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journal article·2026-07Open access

Natural Products Inspired Scaffold Diversification Leads to Unnatural Molecular Warhead and Covalent Strategy to Modulating Protein Function through Electrophilic Bromine Transfer

Beau R. Brummel, Sofia Kokkaliari, Qiwen Gao, Jinjing Chen, Larissa Costa de Almeida, Srinivasarao Tenneti, Derek A. Leas, Eli Levit, Lewis S. Alexander, Khalil A. Abboud, Pingrong Wei, Michael D. Cameron, James R. Rocca, Ranjala Ratnayake, Donna D. Zhang, Hendrik Luesch, Robert W. Huigens

Advanced Science· Volume 13· Issue 42
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Source abstract

Abstract

ABSTRACT We discovered a thiolate‐reactive α,α‐ gem ‐dibromo lactam warhead that activates transcription factor Nrf2 and demonstrates anti‐inflammatory activities, which have implications in cancer, neurodegeneration, and cardiovascular diseases. Our findings originated from new compounds accessed through aza‐oxyallyl cation‐mediated [3+2]‐cycloadditions of ajmalicine and inspired indoles. RNA‐seq and Ingenuity Pathway Analysis illuminated detailed transcriptional profiles of α,α‐ gem ‐dibromo lactams to show activation of the antioxidant Keap1/Nrf2 pathway and suppressed NF‐κB‐mediated inflammatory signaling. We demonstrated the importance of the α,α‐ gem ‐dibromo lactam, as the corresponding α,α‐ gem ‐dichloro lactam is unable to activate the Nrf2 pathway. Chemical reactions with cysteine‐containing compounds suggested α,α‐ gem ‐dibromo lactams react with cysteine residues to transfer electrophilic bromine to target molecules, linking unique chemistry to our biological findings. In contrast to electrophiles that activate the canonical Nrf2 pathway by covalently targeting C151 of Keap1, the α,α‐ gem ‐dibromo lactams function in a C151‐independent manner, indicating a distinct selectivity and consequently mode of action. Pharmacological profiling of several α,α‐ gem ‐dibromo lactams compared with ajmalicine against adrenergic receptors revealed substantial differences, indicating tunability and novel pharmacology. Future investigations aim to explore the fundamental activities of the dibromo lactam warhead related to human disease. Installation of this warhead into various molecular scaffolds may be a generalizable method to create cystein‐reactive electrophiles.
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Research context

OpenAlex topics: Genomics, phytochemicals, and oxidative stress · Phosphodiesterase function and regulation · Synthesis and Reactivity of Heterocycles

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3) College of Pharmacy University of Florida Gainesville Florida USA

Department of Pharmaceutical & Biomedical Sciences College of Pharmacy University of Georgia Athens Georgia USA

Department of Molecular Medicine Center for Inflammation Science and Systems Medicine The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology Jupiter Florida USA

Department of Pharmacology and Therapeutics College of Medicine University of Florida Gainesville Florida USA

Department of Chemistry University of Florida Gainesville Florida USA

Department of Chemistry Franklin College of Arts and Sciences University of Georgia Athens Georgia USA

Department of Molecular Medicine The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology Jupiter Florida USA

McKnight Brain Institute University of Florida Gainesville Florida USA

University of Florida Health Cancer Center University of Florida Gainesville Florida USA

Program in Cancer and Stem Cell Biology Duke‐NUS Medical School Singapore Singapore

Department of Infectious Diseases College of Veterinary Medicine University of Georgia Athens Georgia USA

Funding

National Institute of General Medical Sciences · American Cancer Society · National Cancer Institute · National Institute of Dental and Craniofacial Research · National Institutes of Health · National Science Foundation

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