Suramin sodium Chemical Properties

Melting point:

>260°C (dec.)

storage temp. 

0-6°C

solubility 

H₂O: >10mg/mL

form 

Crystalline Powder

color 

White

PH

pH(10g/l, 25℃) : 5.0～8.0

Water Solubility 

soluble

BRN 

3694087

Stability:

Hygroscopic

InChI

InChI=1S/C51H40N6O23S6.6Na/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);;;;;;/q;6*+1/p-6

InChIKey

VAPNKLKDKUDFHK-UHFFFAOYSA-H

SMILES

C12C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=CC=1C(S([O-])(=O)=O)=CC=C2NC(=O)C1C=CC(C)=C(NC(=O)C2=CC=CC(NC(=O)NC3=CC=CC(C(=O)NC4=C(C)C=CC(C(=O)NC5=CC=C(S([O-])(=O)=O)C6C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C5=6)=C4)=C3)=C2)C=1.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]

Safety Information

Safety Statements 

22-24/25

WGK Germany 

3

RTECS 

QM7000000

F 

3-10

HS Code 

29242998

Toxicity

LD50 in mice (mg/kg): ~620 i.v. (Hawking)

MSDS

• Language:English Provider:Suramin sodium
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS

Suramin sodium Usage And Synthesis

Pharmacology and mechanism of action

Suramin is a polysulphonated naphthylurea introduced in Germany in 1920 for the treatment of trypanosomiasis. The drug was later found to be an effective macrofilaricide in onchocerciasis. Today suramin is mainly used for the treatment of African trypanosomiasis. It is effective against early-stages of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense without CNS involvement. However, in the case of Trypanosoma brucei gambiense pentamidine is generally preferred ^[1].
The mechanism of action of suramin is unknown. The drug has a broad spectrum of enzymatic actions, which is mainly due to its strong affinity for proteins. It interferes with the DNA-RNA replication mechanism of the cell, thus stopping cell growth. In vitro, suramin slowly inhibits the oxygen consumption of trypanosomes ^{[1, 2]}. In Brugia pahangi, the drug acts on the surface of the intestinal epithelium resulting in ultrastructural changes^[3]. Suramin also impairs the in vitro infectivity of human immunodeficiency virus type I (HIV) ^[4], but the drug had little success in patients with AIDS and with different types of cancer ^{[4, 5]}.
 

Indications

Suramin is used in the treatment of early-stage infections of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. It is used prior to melarsoprol treatment to clear the blood and lymph of trypanosomes. Pentamidine is generally preferred for the treatment of early-stage Trypanosoma brucei gambiense.
Suramin is also the only drug available for effectively eliminating the adult filariae (macrofilariae) in onchocerciasis. It should only be used in individual cases.
 

Side effects

Suramin is a toxic drug, and adverse reactions can be serious especially in malnourished patients ^[1]. They are also more frequently observed in patients with onchocerciasis than in patients with trypanosomiasis. Adverse reactions due to suramin can be classified into three types:
 
1. Immediate reactions: with a frequency of about 0.1–0.3%. These include nausea, vomiting and loss of consciousness. Slight fever, acute urticaria and colic pain are other acute reactions. These reactions can be avoided by a slow i.v. injection. It is a general clinical practice to start with a small test dose to assess the patients tolerance.
2. Late reactions (3–48 hours after i.v. injection): these include fever up to 40°C, photophobia and lacrimation. Flatulence, constipation and hyperaesthesia in the palms of the hands and the soles of the feet which can last for weeks.
3. Delayed reactions: these include kidney damage, which can occur several days after treatment and is a result of drug accumulation in the epithelial cells of the proximal convoluted tubules. Other delayed toxic reactions include dermatitis, stomatitis of theexfoliative type, agranulocytosis, haemolytic anaemia, jaundice and severe diarrhoea which may be fatal.

During onchocerciasis treatment, reactions such as urticaria, itching, formation of deep abscesses and muscle pains are common which are due to the dying worm. Nodulectomy prior to suramin therapy decreases the severity of this reaction. These reactions should be treated with 1 mg of betamethasone (equivalent to 6 mg of prednisolone) 3 times daily for 3 days^[1].

Contraindications and precautions

Suramin is a toxic drug and it should always be administered under medical supervision. Great caution should be exercised in malnourished patients and those with kidney diseases. Therapy should be discontinued or postponed in patients with heavy albuminuria with casts^[1].
 

Interactions

There have been no reports.

Preparations

• Suramin® (Bayer). Substance for injection 1 g.
• Germanin® (Bayer). Substance for injection 1 g.

