Bromopyruvic acid

Bromopyruvic acid

Names
IUPAC name 3-bromo-2-oxopropanoic acid
Other names bromopyruvate 3-bromopyruvic acid 3-bromopyruvate 3-BrPA 3BP 3-Br-Pyr
Identifiers
CAS Number	1113-59-3 Y
3D model (JSmol)	Interactive image Interactive image
ChEMBL	ChEMBL177837 Y
ChemSpider	63850 Y
ECHA InfoCard	100.012.915
PubChem CID	70684
CompTox Dashboard (EPA)	DTXSID7040940
InChI InChI=1S/C3H3BrO3/c4-1-2(5)3(6)7/h1H2,(H,6,7) Y Key: PRRZDZJYSJLDBS-UHFFFAOYSA-N Y InChI=1/C3H3BrO3/c4-1-2(5)3(6)7/h1H2,(H,6,7) Key: PRRZDZJYSJLDBS-UHFFFAOYAU
SMILES C(C(=O)C(=O)O)Br BrCC(=O)C(=O)O
Properties
Chemical formula	C3H3BrO3
Molar mass	166.95812
Melting point	79-82 °C (hydrate)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

3-bromopyruvate molecule

3-bromopyruvic acid, or its alkaline form, 3-bromopyruvate, are synthetic brominated derivatives of pyruvic acid. They are lactic acid and pyruvate analogs.  

The characteristics of 3-bromopyruvate in vitro and in vivo have been reported in the scientific literature since the 1940s. Because it is a highly reactive alkylating agent and it is inherently unstable, it had been described as a metabolic poison.  

Research activity

In 1993 researchees at the Johns Hopkins School of Medicine reported that a pyruvate transporter system could be used to deliver 3-bromopyruvate inside trypanosomal cells where its primary target is glyceraldehyde-3-phosphate dehydrogenase, which is highly sensitive to inhibition by 3-bromopyruvate.15;268(5):3654-61

Young Hee Ko at the Pedersen Laboratory at Johns Hopkins has performed experiments that indicate that 3-bromopyruvate could be used to selectively kill cancer cells, while leaving normal cells alone.Pedersen, Peter L. (2012). "3-bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: Introduction to a special issue". Journal of Bioenergetics and Biomembranes. 44 (1): 1–6. doi:10.1007/s10863-012-9425-4. PMID 22382780.

Professor Pedersen (PLP) described this event in the Journal of Bioenergetics and Biomembranes (2012), volume 44, on page 164, "Assigned by coauthor PLP the role of identifying (discovering) an anticancer agent specifically targeted at energy metabolism, YHK (Young Hee Ko) knew that the essential criteria for success (Pedersen 2007a) were to find an agent that

1) leaves normal cells intact while

2) inhibiting both the most common biochemical phenotype of cancer cells, i.e., the “Warburg Effect”, elevated glycolysis even in the presence of oxygen (Warburg 1956), and also mitochondrial ATP production.

Then, both energy (ATP [adenosine triphosphate]) production factories (mitochondria and glycolysis) of the cancer cells would be destroyed and normal cells would remain intact.

Ko selected only a few candidate compounds (<20) for the initial screen, and of these showed that only one, i.e., 3-bromopyruvate (3BP), met the two criteria noted above (Ko et al. 2001)."   

The mechanism of action of 3-bromopyruvate in cancer cells involves a number of different biological processes, ranging from inhibiting GAPDH, an enzyme used in the sixth step of glycolysis, to disrupting cell signalling to an elevation in intracellular pH gradient to cell signal transduction cascades affecting metabolic pathways.

The most important of these processes relies on the fact that malignant cells overexpress lactic acid transporters on their surface, while normal cells have very few lactic acid transporters.  

Because 3-bromopyruvate is a lactic acid analog, malignant cells will absorb 3-bromopyruvate through their lactic acid transporters. Once inside the cell, 3-bromopyruvate can both inhibit oxidative phosphorylation in the cytoplasm and glycolysis in the mitochondria. 

Cancer cells overexpress hexokinase II, an enzyme which is essential in the first step of glycolysis. Inside their mitochondria, Akt induces the translocation of hexokinase II to the outer mitochondrial membrane where it binds to a protein known as the voltage-dependent anion channel (VDAC).  

3-bromopyruvate is a highly specific inhibitor of hexokinase II.  When this happens, hexokinase II becomes disassociated from the mitochondira, resulting in a rapid depletion of adenosine triphosphate (ATP).  

In turn, this results in apoptosis or necrosis or both, depending upon the concentration of 3-bromopyruvate. No other anti-cancer agent combines the following exceptional characteristics of 3-bromopyruvate:

• It is highly selective - this is the most important characteristic of any cancer drug.  It is easy to find something which kills cancer cells - ordinary soap will suffice - but it is difficult to find something which only kills cancer cells.  The more selective a cancer drug is, the less toxicity it is likely to have.

• It is preferentially absorbed and retained by cancer cells.

• In vitro, it is effective against approximately 95% of cancer phenotypes tested. This is because 3-bromopyruvate's mechanism of action, as described above, is shared by the overwhelming major of cancers. In contrast, most other anti-cancer agents may only be effective for certain kinds of cancer.

• It is very fast acting, and its results can be visualized using metabolic imaging.

• It breaks down and is excreted through the renal system is just over 24 hours. This allows shorter and more frequent dosing intervals

• It is more potent than platinum chemotherapy on a per unit of weight basis.

Early success in eradicating cancer in rats at Johns Hopkins

A Johns Hopkins press release dated October 14, 2004, stated that, "Building on their earlier work, Johns Hopkins researchers have discovered that an apparently nontoxic cellular "energy blocker" can eradicate large liver tumors grown in rats, although "clinical trials ... are likely some years away".

References

1. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue.Pedersen PL.J Bioenerg Biomembr. 2012 Feb;44(1):1-6.

2. A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL.J Bioenerg Biomembr. 2012 Feb;44(1):163-70

3. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen.Pedersen PL. J Bioenerg Biomembr. 2007 Jun;39(3):211-22

5. Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.Mathupala SP, Ko YH, Pedersen PL.Semin Cancer Biol. 2009 Feb;19(1):17-24  

6. Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.Mathupala SP, Ko YH, Pedersen PL.Oncogene. 2006 Aug 7;25(34):4777-86.  

7. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP.Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL.Biochem Biophys Res Commun. 2004 Nov 5;324(1):269-75. 

8. The Scarlet Letter of Alkylation: A Mini Review of Selective Alkylating Agents Bryan T. Oronsky, Tony Reid, Susan J. Knox and Jan J. Scicinski Translational Oncology Volume 5 Number 4 August 2012 pp. 226-229

External links

• Mathupala, Saroj P.; Ko, Young H.; Pedersen, Peter L. (2010). "The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1797 (6–7): 1225. doi:10.1016/j.bbabio.2010.03.025.
• The cancer cell's "power plants" as promising therapeutic targets: An overview, by Peter Pederson
• Johns Hopkins: Energy Blocker Kills Big Tumors in Rats