Chemical Properties
White crystalline powder
Uses
Sodium salt of Suramin, a hepatitis C virus NS3 helicase inhibitor. Also used in the treatment of arthritis due to problematic collagen.
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.
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.
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-).
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.
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
Cmax 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
African sleeping sickness (early stage before CNS involvement)
Onchocerciasis
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
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.
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.