References

1. Hawking, F (1978). Suramin: with special reference to onchocerciasis. Adv Pharmacol Ther, 15, 289–322.
2. Fairlamb AH, Bowman IBR (1980). Uptake of the trypanocidal drug suramin by blood stream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo. Mol Biochem Parasitol, 1, 315–333.
3. Howells RE, Mendis AM, Bray PG (1983). The mode of action of suramin on filarial worm Brugia pahangi. Parasitology, 87, 29–48.
4. Broder S, Yarchoan R, Collins JM, Lane HC, Markham PD, Klecher RW, Redfield RR, Mitsuya H, Hoth DF, German E (1985). Effects of suramin on HTLV-III/LAV infection presenting as Kaposi’s sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo. Lancet, ii, 627–630.
5. Stein CA, LaRocca RV, Thomas R, McAtee N, Myers CE (1989). Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol, 7, 499–508.

Description

Introduced into therapy for the treatment of early trypanosomiasis in the 1920s, suramin, a bis-hexasulfonatednaphthylurea, is still considered to be the drug of choice for treatment of non-CNS-associated African trypanosomiasis.

Chemical Properties

White crystalline powder

Uses

antiviral

Uses

Suramin sodium is a compound with a dyelike structure. Suramin is most effective against T. b. rhodesiense, but has also been used against T. b. gambiense infection. The compound causes side effects such as nausea, photophobia, and peripheral neuropathy which disappear shortly after conclusion of administration. Because the drug is unable to pass the bloodbrain barrier, prompt treatment of patients is essential. Suramin in combination with tryparsamide is an alternative that has been investigated.

Uses

Sodium salt of Suramin, a hepatitis C virus NS3 helicase inhibitor. Also used in the treatment of arthritis due to problematic collagen.

Definition

ChEBI: Suramin sodium is an organic sodium salt that is the hexasodium salt of suramin. It is an FDA approved drug for African sleeping sickness and river blindness. It has a role as an antinematodal drug, a trypanocidal drug, an antineoplastic agent, an angiogenesis inhibitor, an apoptosis inhibitor, an EC 2.7.11.13 (protein kinase C) inhibitor, a GABA antagonist, a GABA-gated chloride channel antagonist, a purinergic receptor P2 antagonist and a ryanodine receptor agonist. It contains a suramin(6-).

Indications

Suramin (Germanin) is a derivative of a nonmetallic dye whose antiparasitic mechanism of action is not clear. It appears to act on parasite specificα-glycerophosphate oxidase, thymidylate synthetase, dihydrofolate reductase, and protein kinase but not on host enzymes.

Indications

Suramin is widely used as a macrofilaricide in human onchocerciasis, and its action on microfilariae also is considerable. It also is useful in the treatment of the hemolymphatic stage of African trypanosomiasis. Early treatment of the infection with suramin clears trypanosomes from the blood and lymphatics within 30 minutes and keeps them clear for approximately 3 months. Suramin inhibits a number of filarial enzymes involved with carbohydrate metabolism as well as the production of adenosine triphosphate (ATP). It is 35 times more inhibitory to the dihydrofolate reductase of O. volvulus than to the same enzyme in human tissue. It is a potent inhibitor of reverse transcriptase, the DNA polymerase of retroviruses, and also has some effects on the infective and cytopathic effects of HIV. It is being evaluated as an anticancer drug, reducing pain and delaying progression in hormone-refractory prostate cancer. Its most significant toxicity has been the development of severe polyradiculoneuropathy.

Antimicrobial activity

Suramin has no significant trypanocidal activity in vitro, but is effective in animals infected with T. brucei. Trypanosomes take up suramin bound to plasma protein by a combination of fluid phase and receptor-mediated endocytosis. It acts synergistically with nitroimidazoles and eflornithine in the elimination of trypanosomes from CSF of infected mice.

Acquired resistance

Relapse rates of 30–50% have been recorded in Kenya and Tanzania but there is no evidence of resistant parasites. Stable resistance has been described in the related camel parasite Trypanosoma evansi.

Pharmaceutical Applications

A complex symmetrical molecule originally developed in Germany in the early 1920s for the treatment of African trypanosomiasis. Its useful anthelmintic activity is restricted to O. volvulus and it has been used to achieve a radical cure of onchocerciasis by killing the adult worms. However, it is an extremely toxic drug and its use has become increasingly uncommon since ivermectin became available.

Pharmaceutical Applications

A sulfated naphthylamine formulated for intravenous administration. It is freely soluble in water. The dry powder is stable, but it is hygroscopic and unstable in solution.

Biological Activity

Non-selective P2 purinergic antagonist. Also blocks calmodulin binding to recognition sites and G protein coupling to G protein-coupled receptors. Anticancer and antiviral agent.

Mechanism of action

Suramin is not absorbed from the intestinal tract and is administered intravenously. Although the initial high plasma levels drop rapidly, suramin binds tightly to and is slowly released from plasma proteins, and so it persists in the host for up to 3 months. Suramin neither penetrates red blood cells nor enters the CNS. It is taken up by the reticuloendothelial cells and accumulates in the Kupffer cells of the liver and in the epithelial cells of the proximal convoluted tubules of the kidney. It is excreted by glomerular filtration, largely as the intact molecule.

