Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases
A folate receptor targeted didemnin B conjugate was synthesized using a hydrophilic peptide spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity and TNF-α inhibition in RAW264.7 macrophage-like cells exhibited IC50s of 13 and 5nM, respectively. Folate didemnin B was...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.709-712 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 22 |
| creator | Henne, Walter A. Kularatne, Sumith A. Ayala-López, Wilfredo Doorneweerd, Derek D. Stinnette, Torian W. Lu, Yingjuan Low, Philip S. |
| description | A folate receptor targeted didemnin B conjugate was synthesized using a hydrophilic peptide spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity and TNF-α inhibition in RAW264.7 macrophage-like cells exhibited IC50s of 13 and 5nM, respectively. Folate didemnin B was found to be ∼50–100 fold more potent than didemnin B itself. More importantly, activity of the prodrug was blocked by excess folic acid, demonstrating receptor-mediated cellular uptake of the conjugate. |
| doi_str_mv | 10.1016/j.bmcl.2011.10.042 |
| format | Article |
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Cell cytotoxicity and TNF-α inhibition in RAW264.7 macrophage-like cells exhibited IC50s of 13 and 5nM, respectively. Folate didemnin B was found to be ∼50–100 fold more potent than didemnin B itself. More importantly, activity of the prodrug was blocked by excess folic acid, demonstrating receptor-mediated cellular uptake of the conjugate.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.10.042</identifier><identifier>PMID: 22100311</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Biological and medical sciences ; Carbon - chemistry ; cytotoxicity ; Depsipeptides - chemical synthesis ; Depsipeptides - pharmacology ; Dose-Response Relationship, Drug ; Folate ; Folate didemnin B ; Folate receptor ; folic acid ; Folic Acid - chemistry ; hydrophilicity ; Hydrophobic and Hydrophilic Interactions ; Inflammation ; Inflammation - drug therapy ; Inhibitory Concentration 50 ; Macrophage ; Macrophages - cytology ; Medical sciences ; Mice ; Models, Biological ; Models, Chemical ; Peptides - chemistry ; Pharmacology. 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Cell cytotoxicity and TNF-α inhibition in RAW264.7 macrophage-like cells exhibited IC50s of 13 and 5nM, respectively. Folate didemnin B was found to be ∼50–100 fold more potent than didemnin B itself. More importantly, activity of the prodrug was blocked by excess folic acid, demonstrating receptor-mediated cellular uptake of the conjugate.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Carbon - chemistry</subject><subject>cytotoxicity</subject><subject>Depsipeptides - chemical synthesis</subject><subject>Depsipeptides - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Folate</subject><subject>Folate didemnin B</subject><subject>Folate receptor</subject><subject>folic acid</subject><subject>Folic Acid - chemistry</subject><subject>hydrophilicity</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Inhibitory Concentration 50</subject><subject>Macrophage</subject><subject>Macrophages - cytology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Models, Chemical</subject><subject>Peptides - chemistry</subject><subject>Pharmacology. 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| subjects | Animals Biological and medical sciences Carbon - chemistry cytotoxicity Depsipeptides - chemical synthesis Depsipeptides - pharmacology Dose-Response Relationship, Drug Folate Folate didemnin B Folate receptor folic acid Folic Acid - chemistry hydrophilicity Hydrophobic and Hydrophilic Interactions Inflammation Inflammation - drug therapy Inhibitory Concentration 50 Macrophage Macrophages - cytology Medical sciences Mice Models, Biological Models, Chemical Peptides - chemistry Pharmacology. Drug treatments Prodrugs - pharmacology tumor necrosis factor-alpha Tumor Necrosis Factor-alpha - metabolism |
| title | Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases |
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