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European Journal of Medicinal Chemistry May 2017Triterpenoids are structurally diverse organic compounds that exist widely as natural products. Triterpenoids and their derivatives possess a wide range of biological... (Review)
Review
Triterpenoids are structurally diverse organic compounds that exist widely as natural products. Triterpenoids and their derivatives possess a wide range of biological effects including hepatoprotective, hypoglycemic, immunomodulatory, anti-inflammatory, anti-oxidant, and antitumor activities. In particular, the lupane-, oleanane-, and ursane-type triterpenes have been reported to exhibit pharmacological effects without prominent toxicity even at higher concentrations. Whereas, the poor drug-like properties (e.g., low solubility and selectivity, poor bioavailability, and short half-life) severely limit their applications. This review summarized the advances in prodrug strategies for improving the drug-like properties of different types of triterpenoids, and the information indicated in the review will surely stimulate further efforts toward the development of these compounds for potential clinical uses.
Topics: Animals; Humans; Molecular Structure; Prodrugs; Terpenes
PubMed: 28329729
DOI: 10.1016/j.ejmech.2017.03.005 -
Chembiochem : a European Journal of... Sep 2023Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs... (Review)
Review
Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs through chemical or enzymatic cleavage. The prodrug approach holds tremendous potential to create the enhanced version of an existing pharmacological agent and leverage those improvements to augment the drug molecules' bioavailability, targeting ability, therapeutic efficacy, safety, and marketability. Especially in cancer therapy, prodrug application has received substantial attention. A prodrug can effectively broaden the therapeutic window of its parent drug by enhancing its release at targeted tumor sites while reducing its access to healthy cells. The spatiotemporally controlled release can be achieved by manipulating the chemical, physical, or biological stimuli present at the targeted tumor site. The critical strategy comprises drug-carrier linkages that respond to physiological or biochemical stimuli in the tumor milieu to yield the active drug form. This review will focus on the recent advancements in the development of various fluorophore-drug conjugates that are widely used for real-time monitoring of drug delivery. The use of different stimuli-cleavable linkers and the mechanisms of linker cleavage will be discussed. Finally, the review will conclude with a critical discussion of the prospects and challenges that might impede the future development of such prodrugs.
Topics: Humans; Prodrugs; Drug Delivery Systems; Drug Carriers; Neoplasms
PubMed: 37341379
DOI: 10.1002/cbic.202300155 -
Journal of Medicinal Chemistry Dec 2016Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their... (Review)
Review
Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.
Topics: Humans; Neoplasms; Nucleosides; Phosphates; Prodrugs; Virus Diseases
PubMed: 27559756
DOI: 10.1021/acs.jmedchem.6b00523 -
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 -
Chemical Society Reviews Nov 2023Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The... (Review)
Review
Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.
Topics: Prodrugs
PubMed: 37905601
DOI: 10.1039/d2cs00889k -
Drug Development Research Aug 2022The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and... (Review)
Review
The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and lead candidates. The "phosphate" is one of the key counterions/promoiety used in the salt formation and prodrug synthesis. Salification with phosphoric acid enhances the aqueous solubility and thereby facilitates the administration of a drug by the parenteral route. Phosphate moiety in prodrug synthesis mainly improves permeability by lipophilic substitution. Histamine phosphate is the first phosphate salt, and hydrocortisone phosphate was the first prodrug approved by FDA in 1939 and 1952, respectively. The orange book enlists 12 phosphate salts and 17 phosphate prodrugs. Phosphate prodrugs, namely combretastatin A-4 diphosphate, combretastatin A-4 phosphate, lufotrelvir, TP-1287, pyridoxal phosphate, riboflavin phosphate, and psilocybin are clinical candidates. This review focuses on the FDA-approved phosphate salts and prodrugs from 1939 to 2021. The biopharmaceutical advantage of phosphate salts and prodrugs over the parent molecule is also deliberated.
Topics: Indoles; Leucine; Phosphates; Prodrugs; Pyrrolidinones; Salts; Solubility
PubMed: 35656613
DOI: 10.1002/ddr.21953 -
Chemical Society Reviews Apr 2020Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate... (Review)
Review
Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate administration. Supramolecular chemistry is providing a new approach to developing prodrug-like systems, wherein the characteristics of a drug are modified in a beneficial manner by creating host-guest complexes that then permit the stimulus-induced release of the active species in a controlled manner. These complexes are termed "supramolecular prodrugs". In this review, we outline the concept of supramolecular drugs via host-guest chemistry and detail progress made in the area. This summary is designed to highlight the many advantages of supramolecular prodrugs, including ease-of-preparation, molecular-level protection, sensitive response to bio-stimuli, traceless release, and adaptability to different drugs. Limitations of the approach and opportunities for future growth are also detailed.
Topics: Biomarkers; Biotransformation; Oxidation-Reduction; Prodrugs
PubMed: 32181453
DOI: 10.1039/c9cs00622b -
Advanced Drug Delivery Reviews Sep 2017Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting prodrugs into drugs at the demanded time and space,... (Review)
Review
Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting prodrugs into drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization. The existing MEMs can be classified into three categories: catalytic core-scaffold MEM (csMEM), nanoparticle MEM (npMEMs) and metal-organic framework (MOF) MEM (mofMEM). These MEMs can mimic diverse functions corresponding to natural enzymes, and some of which are potentially used in prodrug activation, such as DNase, RNase, carbonate esterase, etc. In this review, we briefly summarize the MEMs according to their structure and composition, and highlight the successful and potential applications for prodrug activation mediated by hydrolase-like and oxidoreductase-like MEMs.
Topics: Enzyme Therapy; Humans; Hydrolases; Metals; Nanoparticles; Neoplasms; Oxidoreductases; Prodrugs
PubMed: 28412325
DOI: 10.1016/j.addr.2017.04.002 -
Advanced Drug Delivery Reviews Sep 2017Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This... (Review)
Review
Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs - individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner. This technology is also unique for site-specific synthesis of drugs with short half-life, such as nitric oxide. This review presents historical development of SMEPT from early reports to the most recent examples, and also outlines potential avenues for subsequent development of this platform.
Topics: Animals; Biocompatible Materials; Enzyme Therapy; Half-Life; Humans; Neoplasms; Prodrugs
PubMed: 28457884
DOI: 10.1016/j.addr.2017.04.013 -
Advanced Drug Delivery Reviews Sep 2017Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the... (Review)
Review
Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the drug is masked and is recovered within the human body upon bioconversion of the prodrug, a process that is typically mediated by enzymes. This concept is highly successful and a significant fraction of marketed therapeutic formulations is based on prodrugs. An advanced subset of prodrugs can be engineered such as to achieve site-specific bioconversion of the prodrug - to comprise the highly advantageous "enzyme prodrug therapy", EPT. Design of prodrugs for EPT is similar to the prodrugs in general medicinal use in that the pharmacological activity of the drug is masked, but differs significantly in that site-specific bioconversion is a prime consideration, and the enzymes typically used for EPT are non-mammalian and/or with low systemic abundance in the human body. This review focuses on the design of prodrugs for EPT in terms of the choice of an enzyme and the corresponding prodrug for bioconversion. We also discuss the recent success of "self immolative linkers" which significantly empower and diversify the prodrug design, and present methodologies for the design of prodrugs with extended blood residence time. The review aims to be of specific interest for medicinal chemists, biomedical engineers, and pharmaceutical scientists.
Topics: Animals; Chemistry, Pharmaceutical; Drug Design; Enzyme Therapy; Humans; Prodrugs
PubMed: 28676386
DOI: 10.1016/j.addr.2017.06.013