53123-88-9 Usage
Uses
Used in Pharmaceutical Industry:
Rapamycin is used as an immunosuppressant for preventing the rejection of organ and bone marrow transplants. It specifically interacts with the cytosolic FK-binding protein 12 (FKBP12) to form a complex which inhibits the mammalian target of rapamycin (mTOR) pathway by directly binding to mTOR Complex 1 (mTORC1). This interaction helps in suppressing the immune response and reducing the risk of transplant rejection.
Used in Cancer Treatment:
Rapamycin and other inhibitors of mTORC1 signaling show potential in treating cancer. The inhibition of mTOR pathway by Rapamycin can help in controlling tumor growth and progression.
Used in Antirestenotic Applications:
Rapamycin is used as an antirestenotic agent, which helps in preventing the narrowing or blockage of blood vessels after angioplasty or stenting procedures.
Used in Research Applications:
Labelled Rapamycin, a triene macrolide antibiotic isolated from Streptomyces hygroscopicus, is used in research applications to study the mTOR pathway and its role in various cellular processes.
in vivo
Rapamycin (2.0 mg/kg; intraperitoneal injection; every other day; 28 days) alone has a moderate inhibitory effect. However, the combination of Metformin and Rapamycin exerts a significantly increased inhibition of tumor growth compared with the control group, the Rapamycin monotherapy group and the Metformin monotherapy group.
Indications and Usage
Rapamycin (Rapa, or Sirolimus) is a new form of macrolide immunosuppressive agent. It is a white solid crystal. Its melting point is 183-185℃ and it is lipophilic. It is soluble in methanol, ethanol, acetone, chloroform, and other organic solvents, very slightly soluble in water, and almost insoluble in ether. It was first discovered in 1975 on the Chilean Easter Island as a secondary metabolite secreted by soil Streptomyces, and its chemical structure is that of a three-polyene macrolide compound.
Rapamycin is a new form of immunosuppressive agent with good curative effects, low toxicity, and no nephrotoxicity. It can be used to maintain the immunity of transplant organs (especially in kidney transplants) to alleviate immunological rejections after organ transplant surgeries. The latest research has shown that Rapamycin can also be used to treat Alzheimer’s. When used on afflicted lab rats, it had a memory-restoring effect. Rapamycin oral tablets can be taken with grapefruit juice to treat melanoma (a type of benign tumor common among Western populations), dramatically increase other chemotherapy drugs’ anticancer effects, and extend patient survival. Rapamycin is a mammalian target of rapamycin (mTOR) targeting inhibitor, which can treat tumors that are related to this pathway including kidney cancer, lymphoma, lung cancer, liver cancer, breast cancer, neuroendocrine carcinoma, gastric cancer, etc. Its curative effects are especially strong for the rare diseases LAM (lymphangiomyomatosis) and TSC (tuberous sclerosis).
Mechanisms of Action
Rapamycin is a type of macrolide antibiotic and has a similar structure to Prograf (FK506), but has very different immunosuppressing mechanisms. FK506 suppresses T lymph cells from proliferating from G0 to G1 stage, while RAPA uses different cytokine receptors to block signal transduction, thus preventing T lymph cells and other cells from proliferating from G1 to S stage. Compared to Prograf, Rapamycin can block the signal transduction pathways of the calcium dependency and calcium non-dependency of T lymph cells and B lymph cells.
Adverse reactions
Rapamycin has similar side effects to those of Prograf. Many clinical trials have found that its side effects are dose dependent and reversible. A treatment dosage of Rapamycin has not been found to lead to any significant nephrotoxicity or gingival hyperplasia. Its main toxic side effects include: headache, nausea, dizziness, nosebleed, and join pain. Laboratory inspections for anomalies found: thrombocytopenia, decreased white blood cells, decreased hemoglobin, hypertriglyceridemia, hypercholesterolemia, hyperglycemia, increased liver enzymes (SGOT, SGPT), increased lactate dehydrogenase, hypokalemia, hypokalemia, etc. Rapamycin may lead to puffiness of eyelids and lead to lowered plasma phosphate levels. Similar to other immunosuppressants, Rapamycin may also increase the chance of infection, with reports of increased tendency towards pneumonia.
