
John A. Beutler, Ph.D.
- Center for Cancer Research
- National Cancer Institute
- Building 576, Room 103
- Frederick, MD 21702-1201
- 301-846-1942
- beutlerj@mail.nih.gov
RESEARCH SUMMARY
Dr. Beutler has identified several natural products which have potential for development as cancer drugs, among them, englerins, which are in preclinical development for kidney cancer and Ewing’s sarcoma, schweinfurthins, which are preclinical candidates in glioblastoma and malignant peripheral nerve sheath tumors, and salicylihalamides, of interest in sarcomas. As a Staff Scientist 2, Dr. Beutler oversees the Program's high-throughput screening libraries, information technology, and drug development efforts.
Areas of Expertise
1) natural products chemistry 2) high-throughput screening 3) molecular pharmacology
Research
We are advancing two natural product projects towards the clinic: englerins for kidney cancer and Ewings sarcoma, and schweinfurthins for central nervous system (CNS) tumors and other NF1-dependent conditions. These natural products both have unique mechanisms of action. In addition, our group builds and maintains the library of chemical diversity with which the Molecular Targets Program conducts high-throughput screening campaigns based on CCR-identified molecular targets.
Publications
Synthesis of a stable and orally bioavailable englerin analogue
Synthesis and biological evaluation of new (-)-englerin analogues
Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality
Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner
Biography

John A. Beutler, Ph.D.
B.A., Chemistry, Vassar College, 1972
M.Sc., Philadelphia College of Pharmacy & Science, 1978
Ph.D., Philadelphia College of Pharmacy & Science, 1980
Postdoctoral Fellowships:
Northeastern University, 1980-1
Assistant Professor, Auburn University School of Pharmacy, 1981-1983
University of Texas Medical School at Houston, 1983-4
AAAS Fellow, 2019
Team
Covers

Neopetrothiazide, an intriguing pentacyclic thiazide alkaloid from the sponge Neopetrosia sp.
Neopetrothiazide (1), a pentacyclic isoquinoline quinone, was isolated from a Neopetrosia sp. sponge. The structure elucidation was facilitated by utilizing long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) pulse sequences optimized to detect four- and five-bond (1)H-(13)C heteronuclear correlations. These NMR experiments can help assign proton-deficient structural motifs like neopetrothiazide (1), which has 14 contiguous nonprotonated centers (C, N, and S). Neopetrothiazide (1), with an unprecedented thiazide-fused structural scaffold, is the first natural product containing a thiazide moiety.
Wang D, Jiang W, Kim CK, Bokesch HR, Woldemichael GM, Gryder BE, Shern JF, Khan J, O'Keefe BR, Beutler JA, Gustafson KR. Neopetrothiazide, an intriguing pentacyclic thiazide alkaloid from the sponge Neopetrosia sp. Org Lett 23: 3278-3281, 2021.

Synthesis and biological assessment of 3,7-dihydroxytropolones
3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.
Hirsch DR, Schiavone DV, Berkowitz AJ, Morrison LA, Masaoka T, Wilson JA, Lomonosova E, Zhao H, Patel BS, Datla SH, Hoft SG, Majidi SJ, Pal RK, Gallicchio E, Tang L, Tavis JE, Le Grice SFJ, Beutler JA, Murelli RP. Synthesis and biological assessment of 3,7-dihydroxytropolones. Organic & biomolecular chemistry 2018; 16: 62-69.
Alumni
Lab Life
Shaking hands with Steve Chu at AAAS Fellows reception in Seattle, just pre-COVID.

Group get together to carve pumpkins and eat good food.

Pumpkins 2023