-
Chembiochem : a European Journal of... Dec 2023Various chemical modifications have been developed to create new antisense oligonucleotides (AONs) for clinical applications. Our previously designed prodrug-type...
Various chemical modifications have been developed to create new antisense oligonucleotides (AONs) for clinical applications. Our previously designed prodrug-type phosphotriester-modified oligonucleotide with cyclic disulfides (cyclic SS PTE ON) can be converted into unmodified ON in an intracellular-mimetic reducing environment. However, the conversion rate of the cyclic SS PTE ON was very low, and the AON with cyclic SS PTE modifications showed much weaker antisense activity than corresponding to the fully phosphorothioate-modified AON. In this study, we synthesized several types of PTE ONs containing linear disulfides (linear SS PTE ONs) and evaluated their conversion rates under reducing conditions. From the results, the structural requirements for the conversion of the synthesized linear SS PTE ONs were elucidated. Linear SS PTE ON with promising promoieties showed a nuclease resistance up to 4.8-fold compared to unmodified ON and a cellular uptake by endocytosis without any transfection reagent. In addition, although the knockdown activity of the linear SS PTE gapmer AON is weaker than that of the fully phosphorothioate-modified gapmer AON, the knockdown activity is slightly stronger than that of the cyclic SS PTE gapmer AON. These results suggest that the conversion rates may be related to the expression of the antisense activity.
Topics: Oligonucleotides; Prodrugs; Disulfides; Oligonucleotides, Antisense; Transfection
PubMed: 37840006
DOI: 10.1002/cbic.202300526 -
Current Topics in Medicinal Chemistry 2011D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach... (Review)
Review
D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.
Topics: Animals; Drug Carriers; Drug Design; Galactose; Humans; Prodrugs; Tissue Distribution
PubMed: 21671867
DOI: 10.2174/156802611797183258 -
European Journal of Medicinal Chemistry 2001Systemic cytotoxic (anti-proliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One... (Review)
Review
Systemic cytotoxic (anti-proliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumour cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumour tissue (tumour-activated prodrugs; TAP). There are several mechanisms potentially exploitable for selective activation. Some utilise unique aspects of tumour physiology such as selective enzyme expression, hypoxia, and low extracellular pH. Others are based on tumour-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumour cells via monoclonal antibodies (ADEPT), or generated in tumour cells from DNA constructs containing the corresponding gene (GDEPT). Because only a small proportion of the tumour cells may be competent to activate the prodrug, whichever activating mechanism is used, TAP need to be capable of killing activation-incompetent cells as well via a "bystander effect", in order to fully exploit these "activator" cells. A wide variety of chemistries have been explored for the selective activation of TAP. These include reduction of quinones, N-oxides, nitroaromatics and metal complexes by endogenous enzymes or radiation, amide cleavage by endogenous peptidases, and metabolism by a variety of exogenous enzymes, including phosphatases, kinases, amidases and glycosidases.
Topics: Animals; Antineoplastic Agents; Drug Design; Enzymes; Epitopes; Humans; Neoplasms; Prodrugs
PubMed: 11600229
DOI: 10.1016/s0223-5234(01)01253-3 -
Biomaterials Science Jan 2023The combination of chemodynamic therapy (CDT) and chemotherapy has shown promise for achieving improved cancer treatment outcomes. However, due to the lack of synergy...
The combination of chemodynamic therapy (CDT) and chemotherapy has shown promise for achieving improved cancer treatment outcomes. However, due to the lack of synergy rationale, a simple one-plus-one combination therapy remains suboptimal in overcoming the obstacles of each treatment approach. Herein, we report a nanoplatform consisting of a pH-sensitive ferrocene- and cinnamaldehyde-based polyprodrug and a hydrogen peroxide-responsive doxorubicin (DOX) prodrug. Under an acidic tumor environment, the cinnamaldehyde polyprodrug will be activated to release free cinnamaldehyde, which can increase the intracellular hydrogen peroxide level and enhance the Fenton reaction. Subsequently, due to the collapse of nanoparticle structures, the DOX prodrug will be released and activated under a hydrogen peroxide stimulus. Meanwhile, the quinone methide produced during DOX prodrug activation can consume glutathione, an important antioxidant, and thus in turn enhance the efficacy of CDT. This design of a nanoplatform with dual-prodrug cascade activation provides a promising mutually beneficial cooperation mode between chemotherapy and CDT for enhancing antitumor efficacy.
