Cidofovir CAS 113852-37-2
Introduction：Basic information about Cidofovir CAS 113852-37-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Cidofovir Basic information
| Product Name: | Cidofovir |
| Synonyms: | Cidofovir (Vistide);(S)-[1-(4-AMino-2-oxo-pyriMidin-1(2H)-yl)-3-hydroxy-propan-2-yl]oxyMethylphosphonic acid;({[(S)-1-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxypropan-2-yl]oxy}methyl)phosphonic acid;CS-1956;Cidofovir(GS-504);(S)-(3-(4-amino-2-oxopyrimidin-1(2H)-yl)-1-hydroxypropan-2-yloxy)methylphosphonic acid;Cidovir;(S)-1-[3-HYDROXY-2-(PHOSPHONYL-METHOXY)PROPYL]-CYTOSINE |
| CAS: | 113852-37-2 |
| MF: | C8H14N3O6P |
| MW: | 279.19 |
| EINECS: | 638-807-0 |
| Product Categories: | Inhibitors;Vistide;API |
| Mol File: | 113852-37-2.mol |
Cidofovir Chemical Properties
| Melting point | 260° (dec) |
| alpha | D20 -97.3° (c = 0.80 in water) |
| Boiling point | 609.5±65.0 °C(Predicted) |
| density | 1.76±0.1 g/cm3(Predicted) |
| storage temp. | Keep in dark place,Sealed in dry,Store in freezer, under -20°C |
| solubility | deionized water: ≥5mg/mL (warmed) |
| form | powder |
| pka | 2.29±0.10(Predicted) |
| color | White to off-white |
| Water Solubility | Soluble to 12 mg/mL(42.98 mM) in Water |
| InChI | InChI=1S/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)/t6-/m0/s1 |
| InChIKey | VWFCHDSQECPREK-LURJTMIESA-N |
| SMILES | P(CO[C@H](CO)CN1C(=O)N=C(N)C=C1)(=O)(O)O |
| CAS DataBase Reference | 113852-37-2(CAS DataBase Reference) |
Safety Information
| Hazard Codes | T |
| Risk Statements | 25-38 |
| Safety Statements | 36-37-45 |
| RIDADR | UN 2811 6.1 / PGIII |
| WGK Germany | 3 |
| RTECS | SZ6545000 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Skin Irrit. 2 |
| Hazardous Substances Data | 113852-37-2(Hazardous Substances Data) |
| Description | Cidofovir launched as a first-line treatment for CMV retinitis inAIDS patients. It is a nucleotide analog with potent activity against a broad spectrumof DNA viruses, e.g., HSVl, HSV2, CMV, adenovirus and papillomavirus. Cidofovircan be synthesized by a number of methods, the most efficient involves ringopenning of (R)-glycidol with cytosine. Metabolically, cidofovir does not requireintracellular activation by virally-encoded enzymes like similar compounds, e.g.,aciclovir or ganciclovir. It is rapidly converted to its active form, cidofovirdiphosphate, which inhibits viral DNA polymerase at concentrations up to 600 foldlower than that required for human DNA polymerase. It is a competitive inhibitor ofdCTP incorporation or if incorporated into viral DNA slows down further DNAsynthesis and causes the destabilization of the viral DNA. There are threeintracellular metabolites which are also active thus giving rise to the long half-life.This results in lower dosing times (once every 1-2 weeks) and the ability to protectpreviously uninfected cells from subsequent infection. |
| Originator | Gilead Sciences (USA) |
| Uses | An injectable antiviral medication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription. It is used in the treatment of acyclovir resistant herpes as well as a complementary intralesional therapy against papillomatosis caused by human papillomavirus (HPV). |
| Uses | Cidofovir suppresses virus replication by selective inhibition of viral DNA synthesis. Cidofovir, a monophosphorylated nucleotide analog, does not require viral thymidine kinase phosphorylation to act and therefore has activity against herpes simplex infections with deficient or altered thymidine kinase activity. It is ineffective against rare strains with mutations in DNA polymerase. It is administered intravenously, 5 mg/kg/week for acyclovir-resistant infections in immunocompromised hosts. Associated side effects include nephrotoxicity and neutropenia. Concomitant administration of cidofovir with probenecid and saline hydration decreases the nephrotoxicity. Cidofovir resistance has not been documented. |
