Design and regioselective synthesis of a new generation of targeted therapeutics. Part 3: Folate conjugates of aminopterin hydrazide for the treatment of inflammation

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 4; pp. 1202 - 1205
• Main Authors: Vlahov, Iontcho R., You, Fei, Santhapuram, Hari Krishna R., Wang, Yu, Vaughn, Jeremy F., Hahn, Spencer J., Kleindl, Paul J., Fan, Mingjin, Leamon, Christopher P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2011; Elsevier
• Subjects: aminopterin; Aminopterin - chemical synthesis; Aminopterin - chemistry; Aminopterin - therapeutic use; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; chemistry; Disulfide linkers; Drug Design; endosomes; Folate; Folate receptor targeting; Folate-aminopterin hydrazide conjugate; folic acid; Folic Acid - analogs & derivatives; Folic Acid - chemical synthesis; Folic Acid - chemistry; Folic Acid - therapeutic use; Humans; Inflammation; Inflammation - drug therapy; Medical sciences; Pharmacology. Drug treatments; Stereoisomerism; therapeutics; Folate-aminopterin hydrazide conjugate; Inflammation; Folate receptor targeting; Disulfide linkers; Folate; Organic hydrazide; Spacer arm; Peptides; Regioselectivity; Antiinflammatory agent; Drug carrier; Organic disulfide; Glycopeptide; Targeted drug; Pterine derivatives; Conjugated compound; Chemical synthesis; Endosome; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.085

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.