Topics: Humans; Prodrugs; Hydrogen Peroxide; Doxorubicin; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 36562486
DOI: 10.1039/d2bm01627c -
Current Medicinal Chemistry 2006The main threshold for the therapeutic applications of nucleotides and oligonucleotides is their ionic structure which implies poor cellular uptake and unfavorable... (Review)
Review
The main threshold for the therapeutic applications of nucleotides and oligonucleotides is their ionic structure which implies poor cellular uptake and unfavorable pharmacokinetic parameters. To circumvent these problems, the anionic phosphate moieties may be temporarily masked with enzymolabile protecting groups to form neutral pronucleotides or pro-oligonucleotides. In cells, enzymes cleave the protecting groups and release the parent drug. Several prodrug strategies have been developed, but the kinetics and mechanisms of the deprotection of potential prodrug candidates are still often poorly known. The purpose of the present review is to summarize the current knowledge on the chemical aspects of alternative prodrug strategies at nucleotide and oligonucleotide level.
Topics: Animals; Nucleotides; Oligonucleotides; Prodrugs
PubMed: 17168716
DOI: 10.2174/092986706779010270 -
Current Drug Metabolism Jul 2000Some antitumor agents encapsulated in liposomes have been used clinically. However, the usefulness of liposomes is limited to the liposomalization of active compounds.... (Review)
Review
Some antitumor agents encapsulated in liposomes have been used clinically. However, the usefulness of liposomes is limited to the liposomalization of active compounds. Irinotecan hydrochloride (CPT-11) is a prodrug of closed lactone ring form of SN-38, which is an active metabolite with antitumor and side toxicity. The plasma concentrations of closed CPT-11 and SN-38 increased with the liposomalization, and their blood circulation was prolonged by the polyethyleneglycol (PEG) modification. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of closed CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. The closed/total ratio of SN-38 in the tumors of the liposomes group was greater than that of the CPT-11 solution group. Namely, SN-38 was thought to be generated in intact liposomes containing CPT-11. The generation of SN-38 in the liposomal membrane was shown after the incubation of liposome containing CPT-11 with carboxylesterase. It is therefore considered that part of CPT-11 is converted to SN-38 in intact liposomes. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased to depend on the closed SN-38 concentrations in the bile by liposomalization. Although the liposomes induce the improved tissue distribution of the prodrug, the tissue distribution of active metabolites do not always improve. However, CPT-11 entrapped liposome was useful.
Topics: Animals; Biotransformation; Drug Carriers; Humans; Liposomes; Prodrugs
PubMed: 11467079
DOI: 10.2174/1389200003339225 -
Expert Opinion on Drug Delivery Feb 2010Generally, a prodrug, a pharmacologically inactive derivative of an active drug, is designed to modulate pharmacokinetic properties of the parent drug. Targeted... (Review)
Review
IMPORTANCE OF THE FIELD
Generally, a prodrug, a pharmacologically inactive derivative of an active drug, is designed to modulate pharmacokinetic properties of the parent drug. Targeted distribution of an orally administered drug at the large intestine confers therapeutic advantages on treatment of colonic diseases, peptide and protein therapy and chronotherapy.
AREAS COVERED IN THIS REVIEW
To achieve such distribution control in the gastrointestinal tract, the adoption of the prodrug concept gives birth to a colon-specific prodrug. The requirement for a prodrug to be colon-specific is described along with the necessary and sufficient conditions of drugs for conversion to a colon-specific prodrug. The known and previously unnoticed factors that negatively influence therapeutic activity and reproducibility of a colon-specific prodrug are presented with suggestions to minimize the negative influence.
WHAT THE READER WILL GAIN
This review provides tactics to satisfy the requirements for being colon-specific and the potential strategies to circumvent obstacles in developing an efficient colon-specific prodrug.
TAKE HOME MESSAGE
On design of a colon-specific prodrug, one should take into consideration not only delivery of a drug to the target site, but also the therapeutic effectiveness there.
