Enzymatically degradable prodrugs: A novel methodology for drug linkage

Abstract

ABSTRACT:We have synthesized a novel enzymatically degradable prodrug system based on poly(ethylene glycol) (PEG) and tyrosine units by employing a synthetic methodology which eliminated the use of conventional blocking and deblocking methodology used for chemical linkage of drug molecule to the pendant -NH 2 group of amino acid. A diester of PEG (6 kDa) and tyrosine hydrochloride was synthesized by dicyclohexyl carbodiimide (DCC)-mediated condensation. In the second stage, oligomers were prepared by condensing phenolic -OH groups of tyrosine in the diester with sebacic acid, using DCC. Finally, the hydrochloride salt of tyrosine in the oligomer was treated with triethylamine to activate -NH 2 groups, which were reacted with benzoyl chloride to obtain a model prodrug system. The products synthesized were characterized by IR, 1 H-NMR, and GPC. The spectral data were in accordance with the proposed structures of products. Chymotrypsin-catalyzed degradation of the oligomers was characterized by both MW measurements and Ninhydrin assay for free tyrosine. Degradation studies indicated that the rate of main-chain degradation (ester hydrolysis) is higher than that of the side chain (amide hydrolysis). This new, simple methodology should be useful for conjugating a variety of bioactive molecules to enzymatically degradable PEG-amino acid based polymers.

Degradability of the linear azo polymer conjugated 5,5′‐azodisalicylic acid segment in the main chain for colon‐specific drug delivery

“…I was synthesized by esterification with DCC as the coupling agent and DMAP as the basic catalyst 16–19. OLZ (0.60 g, 2 mmol) and ethylene glycol (0.40 g, in excess) were dissolved in 40 mL of THF in a sealed flask at room temperature.…”

“…Synthesis of di(2-hydroxyethyl)-5,5 0azodisalicylate (I) I was synthesized by esterification with DCC as the coupling agent and DMAP as the basic catalyst. [16][17][18][19] OLZ (0.60 g, 2 mmol) and ethylene glycol (0.40 g, in excess) were dissolved in 40 mL of THF in a sealed flask at room temperature. After nitrogen purging for 30 min, DMAP (0.07 g, 0.6 mmol) and DCC (1.03 g, 5.0 mmol) in 10 mL of THF were added successively.…”

Designing Smart Polymer Conjugates for Controlled Release of Payloads

“…On the basis of the degradation mechanism, prodrug conjugates can be categorized in two groups: (i) the so-called “self-immolative” conjugates − that usually are completely converted to free drugs and other small inactive molecules after activation, (ii) “polymer–drug conjugates” or “polymeric prodrugs” − that produce free drugs and remaining polymers after degradation or activation. For both categories, the degradation and release of the active agents usually require an external stimulus such a change of pH value, − ,,,,− an enzyme, ,,,− irradiation, − chemicals, or electrochemical oxidation or reduction. ,,,,,,− For self-immolative polymers and dendrimers, the stimulus is used for cleaving the bond linked to the so-called trigger group (Figure c). When the trigger bond is cleaved, depolymerization and immolation continue.…”

Pulmonary vein morphology by free‐breathing whole heart magnetic resonance imaging at 3 tesla versus breathhold multi‐detector computed tomography

“…Synthetic macromolecules with potential pharmacological activity known as polymeric drugs or polymer‐bonded drugs have attracted the considerable attention of a great number of scientific research groups during the last 25 years 1–3. In this sense, the most interesting investigations are those in which pharmacologically active polymers are used as carriers for pharmaceutical agents widely used in medications 4.…”