Gallium maltolate

Chembox new
Name = Gallium maltolate
ImageFile = GaMaltolate.gif
ImageSize =
ImageName = Gallium maltolate
IUPACName = Tris(3-hydroxy-2-methyl-4H-pyran-4-one)gallium|
Section1 = Chembox Identifiers
CASNo = 108560-70-9
Section2 = Chembox Properties
Formula = Ga(C₆H₅O₃)₃
MolarMass = 445.03 g/mol
Appearance = White to pale beige crystalline solid or powder
Density = 1.56 g/cm³, solid
Solubility = 24(2) mM; 10.7(9) mg/mL (25°C)
MeltingPt = 220 °C (decomposes)
Section4 = Chembox Structure
Coordination = Distorted octahedral
CrystalStruct = Orthorhombic; space group "Pbca"

Gallium maltolate is a coordination complex consisting of a trivalent gallium cation coordinated to three maltolate ligands. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease. cite journal |last=Bernstein |first=L.R.|coauthors=Tanner, T.; Godfrey, C.; Noll, B. | title = Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability | journal = Metal Based Drugs | year = 2000 | volume = 7 | pages = 33–48 | doi = 10.1155/MBD.2000.33] cite book |last=Bernstein |first=L.R. |editor=Gielen, M.; Tiekink, E.R.T. |title=Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine|origyear=2005 |publisher=Wiley |location=New York |isbn=978-0-470-86403-6 |pages=259-277 |chapter=Therapeutic gallium compounds |chapterurl=http://home.earthlink.net/~alixapharm/GAMReferences/MetallotherapeuticsChapter14.pdf] cite journal | author = Chitambar, C.R.; Purpi, D.P.; Woodliff, J.; Yang, M.; Wereley J.P. | title = Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate | journal = J. Pharmacol. Exp. Ther. | year = 2007 | volume = 322 | pages = 1228–1236 |url=http://home.earthlink.net/~alixapharm/GAMReferences/Chitambar_GaM_2007.pdf|doi = 10.1124/jpet.107.126342] cite journal | author = Chua, M.-Z.; Bernstein, L.R.; Li, R.; So, S.K. | title = Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma| journal = Anticancer Research | year = 2006 | volume = 26 | pages = 1739–1743 | url = http://home.earthlink.net/~alixapharm/GAMReferences/6910CHUA.pdf] It appears to have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. This is probably because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)₄^-; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.

Chemical properties

Gallium maltolate is stable in aqueous solutions between about pH 5 and 8, and it has significant solubility in both water and lipids (octanol:water partition coefficient = 0.41).

Therapeutic activity

Gallium maltolate is able to deliver gallium with high oral bioavailability: the bioavailability is several times higher than that of gallium salts such as gallium nitrate and gallium(III) chloride. Gallium is antiproliferative to pathologically proliferating cells, particularly cancer cells and some bacteria, due primarily to its ability to mimic ferric iron (Fe³⁺). Ferric iron is essential for DNA synthesis, as it is present in the active site of the enzyme ribonucleotide reductase, which catalyzes the conversion of ribonucleotides to the deoxyribonucleotides required for DNA. Gallium is taken up by the rapidly proliferating cells, but it is not functional for DNA synthesis, so the cells cannot reproduce and they ultimately die by apoptosis. Normally reproducing cells take up little gallium (as is known from gallium scans), and gallium is not incorporated into hemoglobin, accounting for the relatively low toxicity of gallium. cite journal | last = Bernstein |first=L.R. | title = Mechanisms of therapeutic activity for gallium | journal = Pharmacol. Rev. | year = 1998 | volume = 50 | pages = 665–682 | url = http://pharmrev.aspetjournals.org/cgi/reprint/50/4/665.pdf]

The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory T cells and macrophages, as well as possible interference with matrix metalloproteinases. Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.