Originator
Rapamune,Wyeth Laboratories,UK
Indications
Mechanistic target of rapamycin (mTOR) is a serine/threonine-specific protein kinase in the PI3/PI4-kinase family. mTOR was named after the natural macrolide rapamycin, also known as sirolimus, which was isolated from a soil sample from Easter Island in the 1970s and later evaluated as an immunosuppressive agent. The anticancer activity of rapamycin was discovered in the 1980s, although the mechanismof action and the identification of the rapamycin target, mTOR, were not elucidated until the 1990s. Rapamycin and its macrocyclic analogues, such as temsirolimus (Torisel(R), Wyeth/Pfizer) and everolimus (Afinitor(R), Novartis), are grouped as “rapalogs” that constitute the first-generation mTOR inhibitors.
Rapamycin was approved by the US FDA in 1999 as an immunosuppressive agent to prevent organ rejection in patients receiving kidney transplants. Although a large number of clinical studies have been performed to evaluate the anticancer activities of sirolimus in different types of cancers, such as invasive bladder cancer, breast cancer, and leukemia, most studies show limited efficacy. Outside oncological indications, sirolimus was approved by FDA for the treatment of a rare progressive lung disease lymphangioleiomyomatosis in 2015. Temsirolimus was approved for the treatment of advanced RCC. Everolimus was approved in the EU for the prevention of organ rejection in heart and kidney transplant recipients before FDA approved it in 2009 for the treatment of advanced RCC resistant to sunitinib or sorafenib and for the treatment of advanced or metastatic gastrointestinal and lung tumors in 2016. Additionally, rapamycin and rapalogs are being investigated as antiaging therapeutics or for the treatment of age-related diseases. Studies have revealed that mTOR activity can be retained under hypoxic conditions via mutations in the PI3K pathway, leading to increased translation and hypoxic gene expression and tumor progression.
Indications
Sirolimus (Rapamune) is structurally related to
tacrolimus. It is approved for use as an adjunctive agent
in combination with cyclosporine for prevention of
acute renal allograft rejection. It blocks IL-2-dependent
T-cell proliferation by inhibiting a cytoplasmic serine–
threonine kinase. This mechanism of action is different
from those of tacrolimus and cyclosporine. This allows
sirolimus to augment the immunosuppressive effects of
these drugs.
Manufacturing Process
Streptomyces hygroscopicus NRRL 5491 was grown and maintained on
oatmeal-tomato paste agar slants (T. G. Pridham et al.; Antibiotic Annual
1956-1957, Medical Encyclopedia Inc., New York, p. 947) and in Roux bottles
containing the same medium. Good growth was obtained after 7 days of
incubation at 28°C. Spores from one Roux bottle were washed off and
suspended into 50 ml of sterile distilled water. This suspension was used to
inoculate the first stage inoculum.The first-stage inoculum medium consisted of Emerson broth [R. L. Emerson
et al., J. Bacteriol, 52, 357 (1946)] 0.4% peptone, 0.4% sodium chloride,
0.25% yeast extract and 1% glucose; pH 7.0; flasks containing the above
medium were inoculated with 1 % of the spore suspension described above.
The inoculated flasks were incubated for 30 hours at 28°C on a reciprocating
shaker set at 65 r.p.m. (4 inch stroke).Production stageThe production stage was run in 250-liter New Brunswick fermenters Model F-
250, equipped with automatic antifoam addition system and pH recordercontroller.