Pharmacokinetics

Oral absorption: Poor
C_max 1 g intravenous doses (6 doses at weekly intervals): 100 mg/L
Plasma half-life: 44–54 days
Volume of distribution: 20–80 L
Plasma protein binding: >99%
It is normally administered by slow intravenous infusion. It can be detected in blood for 3 months; plasma levels >100 mg/L were observed for several weeks after a 6-week course of treatment. No metabolism was observed and 80% was removed by renal clearance. Distribution to mononuclear phagocytes, especially liver macrophages, the adrenal glands and the kidney is high. It does not enter erythrocytes and penetrates the blood–brain barrier poorly.

Clinical Use

Suramin sodium is a high molecular-weight bisurea derivative containing six sulfonic acid groups as their sodium salts. It was developed in Germany shortly after World War I as a byproduct of research efforts directed toward the development of potential antiparasitic agents from dyestuffs. The drug has been used for more than half a century for the treatment of early cases of trypanosomiasis. Not until several decades later, however, was suramin discovered to be a long-term prophylactic agent whose effectiveness after a single intravenous injection is maintained for up to 3 months. The drug is tightly bound to plasma proteins, causing its excretion in the urine to be almost negligible. Tissue penetration of the drug does not occur, apparently because of its high molecular weight and highly ionic character. Thus, an injected dose remains in the plasma for a very long period. Newer, more effective drugs are now available for short-term treatment and prophylaxis of African sleeping sickness. Suramin is also used for prophylaxis of onchocerciasis. It is available from the CDC.

Clinical Use

Suramin is used primarily to treat African trypanosomiasis, for which it is the drug of choice. It is effective in treating disease caused by Trypanosoma gambiense and T. rhodesiense but not T. cruzi (Chagas’ disease). It can be used alone prophylactically or during the initial hemolymphatic stages of the disease. Later stages, particularly those involving the CNS, are more commonly treated with a combination of suramin and the arsenical melarsoprol.
When CNS involvement occurs, the poor penetration of suramin and pentamidine into the CSF requires alternative forms of chemotherapy, such as melarsoprol in combination with suramin. In treating Onchocerca volvulus infections, suramin kills adult worms and is an alternative to ivermectin. Suramin is used after initial treatment with diethylcarbamazine, which is used to kill the microfilariae. It produces favorable results in pemphigus and prolongs the time to disease progression in hormone-refractory prostate cancer.

Clinical Use

African sleeping sickness (early stage before CNS involvement) Onchocerciasis

Side effects

It is important to test for drug sensitivity by administering a small (200 mg) dose by slow intravenous injection before giving the full amount of suramin. Since adverse reactions occur with greater frequency and severity among the malnourished, greater caution is necessary for patients with advanced trypanosomiasis. An acute reaction in sensitive individuals results in nausea, vomiting, colic, hypotension, urticaria, and even unconsciousness; fortunately, this reaction is rare. Rashes, photophobia, paresthesias, and hyperesthesia may occur later; these symptoms may presage peripheral neuropathy. Mild albuminuria is not uncommon, but hematuria with casts suggests nephrotoxicity and the need to stop treatment.

Side effects

Suramin is toxic, especially in malnourished patients. A test dose of 200 mg has been recommended. Immediate febrile reactions (nausea, vomiting, loss of consciousness) can be avoided by slow intravenous administration. Intramuscular or subcutaneous injections are painful and irritating, and can be followed by fever and urticaria. Anaphylactic shock occurs in fewer than 1 in 2000 patients. Delayed reactions include renal damage, exfoliative dermatitis, anemia, leukopenia, agranulocytosis, jaundice and diarrhea.

Synthesis

Suramin, a hexasodium salt of [8,8?ˉ carbonyl-bis-[imino-3,1-phenylencarbonylimino(4-methyl-3,1-phenylen)carbonylimino]]-bis-1,3,5-naphthalintrisulfonic acid (37.4.13), can be made by reacting 1-aminonaphthalene-3,6,8-trisulfonic acid with 4-methyl-3-nitrobenzoyl chloride to make a nitrobenzoic derivative (37.4.8). The nitro group in this compound is reduced by activated iron to an amino derivative (37.4.9), which is acylated by m-nitrobenzoylchloride to make a new nitroderivative, m-nitrobenzoyl-(4-methyl-3-aminobenzoyl)-1-aminonaphthalene-3,6,8-trisulfonic acid (37.4.10).
This is once again reduced to the amine (37.4.11) in the same manner. Reacting the resulting product with phosgene makes [8,8??-carbonyl-bis-[imino-3,1-phenylencarbonylimino(4-methyl-3,1-phenylen]-carbonylimino]-bis-1,3,5-naphthalenetrisulfonic acid (37.4.12), which upon being treated with sodium hydroxide gives suramin.

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