Gallium maltolate

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Gallium maltolate
Gallium maltolate skeletal.svg
Names
IUPAC name
Tris(3-hydroxy-2-methyl-4H-pyran-4-one)gallium
Identifiers
3D model (JSmol)
DrugBank
PubChem CID
UNII
  • InChI=1S/3C6H6O3.Ga/c3*1-4-6(8)5(7)2-3-9-4;/h3*2-3,8H,1H3;/q;;;+3/p-3
    Key: ASYYOZSDALANRF-UHFFFAOYSA-K
  • o1c(c(c(=O)cc1)O[Ga](Oc1c(occc1=O)C)Oc1c(occc1=O)C)C
Properties
Ga(C6H5O3)3
Molar mass 445.03 g/mol
AppearanceWhite to pale beige crystalline solid or powder
Density 1.56 g/cm3, solid
Melting point 220 °C (decomposes)
24(2) mM; 10.7(9) mg/mL (25 °C)
Structure
Orthorhombic; space group Pbca
Distorted octahedral
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Gallium maltolate is a coordination complex consisting of a trivalent gallium cation coordinated to three maltolate ligands. The compound is a potential therapeutic agent for cancer, infectious disease, and inflammatory disease. [1] [2] [3] [4] A cosmetic skin cream containing gallium maltolate is marketed under the name Gallixa. It is a colorless solid with significant solubility in both water and lipids (octanol-water partition coefficient = 0.41). [1]

Contents

Mechanism of action

Gallium maltolate delivers gallium with higher oral bioavailability than that of gallium salts such as gallium nitrate and gallium trichloride. [1] In vitro studies have found gallium to be antiproliferative 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. [5]

Research

Gallium (III) ion shows anti-inflammatory activity in animal models of inflammatory disease. [2] [5] [6] Orally administered gallium maltolate has demonstrated efficacy against two types of induced inflammatory arthritis in rats. [6] Experimental evidence suggests that the anti-inflammatory activity of gallium may be due, at least in part, to down-regulation of pro-inflammatory T-cells and inhibition of inflammatory cytokine secretion by macrophages. [2] [5] [6] 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. [2]

Gallium maltolate has also been proposed for the treatment for primary liver cancer (hepatocellular carcinoma; HCC). In vitro experiments demonstrated efficacy against HCC cell lines, [4] and encouraging clinical results have been reported. [7]

Gallium compounds are active against infection-related biofilms, particularly those caused by Pseudomonas aeruginosa . [8] [9] In related research, locally administered gallium maltolate has shown efficacy against P. aeruginosa in a mouse burn/infection model. [10] The potential of this approach may be somewhat limited by the relatively rapid appearance of gallium-resistant isolates. [11] [12]

Oral gallium maltolate has been 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. [13] [14]

Topically applied gallium maltolate has been studied for use in neuropathic pain (severe postherpetic neuralgia and trigeminal neuralgia). [6] It has been hypothesized that any effect on pain may be related to gallium's anti-inflammatory mechanisms, and possibly from its interactions with certain matrix metalloproteinases and substance P, whose activities are zinc-mediated and which have been implicated in the etiology of pain. [6]

Related Research Articles

Biofilm Aggregation of bacteria or cells on a surface

A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymeric substances (EPSs). The cells within the biofilm produce the EPS components, which are typically a polymeric conglomeration of extracellular polysaccharides, proteins, lipids and DNA. Because they have three-dimensional structure and represent a community lifestyle for microorganisms, they have been metaphorically described as "cities for microbes".

Lactoferrin Mammalian protein found in Homo sapiens

Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMNs and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum has the highest concentration, followed by human milk, then cow milk (150 mg/L).

Phage therapy Therapeutic use of bacteriophages to treat pathogenic bacterial infections.

Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the second world war. Bacteriophages, known as phages, are a form of virus that attach to bacterial cells, and inject their genome into the cell. The viral genome effectively replaces the bacterial genome, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce, and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against.

Cephalosporin Class of pharmaceutical drugs

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.

Colistin Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites.

<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, strict aerobic, Rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

Carbapenem Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for the treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta lactam class of antibiotics, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<i>Stenotrophomonas maltophilia</i> Species of bacterium

Stenotrophomonas maltophilia is an aerobic, nonfermentative, Gram-negative bacterium. It is an uncommon bacterium and human infection is difficult to treat. Initially classified as Bacterium bookeri, then renamed Pseudomonas maltophilia, S. maltophilia was also grouped in the genus Xanthomonas before eventually becoming the type species of the genus Stenotrophomonas in 1993.

Hepcidin Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

Marbofloxacin

Marbofloxacin is a carboxylic acid derivative third generation fluoroquinolone antibiotic. It is used in veterinary medicine under the trade names Marbocyl, Forcyl, Marbo vet and Zeniquin. A formulation of marbofloxacin combined with clotrimazole and dexamethasone is available under the name Aurizon.

