Chemistry:Atiprimod
Atiprimod (INN, codenamed SK&F106615) is a substance being studied in the treatment of certain multiple myelomas and other advanced cancers. It may block the growth of tumors and the growth of blood vessels from surrounding tissue to the tumor. This drug is also being researched as a potential treatment for various autoimmune diseases.
It was first developed by GlaxoSmithKline as a potential treatment for rheumatoid arthritis.[1][2]
This compound has also been shown to kill mantle cell lymphoma cells in vitro.[3]
Mechanism of action
Atiprimod has been shown to inhibit angiogenesis (growth of blood vessels) in a blood vessel model using chicken eggs. It is thought to inhibit the secretion of vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis.[citation needed]
Chemistry
Atiprimod is an amphiphilic compound that exists as a cation at neutral pH and belongs to the heterocyclic class of azaspiranes.
Synthesis
The first part of the synthesis uses protocols that were used for Pramiverine and agents including SIR 117. The second half of the synthesis shares features that are consonant with RS 86
The Johnson–Corey–Chaykovsky reaction on 4-Heptanone [123-19-3] (1) gives 2,2-dipropyloxirane [98560-25-9] (2). Treatment with Boron trifluoride etherate [109-63-7] gave 2-Propylpentanal [18295-59-5] (3). Upon acid treatment with Methyl vinyl ketone [78-94-4] (4) this led to 4,4-Dipropylcyclohex-2-enone [60729-41-1] (5). Catalytic hydrogenation of the enone olefin yielded 4,4-Dipropylcyclohexanone [123018-62-2] (7). The Knoevenagel condensation with ethyl 2-cyanoacetate [1187-46-8] (8) led to Cyano-(4,4-dipropyl-cyclohexylidene)-acetic acid ethyl ester [130065-93-9] (8). Conjugate addition of cyanide anion led to ethyl 2-cyano-2-(1-cyano-4,4-dipropylcyclohexyl)acetate, PC45358714 (9). Acid hydrolysis of both the nitrile groups to acids, saponification of the ester, and decarboxylation of the geminal diacid gave 1-(carboxymethyl)-4,4-dipropylcyclohexane-1-carboxylic acid [130065-94-0] (10). Treatment with acetic anhydride gave 8,8-Dipropyl-2-oxaspiro[4.5]decane-1,3-dione [123018-64-4] (11). Condensation with 3-Diethylaminopropylamine [104-78-9] (12) gave the imide and hence, 2-[3-(diethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane-1,3-dione, PC15634126 (13). Finally reduction of both carbonyl groups with lithium aluminium hydride completed the synthesis of Atiprimod (14).
References
- ↑ "Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma". Myeloma Today (International Myeloma Foundation) 5 (10). Spring 2004. http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=1379&aTab=0. Retrieved 2010-09-30.
- ↑ 2.0 2.1 "Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents". Journal of Medicinal Chemistry 33 (11): 2963–2970. November 1990. doi:10.1021/jm00173a010. PMID 2146392.
- ↑ "Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways". Blood 109 (12): 5455–5462. June 2007. doi:10.1182/blood-2006-12-063958. PMID 17317853.
- ↑ Badger AM, Cheeseman EN, DiMartino MJ, Dorman JW, Mirabelli CK, Picker DH, Schwartz DA, "Immunomodulatory azaspiranes", US patent 4963557, issued 16 October 1990, assigned to Callisto Pharmaceuticals Inc.
- ↑ Dagger RE, Grady CW, "2-[2-(dimethylaminoehtyl]-8,8-diproply-2-azaspiro[4.5]decane dimaleate", US patent 5952365, issued 4 September 1999, assigned to Anormed Inc.
Further reading
External links
- Atiprimod entry in the public domain NCI Dictionary of Cancer Terms
This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms".
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