Dataset Information

A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A.

ABSTRACT: We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn²⁺-uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient-derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N²-acyl-2-aminoimidazole core. Combination treatment with ZnSO₄ strongly potentiated ZNA's cancer-specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn²⁺-dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn²⁺-interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed that tumor-bearing mice treated with ZNA had improved survival outcomes. Collectively, these data demonstrate that the N²-acyl-2-aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

SUBMITTER: Vaden RM

PROVIDER: S-EPMC8489793 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A.

Vaden Rachel M RM Guillen Katrin P KP Salvant Justin M JM Santiago Celine B CB Gibbons Joseph B JB Pathi Satya S SS Arunachalam Sasi S Sigman Matthew S MS Looper Ryan E RE Welm Bryan E BE

ACS chemical biology 20190108 1

We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn<sup>2+</sup>-uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient-derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demons ...[more]

PMID: 30571086

Similar Datasets

Project description:Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C18 skeleton of the parent fatty acid. Overall, this study establishes a foundation to fuel future programs aimed at developing natural-product-inspired fatty acid mimetics as valuable tools in chemical biology and potential therapeutic leads.

Project description:Tuberculosis is a disease caused primarily by the organism Mycobacterium tuberculosis (Mtb), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of Mtb to remain dormant after primary infection, thus creating a reservoir for the disease in the population that reactivates under more ideal conditions. A better understanding of the physiology of dormant Mtb and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating Mtb. Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone (1). Recently, the Rohde group reported that puupehedione (2) and 15-α-methoxypuupehenol (3) exhibit enhanced activity in an in vitro multi-stress dormancy model of Mtb. To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone (1) accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to (1) were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of epi-puupehenol and the natural products (+)-chromazonarol and (+)-yahazunol. In total, we generated a library of 24 compounds, of which 14 were found to be active against Mtb, and the most active compounds retained the enhanced activity against dormant Mtb seen in the parent compound. Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol esters possessed potent activity against actively dividing and dormant Mtb. Intriguingly, the closely related triisobutyl derivative 16 showed similar activity to 1 in actively dividing Mtb but lost about 178-fold activity against dormant Mtb. However, the monopivaloyl compound 13 showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant Mtb relative to the activity of 1 revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant Mtb. Elucidating important structure-activity relationships and the mechanism of action of this natural product-inspired chemical series may yield insights into vulnerable drug targets in dormant bacilli and new therapeutics to more effectively target dormant Mtb.

Dataset Information

A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A.

Publications

A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets