Intramolecular Processes and Their Applications in Prodrugs Approaches- Experimental and Computational Studies
Date
2015-11-15
Authors
Karaman, Rafik
Jumaa, Salma
Awwadallah, Heba
Salah, Samya
Khawaja, Yahya
Karaman, Donia
Journal Title
Journal ISSN
Volume Title
Publisher
Bentham Science
Abstract
This review supplies the reader with a detailed overview on the utilization of intramolecular processes
for a design and synthesis of prodrugs. It is well known that a respected number of drugs suffer from low bioavailability,
toxicity, unpleasant taste and presystemic first-pass metabolism which result in drug inactivation. The classical
prodrug approach in which the linkage attaching the parent drug to its non-toxic linker and cleaved by in vivo
enzyme’s catalyzed reactions has proven its success in solving toxicity and bioavailability related issues. On the
other hand, prodrugs based on chemical interconversion in which the prodrug releases the corresponding active
parent drug via inter or intramolecular chemical process in the absence of an enzyme is considered as a better
alternative approach since the prodrug cleavage is not dependent in the efficiency or quantity of the enzyme catalyzes the interconversion
of the prodrug. Examples of successful prodrugs using the chemical approach via intramolecular processes such as cyclization reactions
are illustrated as well.
In addition, another part of this review is devoted to cover reported studies on enzyme models and their utilization for the design and synthesis
of a variety of novel prodrugs. In this approach, computational calculations using DFT and MM methods were exploited and correlations
between experimentally determined and computed values of the rate-limiting step in the studied intramolecular processes were
utilized in the prodrugs design. Selected examples of the designed prodrugs include aza-nucleosides for the treatment of myelodysplastic
syndromes, the anti-Parkinson’s agent dopamine, the anti-viral acyclovir, the anti-malarial atovaquone, and statins for lowering cholesterol
levels in the blood, the antihypertensive atenolol, the antibacterial cefuroxime, the anti-bleeding tranexamic acid, the decongestant
phenylephrine, and the pain killer paracetamol.
Description
Keywords
Intramolecular , cyclization , prodrug , trimethyl lock , intramolecular Activation , Quantum Mechanics Calculations , lactonization cyclization