Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates.
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.
Vlahov
Iontcho R
IR
Endocyte Inc., 3000 Kent Avenue, Suite A1-100, West Lafayette, Indiana 47906, USA. ivlahov@endocyte.com
Santhapuram
Hari Krishna R
HK
You
Fei
F
Wang
Yu
Y
Kleindl
Paul J
PJ
Hahn
Spencer J
SJ
Vaughn
Jeremy F
JF
Reno
Daniel S
DS
Leamon
Christopher P
CP
D000818:Animals; D000970:Antineoplastic Agents; D002241:Carbohydrates / Q000737:chemistry*; D015195:Drug Design; D011992:Endosomes / Q000378:metabolism; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D014018:Tissue Distribution; D014747:Vinblastine / Q000737:chemistry / Q000627:therapeutic use; D014748:Vinca Alkaloids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity*
D000970:Antineoplastic Agents; D002241:Carbohydrates; C520389:EC145; D014748:Vinca Alkaloids; D014747:Vinblastine; D005492:Folic Acid