The fermenters were charged with 160 L of an aqueous production
medium consisting of the following constituents: 1.0% soluble starch; 0.5%
(NH4)2SO4; 0.5% K2HPO4; 1.5% glucose (Cerelose); 0.025% MgSO4; 0.005%
ZnSO4; 0.001% MnSO4; 0.002% FeSO47H2O; 0.2% CaCO3; 0.5% "Blackstrap"
molasses; 0.5% hydrolyzed casein; 0.2% lard oil; pH 7.1 to 7.3 of first stage
inoculum. Incubation temperature: 28°C; aeration: 0.5 vol/vol/min; agitation:
250 r.p.m. The fermenters were sterilized at 121°C for 45 min, cooled and
inoculated with one flask inoculum).A titre of ca. 20 μg/ml, determined by microbiological assay on agar plates
seeded with Candida albicans, was reached in 5 days. The fermentation was
stopped. The fermentation mixture was extracted twice with 1 v/v of nbutanol.
The combined butanol extracts were washed with 1 v/v of water,
dried with anhydrous sodium sulfate and evaporated to dryness under reduced
pressure to yield a residue. The oily residue was extracted 3 times with 2 L of
methanol. The combined methanol extracts were passed through
diatomaceous earth (Celite) and evaporated to dryness to yield an oily residue
containing crude Rapamycin.
Therapeutic Function
Immunosuppressive, Antifungal
Biological Activity
Antifungal and immunosuppressant. Specific inhibitor of mTOR (mammalian target of Rapamycin). Complexes with FKBP-12 and binds mTOR inhibiting its activity. Inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase.
Biochem/physiol Actions
Rapamycin is a macrocyclic triene antibiotic possessing potent immunosuppressant and anticancer activity. It forms a complex with FKBP12 that binds to and inhibits the molecular target of rapamycin (mTOR). mTOR is a member of the phosphoinositide kinase-related kinase (PIKK) family that enhances cellular proliferation via the phosphoinositol 3-kinase/Akt signaling pathway. Inhibition of this pathway by rapamycin blocks downstream elements that result in cell cycle arrest in G1. The effectors of mTOR action include 4EBP1 and S6K1.
Clinical Use
Immunosuppressant:
Prophylaxis of transplant allograft rejection
in vitro
Rapamycin (12.5-100 nM; 24 hours) treatment exerts modest inhibitory effect on lung cancer cell proliferation in a dose-dependent manner in all cell lines (A549, SPC-A-1, 95D and NCI-H446 cells) tested, achieving about 30-40% reduction in cell proliferation at 100 nM vs. ~10% reduction at 12.5 nM.
Lung cancer cell line 95D cells are exposed to Rapamycin (10 nM, 20 nM) and RP-56976 (1 nM, 10 nM) alone or in combination (Rapamycin 20 nM+ RP-56976 10 nM). After 24 hours exposure to Rapamycin or RP-56976 alone does not significantly alter the level of expression or phosphorylation of ERK1/2, whereas cells treated with the combination of Rapamycin with RP-56976 exhibit a marked reduction in the phosphorylation levels of ERK1/2.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by
clarithromycin - avoid; concentration of both drugs
increased with erythromycin; concentration reduced
by rifampicin and rifabutin - avoid.
Antifungals: concentration increased by itraconazole,
fluconazole, ketoconazole, micafungin, miconazole,posaconazole and voriconazole - avoid with
itraconazole, ketoconazole and voriconazole.
Antivirals: concentration possibly increased by
atazanavir, boceprevir and lopinavir; concentration
of both drugs increased with telaprevir, reduce
dose of sirolimus; concomitant use with dasabuvir
plus ombitasvir/paritaprevir/ritonavir is not
recommended unless the benefits outweigh the risks,
if used together administer sirolimus 0.2 mg twice a
week (every 3 or 4 days on the same two days each
week). Sirolimus blood concentrations should be
monitored every 4-7 days until 3 consecutive trough
levels have shown stable concentrations of sirolimus.
Sirolimus dose and/or dosing frequency should be
adjusted as needed.
Calcium-channel blockers: concentration increased
by diltiazem; concentration of both drugs increased
with verapamil.
Ciclosporin: increased absorption of sirolimus -
give sirolimus 4 hours after ciclosporin; sirolimus
concentration increased; long-term concomitant
administration may be associated with deterioration
in renal function.
