Suramin

Names
Trade names	Antrypol, 309 Fourneau, Bayer 205, others
IUPAC name 8,8'-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid)
Clinical data
Main uses	African sleeping sickness,river blindness[1]
Routes of use	By injection only
Defined daily dose	270 mg[2]
External links
AHFS/Drugs.com	Drugs.com archive
Legal
Legal status	US: Not FDA approved
Chemical and physical data
Formula	C51H40N6O23S6
Molar mass	1297.26 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(Nc1cc(ccc1C)C(=O)Nc3c2c(cc(cc2c(cc3)S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)O)c8cccc(NC(=O)Nc7cc(C(=O)Nc6cc(C(=O)Nc5c4c(cc(cc4c(cc5)S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)O)ccc6C)ccc7)c8
InChI InChI=1S/C51H40N6O23S6/c1-25-9-11-29(49(60)54-37-13-15-41(83(69,70)71)35-21-33(81(63,64)65)23-43(45(35)37)85(75,76)77)19-39(25)56-47(58)27-5-3-7-31(17-27)52-51(62)53-32-8-4-6-28(18-32)48(59)57-40-20-30(12-10-26(40)2)50(61)55-38-14-16-42(84(72,73)74)36-22-34(82(66,67)68)24-44(46(36)38)86(78,79)80/h3-24H,1-2H3,(H,54,60)(H,55,61)(H,56,58)(H,57,59)(H2,52,53,62)(H,63,64,65)(H,66,67,68)(H,69,70,71)(H,72,73,74)(H,75,76,77)(H,78,79,80) Y Key:FIAFUQMPZJWCLV-UHFFFAOYSA-N Y

Suramin is amedication used to treatAfrican sleeping sickness andriver blindness.^[1][3] It is the treatment of choice for sleeping sickness withoutcentral nervous system involvement.^[4] It is given byinjection into a vein.^[5]

Suramin causes a fair number of side effects.^[5] Common side effects include nausea, vomiting,diarrhea, headache, skin tingling, and weakness.^[3] Sore palms of the hands and soles of the feet, trouble seeing,fever, and abdominal pain may also occur.^[3] Severe side effects may includelow blood pressure,decreased level of consciousness,kidney problems, andlow blood cell levels.^[5] It is unclear if it is safe whenbreastfeeding.^[3]

Suramin was made at least as early as 1916.^[6] It is on theWorld Health Organization's List of Essential Medicines.^[7] In the United States it can be acquired from theCenters for Disease Control (CDC).^[4] The cost of the medication for a course of treatment is about US$27.^[8] In regions of the world where the disease is common suramin is provided for free by theWorld Health Organization (WHO).^[9]

Medical uses

Suramin is used for treatment of humansleeping sickness caused bytrypanosomes.^[1] Specifically, it is used for treatment of first-stage African trypanosomiasis caused byTrypanosoma brucei rhodesiense andTrypanosoma brucei gambiense without involvement of central nervous system.^[10][11] It is considered first-line treatment forTrypanosoma brucei rhodesiense, and second-line treatment for early-stageTrypanosoma brucei gambiense, wherepentamidine is recommended as first line.^[11]

It has been used in the treatment ofriver blindness (onchocerciasis).^[3]

Dosage

Thedefined daily dose is 270 mg by injection.^[2] For African trypanosomiasis due to T. b. rhodesiense it is given at a dose of 4.5 mg/kg by injection on day one and than at a dose of 20 mg/kg up to 1 gram on day 3, 10, 17, 24 and 31.^[12]

Side effects

The most frequent adverse reactions are nausea, vomiting, diarrhea, abdominal pain, and afeeling of general discomfort. It is also common to experience various sensations in the skin, from crawling or tingling sensations, tenderness of palms and the soles, and numbness of hands, arm, legs or feet.^[13] Other skin reactions include skin rash, swelling and stinging sensation.^[13] Suramin can also cause loss of appetite and irritability.^[13] Suramin causes non-harmful changes in urine during use, specifically making the urine cloudy.^[13] It may exacerbatekidney disease.^[14]

