Cyclization-activated Prodrugs

Abstract

Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

Mechanistic Studies of the Photoinduced Quinone Trimethyl Lock Decaging Process

“…Figure 1 shows two variants of the well-established trimethyl lock system. [2][3][4] Either reducing a quinone or revealing a phenol produces a nucleophile that can exploit the remarkable rate enhancements associated with the trimethyl lock system, releasing HX as a generic alcohol, amine, thiol, or phosphate. Of course, deprotection of the phenol can be accomplished photochemically using established caging groups, 5,6 but this approach does not lead naturally to longer wavelength systems.…”

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

“…Previous studies have attempted to improve the intestinal absorption of OCT by changing its chemical structure or adding an absorption enhancer to increase paracellular absorption, but with little effect (2,8,9). The elucidation of the factors that affect the oral absorption of OCT would facilitate the development of strategies to improve its absorption.…”

Magnetogenese unter physiologischen Bedingungen mit molekularen Sonden, die auf (bio‐)chemische Analyten ansprechen

“…Ist darüber hinaus ein bestimmter pH-Wert gefordert (insbesondere der physiologisch relevante pH 7. [15][16][17] und in jüngerer Vergangenheit auch für aktivierbare Fluoreszenzsonden vorgeschlagen wurden. [18][19][20][21] Was vielmehr bençtigt wird, ist ein System, das beträchtliche potentielle Energie speichern kann (Sprungfeder-artig), die zur Überwindung des Chelateffekts zur Verfügung steht, sobald die Peripherie des Komplexes durch den gewünschten Stimulus chemisch verändert wird.…”