Seliciclib Chemical compound

Seliciclib is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study.

Enoxacin

Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect. It is no longer available in the United States.

<i>Rhodococcus equi</i> Species of bacterium

Rhodococcus equi is a Gram-positive coccobacillus bacterium. The organism is commonly found in dry and dusty soil and can be important for diseases of domesticated animals. The frequency of infection can reach near 60%. R. equi is an important pathogen causing pneumonia in foals. Since 2008, R. equi has been known to infect wild boar and domestic pigs. R. equi can infect humans. At-risk groups are immunocompromised people, such as HIV-AIDS patients or transplant recipients. Rhodococcus infection in these patients resemble clinical and pathological signs of pulmonary tuberculosis. It is facultative intracellular.

Ribonucleotide reductase inhibitors are a family of anti-cancer drugs that interfere with the growth of tumor cells by blocking the formation of deoxyribonucleotides.

Genta (company)

Genta Incorporated was a biopharmaceutical company started in La Jolla, California, which discovered and developed innovative drugs for the treatment of patients with cancer. Founded in 1989 by a highly skilled entrepreneur, the company focused on a novel technology known as antisense, which targets gene products that are associated with the onset and progression of serious diseases. At that time, only Ionis Pharmaceuticals, Inc. was conducting significant research with this technology. Antisense is a short span of oligonucleotides – modified DNA structures ranging from about 12-24 bases that selectively bind to specific RNA. The intent is to block expression of an aberrant protein that contributes to the disease of interest. Genta in-licensed three different antisense molecules that blocked Bcl-2, a fibroblast growth factor (FGF), and the gene c-myb, respectively.

Pyoverdine Chemical compound

Pyoverdines are fluorescent siderophores produced by certain pseudomonads. Pyoverdines are important virulence factors, and are required for pathogenesis in many biological models of infection. Their contributions to bacterial pathogenesis include providing a crucial nutrient, regulation of other virulence factors, supporting the formation of biofilms, and are increasingly recognized for having toxicity themselves.

Robert E. W. Hancock

Robert Ernest William Hancock is a Canadian microbiologist and University of British Columbia Killam Professor of Microbiology and Immunology, an Associate Faculty Member of the Wellcome Trust Sanger Institute, and a Canada Research Chair in Health and Genomics.

Murepavadin

Murepavadin also known as POL7080 is a Pseudomonas specific peptidomimetic antibiotic. It is a synthetic cyclic beta hairpin peptidomimetic based on the cationic antimicrobial peptide protegrin I (PG-1) and the first example of an outer membrane protein-targeting antibiotic class with a novel, nonlytic mechanism of action, highly active and selective against the protein transporter LptD of Pseudomonas aeruginosa. In preclinical studies the compound was highly active on a broad panel of clinical isolates including multi-drug resistant Pseudomonas bacteria with outstanding in vivo efficacy in sepsis, lung, and thigh infection models. Intravenous murepavadin is in development for the treatment of bacterial hospital-acquired pneumonia and bacterial ventilator-associated pneumonia due to Pseudomonas aeruginosa.

Cefiderocol

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

References

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  2. 1 2 3 4 Bernstein, L.R. (2005). "Therapeutic gallium compounds" (PDF). In Gielen, M.; Tiekink, E.R.T. (eds.). Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine. New York: Wiley. pp. 259–277. ISBN   978-0-470-86403-6.
  3. Chitambar, C.R.; Purpi, D.P.; Woodliff, J.; Yang, M.; Wereley J.P. (2007). "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" (PDF). J. Pharmacol. Exp. Ther. 322 (3): 1228–1236. doi:10.1124/jpet.107.126342. PMID   17600139. S2CID   12427694.
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  8. Kaneko, Y.; Thoendel, M.; Olakanmi, O.; Britigan, B.E.; Singh, P.K. (2007). "The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity". J. Clin. Invest. 117 (4): 877–888. doi:10.1172/JCI30783. PMC   1810576 . PMID   17364024.
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  10. DeLeon K.; Balldin F.; Watters C.; Hamood A.; Griswold J.; Sreedharan S.; Rumbaugh K.P. (2009). "Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice". Antimicrobial Agents and Chemotherapy. 53 (4): 1331–1337. doi:10.1128/AAC.01330-08. PMC   2663094 . PMID   19188381.
  11. Tovar-García, Arturo; Angarita-Zapata, Vanesa; Cazares, Adrián; Jasso-Chávez, Ricardo; Belmont-Díaz, Javier; Sanchez-Torres, Viviana; López-Jacome, Luis Esaú; Coria-Jiménez, Rafael; Maeda, Toshinari; García-Contreras, Rodolfo (2020-04-01). "Characterization of gallium resistance induced in a Pseudomonas aeruginosa cystic fibrosis isolate". Archives of Microbiology. 202 (3): 617–622. doi:10.1007/s00203-019-01777-y. ISSN   1432-072X. PMID   31773196. S2CID   208302170.
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