Less common side effects include extreme fatigue, ulcers in the mouth, and painful tender glands in the neck, armpits and groin.^[13] Suramin uncommonly affects the eyes causing watery eyes, swelling around the eyes, photophobia, and changes or loss of vision.^[13]

Rare side effects include hypersensitivity reactions causing difficulty breathing. Other rare systemic effects include decreased blood pressure, fever, rapid heart rate, and convulsions.^[13] Other rare side effects include symptoms of liver dysfunction such as tenderness in upper abdomen, jaundice in eyes and skin, unusual bleeding or bruising.^[13]

Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition.^[15]

Pregnancy and breastfeeding

It is unknown whether it is safe for the baby when a woman takes it while breastfeeding.^[3] It; however, may be given to pregnant women for with rhodesiense trypanosomiasis.^[12]

Pharmacokinetics

Suramin is not orally bioavailable and must be given intravenously. Intramuscular and subcutaneous administration could result in local tissue inflammation or necrosis. Suramin is approximately 99-98% protein bound in the serum and has a half-life of 41–78 days average of 50 days; however, the pharmacokinetics of suramin can vary substantially between individual patients. Suramin does not distribute well into cerebral spinal fluid and its concentration in the tissues is equivalently lower than its concentration in the plasma. Suramin is not extensively metabolized and about 80% is eliminated via the kidneys.^[14]

Chemistry

The molecular formula of suramin is C₅₁H₄₀N₆O₂₃S₆. It is asymmetricmolecule in the center of which lies aurea (NH–CO–NH) functional group. Suramin contains six aromatic systems – fourbenzene rings, sandwiched by a pair ofnaphthalenemoieties – plus fouramidefunctional groups (in addition to the urea) and sixsulfonic acid groups. When given as a medication, it is usually delivered as the sodiumsulfonatesalt as this formulation is water-soluble, though it does deteriorate rapidly in air.^[14]

Thesynthesis of suramin itself andstructural analogs is by successive formation of the amide bonds from their correspondingamine (aniline) andcarboxyl (asacyl chloride) components. Various routes to these compounds have been developed, including starting from separate naphthalene structures and building towards an eventual unification by formation of the urea^[16][17] or starting with a urea and appending successive groups.^[18]

Mechanism of action

The mechanism of action for suramin is unclear, however, it is thought that parasites are able to selectively uptake suramin via receptor-mediated endocytosis of drug that is bound to low-density lipoproteins and to a lesser extent, other serum proteins.^[14] Once inside parasites, suramin combines with proteins, especially trypanosomalglycolytic enzymes to inhibit energy metabolism.^[19]

History

Suramin was first made by the chemists Oskar Dressel, Richard Kothe and Bernhard Heymann atBayer AG laboratories inElberfeld, after research on a series of urea-like compounds. The drug is still sold by Bayer under thebrand nameGermanin. The chemical structure of suramin was kept secret by Bayer for commercial and strategic reasons, however, it was elucidated and published in 1924 byErnest Fourneau and his team of thePasteur Institute.^{[20]: 378–379 [21]}

Research

It is also used as a researchreagent to inhibit the activation of heterotrimeric G proteins in a variety ofGPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins includingrhodopsin, theA1 adenosine receptor, theD2 receptor,^[22] theP2 receptor,^[23][24] andryanodine receptors.^[25]

Suramin was studied as a possible treatment forprostate cancer in a clinical trial.^[26]

Suramin has been studied in a mouse model ofautism and in a small phase I/IIhuman trial.^{[27][28][29][30]}

References

Further reading

• Zhang YL, Keng YF, Zhao Y, Wu L, Zhang ZY (May 1998)."Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases".J. Biol. Chem.273 (20): 12281–7.doi:10.1074/jbc.273.20.12281.PMID 9575179.

External links

• "Suramin".Drug Information Portal. U.S. National Library of Medicine.Archived from the original on 29 May 2020. Retrieved20 February 2020.
• Suramin sodiumArchived 2 October 2008 at theWayback Machine National Cancer Institute

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