title: Design and regioselective synthesis of a new generation of targeted therapeutics. Part 3: Folate conjugates of aminopterin hydrazide for the treatment of inflammation.
abstract: Efficient syntheses of folate receptor (FR) targeting conjugates of the anti-inflammatory, aminopterin hydrazide, are described. 2-{4-Benzoylamino}-5-oxo-5-{N'-[2-(pyridin-2-yldisulfanyl)-ethoxycarbonyl]-hydrazino}-pentanoic acid is synthesized from commercially available 4-[(2-amino-4-imino-3,4-dihydro-pteridin-6-yl-methyl)-amino]-benzoic acid. Conjugation of this novel, activated aminopterin hydrazide to folic acid through cysteine-terminating (C-terminus), peptide/carbohydrate spacers results in highly water soluble conjugates which allow for the release of free aminopterin hydrazide within the endosomes of targeted cells.
authors.affiliation: Endocyte Inc., 3000 Kent Ave, Suite A1-100, West Lafayette, IN 47906, USA. ivlahov@endocyte.com
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Fei
authors.initials: F
authors.lastname: You
authors.forename: Hari Krishna R
authors.initials: HK
authors.lastname: Santhapuram
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Vaughn
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Hahn
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kleindl
authors.forename: Mingjin
authors.initials: M
authors.lastname: Fan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
mesh_terms: D000630:Aminopterin / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D015195:Drug Design; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: D000893:Anti-Inflammatory Agents; D005492:Folic Acid; D000630:Aminopterin