Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis of New Branched 2-Nitroimidazole as a Hypoxia Sensitive Linker for Ligand-Targeted Drugs of Paclitaxel.

ABSTRACT: Because of the low selectivity and efficiency of normal antitumor agents, the strategy of ligand-targeted drugs was put forward. In this paper, we designed and synthesized a new bioreductive linker based on 2-nitroimidazole, which was used in three paclitaxel (PTX) prodrugs. The drug release mechanism via six-membered ring was demonstrated by chemical reduction and nitroreductase assay. Glucose and acetazolamide, which have been reported widely as ligands, were attached to compound 7 to afford Glu-PTX and AZO-PTX. The prodrugs were considerably stable in phosphate-buffered saline (pH 7.4) and plasma. What is more, PTX releasing could be triggered by nitroreductase rapidly. In in vitro cytotoxicity assay, the prodrugs exhibited moderate selectivity toward hypoxic tumor cells. We considered that the 2-nitroimidazole linker could accelerate the release of prodrugs under hypoxic condition. It was promising in the development of ligand-targeted drugs.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6644517 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis of New Branched 2-Nitroimidazole as a Hypoxia Sensitive Linker for Ligand-Targeted Drugs of Paclitaxel.

Zhang Qiumeng Q Jin Chen C Yu Jiahui J Lu Wei W

ACS omega 20180808 8

Because of the low selectivity and efficiency of normal antitumor agents, the strategy of ligand-targeted drugs was put forward. In this paper, we designed and synthesized a new bioreductive linker based on 2-nitroimidazole, which was used in three paclitaxel (PTX) prodrugs. The drug release mechanism via six-membered ring was demonstrated by chemical reduction and nitroreductase assay. Glucose and acetazolamide, which have been reported widely as ligands, were attached to compound <b>7</b> to a ...[more]

PMID: 31459014

Similar Datasets

Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2-Nitroimidazole.

Project description:Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.

| S-EPMC5512130 | biostudies-literature

Design, synthesis, and validation of a branched flexible linker for bioactive peptides.

Project description:A branched flexible linker that incorporates a fluorescent dansyl moiety was synthesized and used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The linker was incorporated into the conjugate by solid-phase synthesis. In vitro biological evaluations showed that potency of binding to the human melanocortin 4 receptor was not diminished for linker-ligand combinations relative to the corresponding ligand alone.

| S-EPMC3538035 | biostudies-literature

Neutrophil Elastase Promotes Linker Cleavage and Paclitaxel Release from an Integrin-Targeted Conjugate.

Project description:This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte-secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found to accumulate on the surface of ?v ?3 integrin-expressing human renal cell carcinoma 786-O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is a substrate of neutrophil-secreted elastase. In?vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor-targeting conjugate, opening the way to potential therapeutic applications.

| S-EPMC6471013 | biostudies-literature

Design and Synthesis of Vandetanib Derivatives Containing Nitroimidazole Groups as Tyrosine Kinase Inhibitors in Normoxia and Hypoxia.

Project description:Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a-p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50 value (1.64 ?mol/L), the inhibition ratios of 16f over A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 ?M in hypoxia, respectively. All of these results indicated that 16f was a potential cancer therapeutic agent in hypoxia and was worthy of further development.

| S-EPMC6273768 | biostudies-literature

Synthesis and Biological Evaluation of a New Nitroimidazole-99mTc-Complex for Imaging of Hypoxia in Mice Model.

Project description:BACKGROUND This study was specifically designed to develop a new 99mTc compound with 3-amino-4-[2-(2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate (5-ntm-asp) and to verify whether this compound is feasible to be a radiopharmaceutical for hypoxic tumors. MATERIAL AND METHODS Metronidazole derivative 5-ntm-asp was synthesized and then radio-labeled by Na [99mTcO4], forming 99mTc-5-ntm-asp. Another two complexes of 99mTc-2- and 99mTc-5-nitroimidazole-iminodiacetic acid (99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA) were also synthesized based on previous studies. Physicochemical properties (stability, lipophilicity, protein binding) of the compounds were compared, and we also assessed the accumulation status of the compounds within A549 cells under both hypoxic and aerobic conditions. Distribution of the complex was also studied in vivo using BALB/c nude mice that were injected with A549 cells. RESULTS Compared with 99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, 99mTc-5-ntm-asp was more stable in both phosphate-buffered saline (PBS) buffer and human plasma (P<0.05). Besides that, 99mTc-5-ntm-asp offered lower lipophilicity and protein-binding rate than the two complexes (P<0.05). During assessment of hypoxic uptake status and high hypoxic/aerobic ratio in mice injected with A549 cells, 99mTc-5-ntm-asp exhibited a more favorable profile than 9mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, including uptake ratio of tumor/blood and uptake ratio of tumor/muscle. CONCLUSIONS With overall consideration of physicochemical properties and biological uptake behavior, it is feasible to use 99mTc-5-ntm-asp as an imaging agent for tumor hypoxia.

| S-EPMC5072380 | biostudies-literature

Synthesis and characterization of a hypoxia-sensitive MRI probe.

Project description:Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with a 2-nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia-sensitive MRI agent. A control complex, Gd(DO3A-monobutylamide), was also prepared in order to test whether the nitroimidazole side-chain alters either the water proton T(1) relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)(-) as expected for mono-amide derivatives. The water proton T(1) relaxivity (r(1)), bound water residence lifetime (?(M)) and rotational correlation time (?(R)) of both complexes was determined by relaxivity measurements, variable temperature (17) O?NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r(1) =6.38?mM(-1) ?s(-1) at 20?MHz, ?(M) =0.71??s, ?(R) =141?ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A-monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N(2) as evidenced by an approximately twofold decrease in T(1) measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.

| S-EPMC3518072 | biostudies-literature

Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers.

Project description:The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.

| S-EPMC10254852 | biostudies-literature

Targeted delivery of paclitaxel to tumor cells: synthesis and in vitro evaluation.

Project description:We previously reported a novel drug delivery system, drug-linker-Phe-Phe-Arg-methylketone (FFR-mk)-factor VIIa (fVIIa). The method utilizes tissue factor (TF), which is aberrantly and abundantly expressed on many cancer cells. The advantage of this delivery system is its ability to furnish a potent anticancer drug specifically to the tumor vasculature and cancer cells. In this paper, we describe the synthesis of paclitaxel (PTX)-Phe-Phe-Arg-chloromethyl ketone (FFR-ck), followed by coupling with fVIIa to form PTX-FFR-mk-fVIIa. FFRck was separately linked to the OH groups at the C2' or C7 positions of PTX (C2'- or C7-PTX-FFRck), the C2' analogue exhibiting better activity against human head and neck squamous KB 3-1 cells. The activity order against PTX-sensitive KB 3-1 cells is C2'-PTX-FFRmk-fVIIa > PTX > C2'-PTX-FFRck. The C2' complex shows an IC(50) of 12 nM against the PTX-sensitive cell line and 130 nM against PTX-resistant cells.

| S-EPMC2866085 | biostudies-literature

Biological reduction of nitroimidazole-functionalized gold nanorods for photoacoustic imaging of tumor hypoxia.

Project description:Tumor-selective accumulation of gold nanorods (GNR) has been demonstrated for visualization of tumor hypoxia by photoacoustic imaging. We prepared GNRs with hypoxia-targeting nitroimidazole units (G-NI) on their surface. Biological experiments revealed that G-NI produced a strong photoacoustic signal in hypoxic tumor cells and tissues.

| S-EPMC9064429 | biostudies-literature

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

Project description:The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.

| S-EPMC5356508 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data