| Indications | Cidofovir (Vistide) is an acyclic phosphonate cytosineanalogue with activity against herpesviruses includingCMV, HSV-1, HSV-2, EBV, and VZV. It also inhibitsadenoviruses, papillomaviruses, polyomaviruses, andpoxviruses. Activation of cidofovir requires metabolismto a diphosphate by host cellular enzymes. Because thisactivation does not depend upon viral enzymes, similarlevels of cidofovir diphosphate are seen in infected anduninfected cells. Cidofovir diphosphate competes withdeoxycytidine triphosphate (dCTP) for access to viral DNA polymerase and also acts as an alternative substrate.The incorporation of one cidofovir molecule intothe growing DNA chain slows replication; sequential incorporationof two molecules halts DNA polymeraseactivity. |
| Definition | ChEBI: Cytosine substituted at the 1 position by a 3-hydroxy-2-(phosphonomethoxy)propyl group (S configuration). A nucleoside analogue, it is an injectable antiviral used for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. |
| Manufacturing Process | By the alkylation of N-benzoyl uracil with the chiral 2-trityloxy-oxirane wasobtained glycoside-like derivative N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-1,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide as a single isomer. From N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-1,2-dihydroxypyrimidin-4-yl]-Nmethylbenzamide and toluene-(4-sulfomethyl)phosphonic acid diethyl esterwas prepared [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-trityloxymethylethoxymethyl]phosphonic acid diethyl ester. As a result of treatment of the product with hydrogen chloride was synthesized [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-hydroxymethylethoxymethyl]phosphonic acid diethyl ester. Sequential reaction with trimethylsilylbromide and ammonium hydroxide cleaves the phosphite ethyl groups andsaponifies the benzamide function to afford (1S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (Cidofovir). |
| Brand name | Vistide(Gilead Sciences). |
| Therapeutic Function | Antiviral |
| Antimicrobial activity | The phosphonate group enables it to mimic a nucleotide andbypass virus-dependent phosphorylation. Cellular enzymesconvert it to the triphosphate, which has in-vitro and in-vivoactivity against CMV and other herpesviruses, including aciclovir-resistant HSV. Oral hairy leukoplakia resolved on therapy,suggesting that it has activity against EBV. Activity againstadenovirus and papillomaviruses is also reported. |
| General Description | Cidofovir, (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine(HPMPC, Vistide), is an acyclonucleotide analog thatpossesses broad-spectrum activity against several DNAviruses. Unlike other nucleotide analogs that are activated tonucleoside phosphates, Cidofovir is a phosphonic acid derivative.The phosphonic acid is not hydrolyzed by phosphatasesin vivo but is phosphorylated by cellular kinases to yield adiphosphate. The diphosphate acts as an antimetabolite to deoxycytosinetriphosphate (dCTP). Cidofovir diphosphate is acompetitive inhibitor of viral DNA polymerase and can beincorporated into the growing viral DNA strand, causingDNA chain termination. Cidofovir possesses a high therapeutic index against CMVand has been approved for treating CMV retinitis in patientswith AIDS. Cidofovir is administered by slow, constant intravenousinfusion in a dose of 5 mg/kg over a 1-hour periodonce a week for 2 weeks. This treatment is followed by amaintenance dose every 2 weeks. |
| Hazard | A severe skin irritant. |
| Pharmaceutical Applications | An acyclic cytosine analog administered by intravenousinfusion. |
| Biochem/physiol Actions | Selective inhibitor of viral DNA synthesis through the selective inhibition of viral DNA polymerase. |