Cytotoxics: use crizotinib with caution.
Grapefruit juice: concentration of sirolimus increased
- avoid.
Mycophenolate: concomitant use of mycophenolate
and sirolimus increases plasma levels of both
sirolimus and mycophenolic acid.
Metabolism
Sirolimus is metabolised by the cytochrome P450
isoenzyme CYP3A4. Metabolism occurs by
demethylation or hydroxylation, and the majority of a
dose is excreted via the faeces.
References
1) Kay et al. (1991) Inhibition of T and B lymphocyte proliferation by rapamycin. Immunology, 72 544
2) Mita et al., (2003) The molecular target of rapamycin (mTOR) as a therapeutic target against cancer; Cancer Biol. Ther., 2(4 Suppl 1) S169
3) Lamming et al. ( 2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity; Science, 335 1638
4) Sarkar et al. (2009), Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies; Cell Death and Differ., 16 46
Check Digit Verification of cas no
The CAS Registry Mumber 53123-88-9 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 5,3,1,2 and 3 respectively; the second part has 2 digits, 8 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 53123-88:
(7*5)+(6*3)+(5*1)+(4*2)+(3*3)+(2*8)+(1*8)=99
99 % 10 = 9
So 53123-88-9 is a valid CAS Registry Number.
InChI:InChI=1/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12-,31-17+,35-25+/t30-,32-,33-,34-,36-,37+,38?,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1
53123-88-9Relevant articles and documents
Synthesis process for temsirolimus
-
Paragraph 0009; 0010, (2016/12/26)
The invention discloses a synthesis process for temsirolimus. The synthesis process comprises the following steps: step 1, preparing 2,2,5-trimethyl-5-carboxyl-1, 3-dioxane; step 2, preparing anhydride; step 3, carrying out esterification reaction; step 4, carrying out hydrolysis reaction and finally obtaining the target product, temsirolimus. According to the synthesis process disclosed by the invention, in the reaction of the step 2, DIPEA (diisopropanolamine) is selected as alkali and methylene chloride is selected as a solvent so that anhydride reaction liquid can be directly used in the reaction in the step 3, and technological operation is reduced; the selectivity of the direct esterification reaction is achieved by lowering the temperature and controlling the usage amount of DMAP (dimethylaminopyridine) and the usage amount of anhydride, and the by-products of 31-esterification are reduced; the esterification selectivity is improved greatly, and the reaction route is simplified; and by selecting an ethylene glycol, para-toluenesulfonic acid and tetrahydrofuran deprotection system, the reaction time is reduced greatly, and the yield is improved.
Therapeutic Targets for Alzheimer's Disease
-
Page/Page column, (2015/05/26)
The present invention relates to novel methods for the prevention, treatment and diagnosis of Alzheimer's disease. In addition, the invention relates to methods for assessing an individual's susceptibility or pre-disposition to Alzheimer's disease. The methods of the present invention involve the use of therapeutic targets and diagnostic and/or predictive markers within the mTOR signalling pathway. The methods also involve screening subjects for genetic polymorphisms associated with rapamycin-sensitive genes.
METHOD FOR PREPARING 42-(DIMETHYLPHOSPHINATE) RAPAMYCIN
-
, (2014/03/24)
A method for preparing 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I) is provided, which has advantages of high conversion rate and no 31,42-bis(dimethyl phosphinate) Rapamycin (III) generated. In the method of the present invention, Rapamycin (II) is firstly reacted with triethyl chlorosilane in a base condition to form 31,42-bis(triethylsilylether) Rapamycin (IV-b), followed by a selective deprotection process to obtain 31-triethylsilylether Rapamycin (V-b). Next, a phosphorylation reaction is performed by using dimethylphosphinic chloride under a base solution to obtain a crude product. Finally, a deprotection reaction is performed in a diluted sulfuric acid solution to obtain a crude product of Ridaforolimus (I). Since the conversion rate of each step of the method of the present invention is higher than 98%, it indicates that the method of the present invention is suitable for industrial production.
