Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates
Vlahov, IR; Santhapuram, HK; You, F; Wang, Y; Kleindl, PJ; Hahn, SJ; Vaughn, JF; Reno, DS; Leamon, CP
| HERO ID | 4942426 |
|---|---|
| In Press | No |
| Year | 2010 |
| Title | Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates |
| Authors | Vlahov, IR; Santhapuram, HK; You, F; Wang, Y; Kleindl, PJ; Hahn, SJ; Vaughn, JF; Reno, DS; Leamon, CP |
| Journal | Journal of Organic Chemistry |
| Volume | 75 |
| Issue | 11 |
| Page Numbers | 3685-3691 |
| Abstract | To better regulate the biodistribution of the vinblastine-folate conjugate, EC145, a new folate-spacer that incorporates 1-amino-1-deoxy-D-glucitol-gamma-glutamate subunits into a peptidic backbone, was synthesized. Synthesis of Fmoc-3,4;5,6-di-O-isopropylidene-1-amino-1-deoxy-D-glucitol-gamma-glutamate 20, suitable for Fmoc-strategy solid-phase peptide synthesis (SPPS), was achieved in four steps from delta-gluconolactone. Addition of alternating glutamic acid and 20 moieties onto a cysteine-loaded resin, followed by the addition of folate, deprotection, and cleavage, resulted in the isolation of the new folate-spacer: Pte-gammaGlu-(Glu(1-amino-1-deoxy-D-glucitol)-Glu)(2)-Glu(1-amino-1-deoxy-D-glucitol)-Cys-OH (21). The addition of 21 to an appropriately modified desacetylvinblastine hydrazide (DAVLBH) resulted in a conjugate (25) with an improved therapeutic index. Treatment of 25 with DTT in neutral buffer at room temperature demonstrated that free DAVLBH would be released under the reductive environment of the internalized endosome. |
| Doi | 10.1021/jo100448q |
| Pmid | 20423159 |
| Wosid | WOS:000278063100016 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | Index Medicus; 2010) |
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