Draft:D H

Diisopropylamine dichloroacetate

Diisopropylamine dichloroacetate (DADA) is a chemical compound with the molecular formula C₈H₁₆ClNO₂. It is the active component of pangamic acid, a substance once marketed as "vitamin B15," and has been commercially available for over 50 years primarily for the treatment of chronic liver disease.<ref>https://pmc.ncbi.nlm.nih.gov/articles/PMC5323187/</ref>

Chemical properties

DADA is a derivative of dichloroacetate (DCA) and functions as an inhibitor of pyruvate dehydrogenase kinase 4 (PDK4).<ref>https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098032</ref> The compound has the CAS registry number 660-27-5 and appears as a white to almost white powder or crystal with a melting point of 120.0 to 124.0 °C.<ref>https://www.tcichemicals.com/US/en/p/D5074</ref>

Medical uses

DADA has been investigated for several therapeutic applications:

Liver disease treatment

The compound has been commercially available for decades as a treatment for chronic liver disease, particularly in Japan where it is marketed under the brand name Liverall.<ref>https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098032</ref>

Cancer research

Recent studies have investigated DADA's potential anti-cancer properties. Research has demonstrated that DADA shows superior anti-tumor efficacy compared to dichloroacetate in breast cancer models, with a lower half maximal inhibitory concentration against MDA-MB-231 breast cancer cells.<ref>https://pmc.ncbi.nlm.nih.gov/articles/PMC5323187/</ref>

DADA has also been studied as a radiosensitizer for esophageal squamous cell carcinoma, where it was found to enhance radiation therapy effectiveness by increasing mitochondria-derived reactive oxygen species levels.<ref>https://pmc.ncbi.nlm.nih.gov/articles/PMC5356547/</ref>

Metabolic disorders

Studies have explored DADA's potential in treating metabolic disorders and multiorgan failure in severe influenza, showing that it can restore pyruvate dehydrogenase activity and ATP levels in various organs.<ref>https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098032</ref>

Mechanism of action

DADA functions as a selective inhibitor of pyruvate dehydrogenase kinase 4 (PDK4), which leads to the activation of pyruvate dehydrogenase and shifts cellular metabolism from glycolysis toward oxidative phosphorylation.<ref>https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1447828/full</ref> This metabolic shift can reduce lactate production and glucose uptake in cells, while increasing oxygen utilization.

Performance enhancement in equine sports

DADA is recognized as a performance-enhancing substance in horse racing and equestrian sports. The compound is prohibited for use in the horse racing industry due to its alleged effects to increase oxygen utilization and cortical glucose uptake.<ref>https://horsesport.com/horse-news/riders-suspension-halved-team-vet-admits-injections/</ref><ref>https://pubmed.ncbi.nlm.nih.gov/37459832/</ref>

Detection and regulation

Detection methods for DADA and its primary metabolite diisopropylamine (DIPA) in equine urine have been developed using thin-layer chromatography and gas chromatography, with a lower limit of detection of 0.5 μg/ml urine.<ref>https://pubmed.ncbi.nlm.nih.gov/3215480/</ref> The substance is included on prohibited substance lists for horse racing organizations.

Notable cases

There have been documented cases of equine doping involving DADA, including suspensions of horse trainers for positive findings of the substance in racehorses.<ref>https://paulickreport.com/news/the-biz/hiwu-provisionally-suspends-two-california-trainers-over-banned-substance-findings-supplement-may-be-to-blame/</ref>

Relationship to pangamic acid

DADA is often found in supplements marketed as pangamic acid or "vitamin B15." However, pangamic acid is not recognized as a true vitamin and has no standard chemical identity. The FDA considers products marketed as pangamic acid to be unsafe and subject to seizure.<ref>https://horsesport.com/horse-news/riders-suspension-halved-team-vet-admits-injections/</ref>

Safety and side effects

While DADA has been used clinically for decades, research indicates it can have physiological effects including vasodilation of peripheral and cerebral arterioles and potential diuretic effects.<ref>https://drugs.ncats.io/drug/BR9JLI40NO</ref> The compound's safety profile in humans has been studied primarily in the context of liver disease treatment, where it has been considered relatively safe when used under medical supervision.

Research status

DADA remains an investigational compound for most of its potential therapeutic applications. While it shows promise in cancer research and metabolic disorders, most studies are still in preclinical phases. The compound is not FDA-approved for any specific indication in the United States.