DRUG DELIVERY MEDICAL DEVICE
-
Page/Page column, (2015/01/06)
A medical device that releases a pharmaceutical agent to a target site is disclosed. The medical device includes a balloon, and a coating on at least a portion of the balloon. Each particle of the particles of the pharmaceutical agent is at least partially encapsulated in a polymer layer. The method includes the steps of providing a device including a balloon, and a coating on at least a portion of the balloon, the coating including particles of a pharmaceutical agent, and each particle of the pharmaceutical agent is at least partially encapsulated in a polymer layer; positioning the device to allow the balloon to reach the target site; and inflating the balloon of the device.
MANUFACTURE, METHOD AND USE OF DRUG-ELUTING MEDICAL DEVICES FOR PERMANENTLY KEEPING BLOOD VESSELS OPEN
-
, (2013/02/28)
The invention relates to stents and catheter balloons having optimized coatings for eluting rapamycin as well as methods for manufacturing these coatings.
LIGHT MEDIATED REGULATION OF PROTEIN DIMERIZATION
-
Page/Page column 39, (2012/03/11)
The present invention relates to photoactivatable rapamycin compounds. The invention further relates to the use of photoactivatable rapamycin compounds to regulate the dimerization and/or activity of polypeptides in a light dependent manner.
MANUFACTURE, METHOD AND USE OF ACTIVE SUBSTANCE-RELEASING MEDICAL PRODUCTS FOR PERMANENTLY KEEPING BLOOD VESSELS OPEN
-
, (2010/04/23)
The invention relates to stents and catheter balloons having optimized coatings for eluting rapamycin as well as methods for manufacturing these coatings.
Total Synthesis of rapamycin
Ley, Steven V.,Tackett, Miles N.,Maddess, Matthew L.,Anderson, James C.,Brennan, Paul E.,Cappi, Michael W.,Heer, Jag P.,Helgen, Celine,Kori, Masakuni,Kouklovsky, Cyrille,Marsden, Stephen P.,Norman, Joanne,Osborn, David P.,Palomero, Maria A.,Pavey, John B. J.,Pinel, Catherine,Robinson, Lesley A.,Schnaubelt, Juergen,Scott, James S.,Spilling, Christopher D.,Watanabe, Hidenori,Wesson, Kieron E.,Willis, Michael C.
supporting information; experimental part, p. 2874 - 2914 (2009/12/25)
For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.
A PURE FORM OF RAPAMYCIN AND A PROCESS FOR RECOVERY AND PURIFICATION THEREOF
-
Page/Page column 9, (2008/12/05)
The present invention relates to a pure form of rapamycin with a total impurity content less than 1.2% ; a process for recovery and purification of rapamycin comprising steps of (a) treating the fermentation broth, extracts or solutions containing rapamycin with water immiscible solvent and concentration; (b) addition of a water miscible solvent to effect separation of impurities present; (c) optionally, binding of the solvent containing the product from step (b) to an inert solid, washing the solid with a base and acid, followed by elution; (d) subjecting the elute from step (c) or the solvent containing the product from step (b) to silica gel chromatography; (e) crystallization of the product obtained from step (d); (f) subjecting a solution of the product from step (e) to hydrophobic interaction or reversed phase chromatography; and (g) re-crystallization to afford rapamycin in substantially pure form.
Total synthesis of rapamycin
Maddess, Matthew L.,Tackett, Miles N.,Watanabe, Hidenori,Brennan, Paul E.,Spilling, Christopher D.,Scott, James S.,Osborn, David P.,Ley, Steven V.
, p. 591 - 597 (2008/02/01)
Rapamycin synthesis all wrapped up: A new convergent synthesis of rapamycin (1) is reported that involves a macroetherification/catechol tethering strategy for construction of the macrocyclic core of this intriguing natural product. Other studies on this commercialized potent immunosuppressant delineate new cell signaling pathways of relevance to cancer chemotherapy. (Chemical Equation Presented).
