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Current Opinion in Chemical Biology Apr 2023The rise of supramolecular chemistry offers new tools to design therapeutics and delivery platforms for biomedical applications. This review aims to highlight the recent... (Review)
Review
The rise of supramolecular chemistry offers new tools to design therapeutics and delivery platforms for biomedical applications. This review aims to highlight the recent developments that harness host-guest interactions and self-assembly to design novel supramolecular Pt complexes as anticancer agents and drug delivery systems. These complexes range from small host-guest structures to large metallosupramolecules and nanoparticles. These supramolecular complexes integrate the biological properties of Pt compounds and novel supramolecular structures, which inspires new designs of anticancer approaches that overcome problems in conventional Pt drugs. Based on the differences in Pt cores and supramolecular structures, this review focuses on five different types of supramolecular Pt complexes, and they include host-guest complexes of the FDA-approved Pt(II) drugs, supramolecular complexes of nonclassical Pt(II) metallodrugs, supramolecular complexes of fatty acid-like Pt(IV) prodrugs, self-assembled nanotherapeutics of Pt(IV) prodrugs, and self-assembled Pt-based metallosupramolecules.
Topics: Humans; Prodrugs; Platinum; Drug Delivery Systems; Antineoplastic Agents; Neoplasms
PubMed: 36878171
DOI: 10.1016/j.cbpa.2023.102276 -
Advanced Drug Delivery Reviews Feb 2016Whereas protease inhibitors have been developed successfully against hypertension and viral infections, they have failed thus far as cancer drugs. With advances in... (Review)
Review
Whereas protease inhibitors have been developed successfully against hypertension and viral infections, they have failed thus far as cancer drugs. With advances in cancer profiling we now better understand that the tumor "degradome" (i.e. the repertoire of proteases and their natural inhibitors and interaction partners) forms a complex network in which specific nodes determine the global outcome of manipulation of the protease web. However, knowing which proteases are active in the tumor micro-environment, we may tackle cancers with the use of Protease-Activated Prodrugs (PAPs). Here we exemplify this concept for metallo-, cysteine and serine proteases. PAPs not only exist as small molecular adducts, containing a cleavable substrate sequence and a latent prodrug, they are presently also manufactured as various types of nanoparticles. Although the emphasis of this review is on PAPs for treatment, it is clear that protease activatable probes and nanoparticles are also powerful tools for imaging purposes, including tumor diagnosis and staging, as well as visualization of tumor imaging during microsurgical resections.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Neoplasms; Peptide Hydrolases; Prodrugs
PubMed: 26756735
DOI: 10.1016/j.addr.2015.12.020 -
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 -
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 -
European Journal of Medicinal Chemistry Jan 2018Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as... (Review)
Review
Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as intentions for toxicity reduction and structure-activity relationship (SAR) studying. Hybrid system of colchicine structure with nontoxic biofunctional compounds modified further affords a new entity in chemical structure with enhanced activity and selectivity. Moreover, nanocarrier formulation strategies have been used for colchicine delivery. This review paper focuses on colchicine nanoformulation, chemical synthesis of colchicine prodrugs and codrugs with different linkers, highlights linker chemical nature and biological activity of synthesized compounds. Additionally, classification of colchicine prodrugs based on type of conjugates is discussed, as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug and bioconjugate prodrug. Finally, we briefly summarized the biological importance of colchicine nanoformulation, colchicine prodrugs and codrugs.
Topics: Animals; Colchicine; Drug Design; Humans; Mitosis; Prodrugs; Structure-Activity Relationship; Tubulin Modulators
PubMed: 29274490
DOI: 10.1016/j.ejmech.2017.12.029 -
Pharmacological Reports : PR 2013It is estimated that about 10% of the drugs approved worldwide can be classified as prodrugs. Prodrugs, which have no or poor biological activity, are chemically... (Review)
Review
It is estimated that about 10% of the drugs approved worldwide can be classified as prodrugs. Prodrugs, which have no or poor biological activity, are chemically modified versions of a pharmacologically active agent, which must undergo transformation in vivo to release the active drug. They are designed in order to improve the physicochemical, biopharmaceutical and/or pharmacokinetic properties of pharmacologically potent compounds. This article describes the basic functional groups that are amenable to prodrug design, and highlights the major applications of the prodrug strategy, including the ability to improve oral absorption and aqueous solubility, increase lipophilicity, enhance active transport, as well as achieve site-selective delivery. Special emphasis is given to the role of the prodrug concept in the design of new anticancer therapies, including antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT).
Topics: Antibodies; Antineoplastic Agents; Biological Transport, Active; Drug Delivery Systems; Drug Design; Enzymes; Genetic Therapy; Humans; Prodrugs
PubMed: 23563019
DOI: 10.1016/s1734-1140(13)70959-9 -
Molecules (Basel, Switzerland) Oct 2017: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for... (Review)
Review
: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. : The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. : Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. : Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned.
Topics: Antiviral Agents; Cell Differentiation; Humans; Molecular Structure; Nucleosides; Nucleotides; Prodrugs
PubMed: 29035325
DOI: 10.3390/molecules22101736 -
International Journal of Molecular... May 2016Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor... (Review)
Review
Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.
Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Humans; Paclitaxel; Prodrugs; Small Molecule Libraries; Solubility; Structure-Activity Relationship
PubMed: 27223283
DOI: 10.3390/ijms17050796 -
Journal of Enzyme Inhibition and... Dec 2023Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique... (Review)
Review
Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn.
Topics: Humans; Prodrugs; Esters; Multiple Myeloma; Boronic Acids; Boron Compounds
PubMed: 37318308
DOI: 10.1080/14756366.2023.2220084 -
Bioorganic & Medicinal Chemistry Letters Jun 2022Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma...
Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma stability and nontoxic amino acid metabolites. However, the efficiency of bis-amidate prodrug forms is unclear, as prior studies on this class of prodrugs have not evaluated their activation kinetics. Here, we synthetized a small panel of bis-amidate prodrugs of butyrophilin ligands as potential immunotherapy agents. These compounds were examined relative to other prodrug forms delivering the same payload for their stability in plasma and cell lysate, their ability to stimulate T cell proliferation in human PBMCs, and their activation kinetics in a leukemia co-culture model of T cell cytokine production. The bis-amidate prodrugs demonstrate high plasma stability and improved cellular phosphoantigen activity relative to the free phosphonic acid. However, the efficiency of bis-amidate activation is low relative to other prodrugs that contain at least one ester such as aryl-amidate, aryl-acyloxyalkyl ester, and bis-acyloxyalkyl ester forms. Therefore, bis-amidate prodrugs do not drive rapid cellular payload accumulation and they would be more useful for payloads in which slower, sustained-release kinetics are preferred.
Topics: Esters; Humans; Ligands; Lymphocyte Activation; Organophosphonates; Prodrugs
PubMed: 35405283
DOI: 10.1016/j.bmcl.2022.128724