Topics: Administration, Oral; Chemistry, Pharmaceutical; Colon; Drug Delivery Systems; Drug Design; Humans; Molecular Structure; Prodrugs
PubMed: 20095945
DOI: 10.1517/17425240903490401 -
Journal of Pineal Research Mar 2009Melatonin is easily nitrosated via various mechanisms at the nitrogen atom of the indole ring to give N-nitrosomelatonin (NOMela). This mini-review provides a... (Review)
Review
Melatonin is easily nitrosated via various mechanisms at the nitrogen atom of the indole ring to give N-nitrosomelatonin (NOMela). This mini-review provides a comprehensive view of this N-nitroso compound. With an improved procedure NOMela can now economically synthesized with low laboratory expenditure. The major chemical property of NOMela, i.e. the (formally) transfer of the NO+ function to its target nucleophile, is explained in detail and a variety of detection methods using this reaction are suggested. As the suspected carcinogenical potential of NOMela is clearly overruled it seems attractive to apply this nitroso compound for endogenous generation of S-nitrosothiols that act as nitric oxide donors in vivo.
Topics: Melatonin; Nitroso Compounds; Prodrugs
PubMed: 19141085
DOI: 10.1111/j.1600-079X.2008.00655.x -
Zwitterionic rhodamine-CPT prodrug nanoparticles with GSH/HO responsiveness for cancer theranostics.Theranostics 2023Fluorescently traceable prodrugs, which can monitor their biodistribution and track the kinetics of drug delivery in living cells, are promising for constructing...
Fluorescently traceable prodrugs, which can monitor their biodistribution and track the kinetics of drug delivery in living cells, are promising for constructing theranostic medicines. However, due to their charge and hydrophobicity, most of the fluorescently traceable prodrugs exhibit high protein binding and non-specific tissue retention affecting distribution and toxicity, with high background signals. Herein, the zwitterionic rhodamine (RhB) and camptothecin (CPT) were bridged with a disulfide bond to construct a tumorous heterogeneity-activatable prodrug (RhB-SS-CPT). The interaction of zwitterionic RhB-SS-CPT with proteins was detected by UV and fluorescence spectroscopy, and further demonstrated by molecular docking studies. Then, intracellular tracking and cytotoxicity of RhB-SS-CPT were determined in tumor and normal cells. Finally, the biodistribution, pharmacokinetics, and anticancer efficacy of RhB-SS-CPT were evaluated in a mouse animal model. The tumorous heterogeneity-activatable RhB-SS-CPT prodrug can self-assemble into stable nanoparticles in water based on its amphiphilic structure. Particularly, the zwitterionic prodrug nanoparticles reduce the non-specific binding to generate a low background signal for better identification of cancerous lesions, achieve rapid internalization into cancer cells, selectively release bioactive CPT as a cytotoxic agent in response to high levels of GSH and HO, and exhibit high fluorescence that contributes to the visual chemotherapy modality. In addition, the RhB-SS-CPT prodrug nanoparticles show longer circulation time and better antitumor activity than free CPT . Interestingly, the zwitterionic nature allows RhB-SS-CPT to be excreted through the renal route, with fewer side effects. Zwitterionic features and responsive linkers are important considerations for constructing potent prodrugs, which provide some useful insights to design the next-generation of theranostic prodrugs for cancer.
Topics: Mice; Animals; Prodrugs; Hydrogen Peroxide; Camptothecin; Rhodamines; Tissue Distribution; Molecular Docking Simulation; Precision Medicine; Drug Delivery Systems; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 36593965
DOI: 10.7150/thno.78884 -
Journal of the American Chemical Society Jan 2023Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in targeting those so-called "undruggable" proteins....
Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in targeting those so-called "undruggable" proteins. However, the potential systemic toxicity of PROTACs caused by undesired off-tissue protein degradation may limit the application of PROTACs in clinical practice. Here we reported a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy to precisely and spatiotemporally control protein degradation through X-ray radiation. We demonstrated this concept by incorporating an X-ray inducible phenyl azide-cage to a bromodomain (BRD)-targeting PROTAC to form the first RT-PROTAC. The RT-PROTAC prodrug exhibits little activity but can be activated by X-ray radiation and . Activated RT-PROTAC degrades BRD4 and BRD2 with a comparable effect to the PROTAC degrader and shows a synergistic antitumor potency with radiotherapy in the MCF-7 xenograft model. Our work provides an alternative strategy to spatiotemporally control protein degradation and points to an avenue for reducing the undesired systemic toxicity of PROTACs.
Topics: Humans; Prodrugs; Nuclear Proteins; Proteolysis Targeting Chimera; Transcription Factors; Proteolysis; Neoplasms; Cell Cycle Proteins
PubMed: 36542856
DOI: 10.1021/jacs.2c10177