Abstract
Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new (veraguamide O (1) and veraguamide P (2)) and one known (veraguamide C (3)) analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane-bound receptors. The planar structures were determined based on NMR and MS data along with a comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be an Okeania sp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 μM) against ER-positive cells (MCF-7) with 13 μM IC50 against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor, making them potential leads for the development of non-toxic sigma 2 targeting ligands.
| Original language | English |
|---|---|
| Article number | 680 |
| Journal | Molecules |
| Volume | 30 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 2025 |
Bibliographical note
Publisher Copyright:© 2025 by the authors.
Funding
This research was funded by the National Institutes of Health (NIH) grants NIH NCCIH R15AT008060 (BJK, KJT) and NIH NINDS R61NS127271 (KJT, BJK) and the Fogarty International Center Panama International Cooperative Biodiversity Grant TW006634 (partially supported collection of material by KJT). This work was further supported by the Center for Pharmaceutical Research and Innovation (CPRI, NIH P20 GM130456). We would like to thank Analise Zapadka, Edward Hilton, and Youstina Seliman for technical assistance. We thank the following departments, funding agency and sponsors: Autoridad Nacional del Ambiente de Panamá (ANAM) and the Smithsonian Tropical Research Institute (STRI). Receptor binding profiles was generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # 75N95023C00021 (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD, USA.
| Funders | Funder number |
|---|---|
| National Institutes of Health (NIH) | |
| KJT | |
| National Institute of Mental Health | 75N95023C00021 |
| National Institute of Mental Health | |
| Center for Pharmaceutical Research and Innovation, University of Kentucky | P20 GM130456 |
| Center for Pharmaceutical Research and Innovation, University of Kentucky | |
| NIH NCCIH | R15AT008060 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R61NS127271 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | |
| Fogarty International Center Panama International Cooperative Biodiversity | TW006634 |
Keywords
- TMEM-97
- cyanobacteria
- sigma 2
- veraguamide
ASJC Scopus subject areas
- Analytical Chemistry
- Chemistry (miscellaneous)
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
- Physical and Theoretical Chemistry
- Organic Chemistry
