CAS 498-77-1 Benzethonium - Vaccine Lab / Alfa Chemistry

Benzethonium as a Negative Modulator of Mitochondrial Calcium Uniporter in Cancer Progression

Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter Mario AD, et al. Cell Reports, 2021, 35(12), 109275.

Benzethonium, a quaternary ammonium compound, has emerged as a notable negative modulator of the mitochondrial calcium uniporter (MCU), a key channel facilitating mitochondrial Ca²⁺ uptake. High-throughput screening of FDA-approved drugs identified benzethonium as a selective inhibitor of MCU, revealing its potential to influence cancer cell physiology, particularly in triple-negative breast cancer (TNBC) cell lines like MDA-MB-231.
The study demonstrated that benzethonium inhibits mitochondrial Ca²⁺ uptake without significantly affecting cytosolic Ca²⁺ levels or mitochondrial membrane potential (ΔΨm). This selective inhibition is critical, as mitochondrial Ca²⁺ uptake is pivotal in maintaining cellular energetics, driving cell proliferation, and regulating apoptosis. By suppressing mitochondrial Ca²⁺ uptake, benzethonium delays TNBC cell growth and migration. Interestingly, it also protects cells from ceramide-induced apoptosis, contrasting the pro-apoptotic effects typically associated with excessive mitochondrial Ca²⁺ entry.
Despite these promising results, benzethonium's low cell permeability presents a challenge for its therapeutic application. Additionally, it was found to modestly inhibit the Na⁺/Ca²⁺ exchanger (NCLX), complicating its role as a purely MCU-targeting agent. Nonetheless, the inhibitory effect on the MCU appears to be the dominant action at lower concentrations, where the effects on cell growth inhibition and apoptosis prevention are observed.
Benzethonium's ability to modulate mitochondrial Ca²⁺ uptake without inducing apoptosis at specific concentrations positions it as a potential candidate for cancer therapies that require precise control over mitochondrial functions. Further studies are warranted to optimize benzethonium's cellular delivery and evaluate its broader applicability across different cancer types and pathophysiological conditions.

Catalog Number	ACM498771-1
CAS	498-77-1
Structure
Synonyms	Benzethonium hydroxide solution
IUPAC Name	Benzyl-dimethyl-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]azanium
Molecular Weight	412.6
Molecular Formula	C27H42NO2
Canonical SMILES	SIYLLGKDQZGJHK-UHFFFAOYSA-N
InChI	InChI=1S/C27H42NO2/c1-26(2,3)22-27(4,5)24-13-15-25(16-14-24)30-20-19-29-18-17-28(6,7)21-23-11-9-8-10-12-23/h8-16H,17-22H2,1-7H3/q+1
InChI Key	SIYLLGKDQZGJHK-UHFFFAOYSA-N
Purity	99%
Complexity	466
Covalently-Bonded Unit Count	1
Defined Atom Stereocenter Count	0
Exact Mass	412.321554582
Heavy Atom Count	30
Hydrogen Bond Acceptor Count	2
Hydrogen Bond Donor Count	0
Monoisotopic Mass	412.321554582
Rotatable Bond Count	12
Topological Polar Surface Area	18.5 Å²