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. 2014 Feb 15;24(4):1144-7.
doi: 10.1016/j.bmcl.2013.12.126. Epub 2014 Jan 8.

Undesired Versus Designed Enzymatic Cleavage of Linkers for Liver Targeting

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Free PMC article

Undesired Versus Designed Enzymatic Cleavage of Linkers for Liver Targeting

Srinivas R Chirapu et al. Bioorg Med Chem Lett. .
Free PMC article

Abstract

A design for the selective release of drug molecules in the liver was tested, involving the attachment of a representative active agent by an ester linkage to various 2-substituted 5-aminovaleric acid carbamates. The anticipated pathway of carboxylesterase-1-mediated carbamate cleavage followed by lactamization and drug release was frustrated by unexpectedly high sensitivity of the ester linkage toward hydrolysis by carboxylesterase-2 and other microsomal components.

Keywords: Carboxylesterase; Cleavable linkers; Drug targeting; Liver targeting.

Figures

Figure 1
Figure 1
Design of sequential enzymatic carbamate cleavage and δ-lactamization steps for release of drug conjugates targeted to the liver.
Figure 2
Figure 2
Potential cleavage products from test compounds 8 and 9.
Scheme 1
Scheme 1
Reagents and conditions: (a) i) t-BuLi, −78 °C, THF, warm to 0°C, 15 min; ii) R1X 60–80%. (b) (for R2 = Me, Bn) i) t-BuLi, KOtBu, −78 °C, THF, warm to 0°C, 15 min; ii) R2X 60–80%. (c) 0.1M HCl, CHCl3, RT, overnight, 78%. (d) methyl chloroformate, iPr2NEt, 0°C to RT, 2 h, 85%. (e) LiOH, THF: MeOH: H2O (3:1:1), RT, 6 h, 75–85%; or 1 N NaOH, THF:H2O (1:1), reflux, 6 h, 75%. (f) BnN3, CuSO4, Na ascorbate, DMF:H2O (3:1), RT, 1 h, 90%. (g) EDCI, DMAP, DMF, RT, 6 h, 90%.

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