Pharmaceutical development

Gallium maltolate was invented and patented by Dr. Lawrence R. Bernstein (e.g., [http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5,574,027.PN.&OS=PN/5,574,027&RS=PN/5,574,027 U.S. Patent No. 5,574,027] ). Some of the patent rights are licensed to Titan Pharmaceuticals, which is developing an oral formulation of gallium maltolate for the treatment of cancer, inflammatory disease, and infectious disease.

Dr. Christopher Chitambar and his associates at the Medical College of Wisconsin have found that gallium maltolate is active against several lymphoma cell lines, including those resistant to gallium nitrate.

Studies of gallium maltolate as a potential treatment for liver cancer and gastrointestinal cancers are being undertaken at Stanford University by Dr. Mei-Sze Chua, Dr. Samuel So, and their colleagues.

The activity of gallium against infection-related biofilms, particularly those caused by "Pseudomonas aeruginosa", is being studied by Dr. Pradeep Singh at the University of Washington, and by others, who have reported encouraging results in mice. [cite journal |author=Kaneko, Y.; Thoendel, M.; Olakanmi, O.; Britigan, B.E.; Singh, P.K. |title=The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity |journal= J. Clin. Invest. |volume=57 |pages=877–888 |year=2007 |doi=10.1172/JCI30783] [cite conference | author=Wirtz, U.F.; Kadurugamuwa, J.; Bucalo, L.R.; Sreedharan, S.P.| title = Efficacy of gallium maltolate in a mouse model for "Pseudomonas aeruginosa" chronic urinary tract infection | booktitle = American Society for Microbiology 106th general meeting | place = Orlando, Florida |pages=poster A-074 | year = 2006 | url = http://home.earthlink.net/~alixapharm/GAMReferences/ASM_2006_poster.pdf] Pulmonary "P. aeruginosa" biofilms are responsible for many fatalities in cystic fibrosis and immunocompromised patients; in general, bacterial biofilms are responsible for significant morbidity and mortality. [cite journal |author=Parsek, M.; Singh, P. |title=Bacterial biofilms: an emerging link to disease pathogenesis |journal=Annu. Rev. Microbiol. |volume=57 |pages=677–701 |year=2003 |pmid=14527295 |doi=10.1146/annurev.micro.57.030502.090720] In related research, locally administered gallium maltolate has shown potent efficacy against "P. aeruginosa" in a mouse burn/infection model. [cite conference|author=DeLeon K.; Hamood A.; Griswold J.; Wirtz U.; Sreedharan S.; Rumbaugh K.P.|title=Efficacy of gallium maltolate in treating "Pseudomonas aeruginosa" infection in a thermally-injured mouse model |pages=Poster A-072|booktitle=American Society for Microbiology 108th general meeting|place=Boston, Massachusetts|year= 2008|url=http://home.earthlink.net/~alixapharm/GAMReferences/DeLeonASM2008.pdf]

Oral gallium maltolate is also being investigated as a treatment for "Rhodococcus equi" foal pneumonia, a common and often fatal disease of newborn horses. "R. equi" can also infect humans with AIDS or who are otherwise immunocompromized. The veterinary studies are being conducted by researchers at Texas A&M University, led by Dr. Ronald Martens, Dr. Noah Cohen, and Dr. M. Keith Chaffin. [cite journal |author=Harrington, J.R.; Martens, R.J.; Cohen, N.D.; Bernstein, L.R. |title=Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo |journal=J. Vet. Pharmacol. Ther. |volume=29 |pages=121–127 |year=2006 |doi=10.1111/j.1365-2885.2006.00723.x] [cite journal |author=Martens, R.J.; Mealey, K.; Cohen, N.D.; Harrington, J.R.; Chaffin, M.K.; Taylor, R.J.; Bernstein, L.R. |title=Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals |journal=Am. J. Vet. Res. |volume=68 |pages=1041–1044 |year=2007 |url=http://avmajournals.avma.org/doi/abs/10.2460/ajvr.68.10.1041 |doi=10.2460/ajvr.68.10.1041]

References

External links

* [http://home.earthlink.net/~alixapharm/index.html Gallium maltolate information and references]