-
International Journal of Molecular... May 2020Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step... (Review)
Review
Prodrugs are designed to improve pharmaceutical/biopharmaceutical characteristics, pharmacokinetic/pharmacodynamic properties, site-specificity, and more. A crucial step in successful prodrug is its activation, which releases the active parent drug, exerting a therapeutic effect. Prodrug activation can be based on oxidation/reduction processes, or through enzyme-mediated hydrolysis, from oxidoreductases (i.e., Cytochrome P450) to hydrolytic enzymes (i.e., carboxylesterase). This study provides an overview of the novel in silico methods for the optimization of enzyme-mediated prodrug activation. Computational methods simulating enzyme-substrate binding can be simpler like molecular docking, or more complex, such as quantum mechanics (QM), molecular mechanics (MM), and free energy perturbation (FEP) methods such as molecular dynamics (MD). Examples for MD simulations used for elucidating the mechanism of prodrug (losartan, paclitaxel derivatives) metabolism via CYP450 enzyme are presented, as well as an MD simulation for optimizing linker length in phospholipid-based prodrugs. Molecular docking investigating quinazolinone prodrugs as substrates for alkaline phosphatase is also presented, as well as QM and MD simulations used for optimal fit of different prodrugs within the human carboxylesterase 1 catalytical site. Overall, high quality computational simulations may show good agreement with experimental results, and should be used early in the prodrug development process.
Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Molecular Docking Simulation; Molecular Dynamics Simulation; Prodrugs; Protein Binding
PubMed: 32443905
DOI: 10.3390/ijms21103621 -
Molecules (Basel, Switzerland) Sep 2018Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable... (Review)
Review
Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.
Topics: Amino Acids; Animals; Biological Availability; Drug Development; Humans; Prodrugs
PubMed: 30208629
DOI: 10.3390/molecules23092318 -
Journal of Medicinal Chemistry Mar 2018The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this... (Review)
Review
The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.
Topics: Animals; Chemistry, Pharmaceutical; Humans; Nucleosides; Prodrugs; Structure-Activity Relationship
PubMed: 28792763
DOI: 10.1021/acs.jmedchem.7b00734 -
Trends in Pharmacological Sciences Nov 2014Despite the rapid developments in nanotechnology and biomaterials, the efficient delivery of chemotherapeutic agents is still challenging. Prodrug-based nanoassemblies... (Review)
Review
Despite the rapid developments in nanotechnology and biomaterials, the efficient delivery of chemotherapeutic agents is still challenging. Prodrug-based nanoassemblies have many advantages as a potent platform for anticancer drug delivery, such as improved drug availability, high drug loading efficiency, resistance to recrystallization upon encapsulation, and spatially and temporally controllable drug release. In this review, we discuss prodrug-based nanocarriers for cancer therapy, including nanosystems based on polymer-drug conjugates, self-assembling small molecular weight prodrugs and prodrug-encapsulated nanoparticles (NPs). In addition, we discuss new trends in the field of prodrug-based nanoassemblies that enhance the delivery efficiency of anticancer drugs, with special emphasis on smart stimuli-triggered drug release, hybrid nanoassemblies, and combination drug therapy.
Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Prodrugs
PubMed: 25441774
DOI: 10.1016/j.tips.2014.09.008 -
Journal of Labelled Compounds &... May 2024Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has...
Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.
Topics: Quinolones; Deuterium; Chemistry Techniques, Synthetic; Prodrugs; Antimalarials
PubMed: 38661253
DOI: 10.1002/jlcr.4092 -
ACS Nano Sep 2022Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted to parent drugs and induce the... (Review)
Review
Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted to parent drugs and induce the mechanism of action. The development of prodrugs has upgraded conventional drug treatments in terms of bioavailability, targeting, and reduced side effects. Especially in cancer therapy, the application of prodrugs has achieved substantial therapeutic effects. From serendipitous discovery in the early stage to functional design with pertinence nowadays, the importance of prodrugs in drug design is self-evident. At present, studying stimuli-responsive activation mechanisms, regulating the stimuli intensity , and designing nanoscale prodrug formulations are the major strategies to promote the development of prodrugs. In this review, we provide an outlook of recent cutting-edge studies on stimuli-responsive prodrug nanosystems from these three aspects. We also discuss prospects and challenges in the future development of such prodrugs.
Topics: Biological Availability; Drug Delivery Systems; Drug Design; Humans; Neoplasms; Prodrugs
PubMed: 36048467
DOI: 10.1021/acsnano.2c05379 -
Journal of Pharmacy & Pharmaceutical... Feb 2016Prodrugs are the pharmacologically inactive derivatives of active drugs typically intended to optimize the exposure of active drug at target site, through manipulation... (Review)
Review
Prodrugs are the pharmacologically inactive derivatives of active drugs typically intended to optimize the exposure of active drug at target site, through manipulation of its physicochemical, biopharmaceutical or pharmacokinetic properties. This approach has a number of advantages over conventional drug administration. Antiinfective agents are associated with number of limitations, responsible for their reduced bioavailability. Various antiinfective prodrugs have been synthesized with reduced side effects and improved pharmacological properties. The present paper illustrates different vistas of prodrug approach of antiinfective agents describing brief classification, synthetic approaches, pharmacological aspects and recent patents. It is a very productive area of research and its prologue in human therapy has given triumphant outcomes in improving the clinical and therapeutic effectiveness of drugs.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Anti-Infective Agents; Biological Availability; Communicable Diseases; Humans; Prodrugs
PubMed: 27096695
DOI: 10.18433/J3X61S -
Infectious Disorders Drug Targets 2016Quinolones and fluoroquinolones are principal weapons against variety of bacterial infections and exert their antibacterial potential by interfering the activities of... (Review)
Review
Quinolones and fluoroquinolones are principal weapons against variety of bacterial infections and exert their antibacterial potential by interfering the activities of bacterial enzymes. As these agents are associated with some limitations, an important approach to overcome these major constraints is to prepare covalent derivatives, i.e. prodrugs. Prodrug design has been employed to improve the limitations of these drugs such as less aqueous solubility, poor absorption and distribution, toxicity, disagreeable taste, poor lipophilicity etc and for improving their pharmacological profile. This paper highlights the utility of various prodrug strategies in optimizing the therapeutic index of these antibacterial agents and their recent patents. Some of their prodrugs being utilized at preclinical and clinical levels have also been discussed. Hence, this paper has been prepared to present the significant findings of various research papers that would be helpful in motivating scientific researchers to forward the research in direction of utilization of prodrugs in clinical therapy.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Design; Fluoroquinolones; Humans; Prodrugs; Quinolones; Solubility
PubMed: 27558786
DOI: 10.2174/1871526516666160824153226 -
The AAPS Journal Sep 2014Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in... (Review)
Review
Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.
Topics: Animals; Antineoplastic Agents; Biotransformation; Drug Design; Enzyme Therapy; Humans; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Prodrugs; Protein Engineering; Recombinant Proteins; Structure-Activity Relationship
PubMed: 25004822
DOI: 10.1208/s12248-014-9638-z -
Journal of Drug Targeting 2015Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to... (Review)
Review
UNLABELLED
Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent on
NAD(P)H
quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Design; Humans; Maximum Tolerated Dose; NAD(P)H Dehydrogenase (Quinone); Nanoparticles; Nanotechnology; Naphthoquinones; Neoplasms; Prodrugs
PubMed: 26453163
DOI: 10.3109/1061186X.2015.1073296