| Mechanism of action | Cidofovir is a synthetic acyclic pyrimidine nucleotide analogue of cytosine. It is a phosphorylatednucleotide that is additionally phosphorylated by host cell enzymes to its active intracellular metabolite,cidofovir diphosphate. This reaction occurs without initial virus-dependent phosphorylation by viralnucleoside kinases. It has antiviral effects by interfering with DNA synthesis and inhibiting viralreplication. |
| Pharmacokinetics | Oral absorption： <5% Cmax 3 mg/kg intravenous infusion： 7.7 mg/L end infusion 10 mg/kg intravenous infusion： 23 mg/L end infusion Plasma half-life： c. 3–4 h Volume of distribution： c. 0.6 L/kg Plasma protein binding： <6% The intracellular half-life of the diphosphate is 17–65 h. Itis excreted unchanged by the kidney by glomerular filtrationand tubular secretion. |
| Clinical Use | Treatment of CMV retinitis Because of nephrotoxicity it is a drug of last resort. It has beenused experimentally in the treatment of adenovirus pneumoniaand BK virus in transplant patients and juvenile laryngealpapillomatosis. |
| Clinical Use | Cidofovir is approved for the treatment and prophylaxisof CMV retinitis in AIDS patients. It has also beenused in the treatment of acyclovir-resistant (viral thymidinekinase-deficient) HSV infections, polyomavirusassociatedprogressive multifocal leukoencephalopathy,condylomata acuminata (anogenital warts), and molluscumcontagiosum. |
| Side effects | The most immediately serious adverse effect associatedwith cidofovir therapy is nephrotoxicity. Accumulationof the drug within the proximal tubule epithelial cellscan lead to proteinuria, azotemia, glycosuria, elevatedserum creatinine, and rarely, Fanconi’s syndrome.Probenecid is administered along with cidofovir toblock its uptake into the proximal tubule epithelial cellsand thereby inhibit its tubular secretion as well as itstoxicity. Probenecid carries its own adverse effects, includinggastrointestinal upset, hypersensitivity reactions,and a decrease in the elimination of drugs thatalso undergo active tubular secretion (e.g. nonsteroidalantiinflammatory drugs [NSAIDs], penicillin, acyclovir,zidovudine). Anterior uveitis and neutropenia are fairly commonside effects of cidofovir therapy. Ocular hypotony andmetabolic acidosis are rare. Exposure to therapeuticlevels of cidofovir causes cancer in rats; therefore, thisdrug should be considered a potential human carcinogen.Animal studies have also shown cidofovir to produceembryotoxic and teratogenic effects and to impairfertility. |
| Side effects | Nephrotoxicity, heralded by proteinuria, occurred at weeklydoses of ≤3 mg/kg in two of five patients after 6 and 14 consecutiveweeks of therapy. Two of five patients given 10 mg/kgdeveloped nephrotoxicity, manifested as a Fanconi-like syndrome,after only two doses. Biopsy revealed proximal tubulareffects. Prehydration and extended dosing intervals seem tobe nephroprotective. |
| Drug interactions | Potentially hazardous interactions with other drugs Antivirals: avoid concomitant use with tenofovir. |
| Metabolism | After IV doses of cidofovir, serum concentrations decline with a reported terminal half-life of about 2.2 hours (the intracellular half-life of the active diphosphate may be up to 65 hours). Cidofovir is eliminated mainly by renal excretion, both by glomerular filtration and tubular secretion. About 80-100% of a dose is recovered unchanged from the urine within 24 hours. Use with probenecid may reduce the excretion of cidofovir to some extent by blocking tubular secretion, although 70-85% has still been reported to be excreted unchanged in the urine within 24 hours. |
Cidofovir Preparation Products And Raw materials
| Raw materials | Silica gel-->Glycerol-->Triethyl phosphate-->Cytosine-->Buffer solution, pH 1.00 (±0.01 at 25°C), No Color, Specpure, NIST Traceable-->Bromotrimethylsilane-->Hydrochloric acid-->Ammonium hydroxide |
