and grew up in Richmond, MA. Following a year abroad at the Swiss Federal Institute (ETH-Zurich), he received his B.Sc. in chemistry from Rensselaer Polytechnic Institute (1994, summa cum laude). He is currently pursuing a Ph.D. under the direction of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylation agents related to the CC-1065 and duocarmycin families. Robert M. Garbaccio (standing right) was born on January 20, 1972, and grew up in Old Tappan, NJ. He received his B.A. in chemistry and graduated summa cum laude from Boston University in 1994 where he conducted research in the laboratory of Professor James S. Panek. Presently, he is pursuing a Ph.D. in chemistry at The Scripps Research Institute under the guidance of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylating agents from the duocarmycin and mitomycin families of antitumor antibiotics. Joel A. Goldberg (standing center) was born June 17, 1972, and grew up in Bedford, NH. After receiving his B.Sc. from Tufts University he joined Professor Boger's laboratory at The Scripps Research Institute where he is pursuing his Ph.D. in Chemistry. His research concentrates on the synthesis and evaluation of potent alkylating agents related to CC-1065 and the duocarmycins.

Concise, efficient total syntheses of ningalin A (1), lamellarin O (2), lukianol A (3), and permethyl storniamide A (5) are detailed on the basis of a common heterocyclic azadiene Diels−Alder strategy (1,2,4,5-tetrazine → 1,2-diazine → pyrrole) ideally suited for construction of the densely functionalized pyrrole cores found in the three classes of marine natural products. Examination of the natural products and a number of synthetic intermediates revealed that some including lamellarin O (2) and lukianol A (3) exhibit modest cytotoxic activity against both wild-type and multidrug-resistant tumor cell lines. Fundamentally more important, a new class of agents including permethyl storniamide A (5) and its precursor 30, which lack inherent cytotoxic activity, are disclosed which 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.

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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.