5006-67-7

Usage

InChI:InChI=1/C5H7N3O3/c9-4-3-7-2-1-6-5(7)8(10)11/h1-2,9H,3-4H2

Upstream product

• 527-73-1 2-nitro-1H-imidazole 
• 96388-83-9 2-tetrahydropyranyloxy-1-iodoethane 
• 540-51-2 2-bromoethanol 
• 22813-31-6 methyl 2-(2-nitro-1H-imidazole-1-yl)acetate 
• 1569296-90-7 2-nitro-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-imidazole 

Downstream Products

• 22813-32-7 2-(2-nitro-1H-imidazol-1-yl)acetic acid 
• 154094-89-0 N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-2-(2-nitro-1H-imidazolyl)ethanamide 

Relevant academic research and scientific papers

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

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.

In Vivo Ester Hydrolysis as a New Approach in Development of Positron Emission Tomography Tracers for Imaging Hypoxia

Hypoxia is an important biochemical and physiological condition associated with uncontrolled growth of tumor. Measurement of hypoxia in tumor tissue may be useful in characterization of tumor progression and monitoring drug treatment. [18F]FMISO is the most widely employed radiotracer for imaging of hypoxic tissue with positron emission tomography (PET). However, it showed relatively low uptake in hypoxic tissues, which led to low target-to-background contrast in PET images. To overcome these shortcomings, two novel 2-fluoroproprioic acid esters, nitroimidazole derivatives 2-fluoropropionic acid 2-(2-nitro-imidazol-1-yl)-ethyl ester (FNPFT, [19F]5) and 2-fluoropropionic acid 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester (FMNPFT, [19F]8), were prepared and tested. Radiolabeling of [18F]5 and [18F]8 was accomplished in 45 min (radiochemical purity >95%, the decay-corrected radiochemical yield of [18F]5 was 11 ± 2%, and that of [18F]8 was 13 ± 2%, n = 5). In vitro cell uptake studies using EMT-6 tumor cells showed that both radiotracers [18F]5 and [18F]8 displayed significantly higher uptake in hypoxic cells than those under normoxic condition, while 2-[18F]fluoropropionic acid (2-[18F]FPA) displayed no difference. Biodistribution studies in mice bearing EMT-6 tumor showed that [18F]5, [18F]8, and 2-[18F]FPA displayed similar tumor and major organ uptakes. Tumor uptake values for all three agents were higher than those of [18F]FMISO, respectively (P a rapid in vivo hydrolysis of [18F]5 and [18F]8 to their metabolite, 2-[18F]FPA. Micro PET imaging studies in the same EMT-6 implanted mice tumor model also demonstrated that both [18F]5 and [18F]8 displayed similar tumor uptake comparable to that of 2-[18F]FPA. In conclusion, two new fluorine-18 labeled nitroimidazole derivatives, [18F]5 and [18F]8, showed good tumor uptakes in mice bearing EMT-6 tumor. However, in vivo biodistribution results suggested that they were more likely reflect the predominance of in vivo produced metabolite, 2-[18F]FPA, which may not be related to tumor hypoxic condition.

Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis, cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC50 6.78 μM and 5.25 μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC50 0.76 μM.

KRAS G12D INHIBITORS

The present invention relates to compounds that inhibit KRas G12D. In particular, the present invention relates to compounds that inhibit the activity of KRas G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.

In Vivo Ester Hydrolysis as a New Approach in Development of Positron Emission Tomography Tracers for Imaging Hypoxia

Hypoxia is an important biochemical and physiological condition associated with uncontrolled growth of tumor. Measurement of hypoxia in tumor tissue may be useful in characterization of tumor progression and monitoring drug treatment. [18F]FMISO is the most widely employed radiotracer for imaging of hypoxic tissue with positron emission tomography (PET). However, it showed relatively low uptake in hypoxic tissues, which led to low target-to-background contrast in PET images. To overcome these shortcomings, two novel 2-fluoroproprioic acid esters, nitroimidazole derivatives 2-fluoropropionic acid 2-(2-nitro-imidazol-1-yl)-ethyl ester (FNPFT, [19F]5) and 2-fluoropropionic acid 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester (FMNPFT, [19F]8), were prepared and tested. Radiolabeling of [18F]5 and [18F]8 was accomplished in 45 min (radiochemical purity >95%, the decay-corrected radiochemical yield of [18F]5 was 11 ± 2%, and that of [18F]8 was 13 ± 2%, n = 5). In vitro cell uptake studies using EMT-6 tumor cells showed that both radiotracers [18F]5 and [18F]8 displayed significantly higher uptake in hypoxic cells than those under normoxic condition, while 2-[18F]fluoropropionic acid (2-[18F]FPA) displayed no difference. Biodistribution studies in mice bearing EMT-6 tumor showed that [18F]5, [18F]8, and 2-[18F]FPA displayed similar tumor and major organ uptakes. Tumor uptake values for all three agents were higher than those of [18F]FMISO, respectively (P a rapid in vivo hydrolysis of [18F]5 and [18F]8 to their metabolite, 2-[18F]FPA. Micro PET imaging studies in the same EMT-6 implanted mice tumor model also demonstrated that both [18F]5 and [18F]8 displayed similar tumor uptake comparable to that of 2-[18F]FPA. In conclusion, two new fluorine-18 labeled nitroimidazole derivatives, [18F]5 and [18F]8, showed good tumor uptakes in mice bearing EMT-6 tumor. However, in vivo biodistribution results suggested that they were more likely reflect the predominance of in vivo produced metabolite, 2-[18F]FPA, which may not be related to tumor hypoxic condition.

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.

Hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol

The invention discloses a hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol. The 2-nitroimidazole-1-alkanol of the prodrug is connected to an antineoplastic drug through a carbonate bond. The prodrug has a structure shown in the formula I and

NITROIMIDAZOLE COMPOUNDS AND THEIR USE IN CANCER THERAPY

The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, formula (I) wherein m, n, X, Y and Z are as defined herein. Also provided are pharmaceutical compositions containing compounds of Formula (I), and methods of treating cancer and/or improving the response of tumors to radiotherapy by administering a compound of Formula (I) to a warm-blooded animal.

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: A new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitisers

A series of novel bis(nitroimidazolyl)alkanecarboxamides has been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitisation in vitro and in vivo. The compounds were prepared by direct coupling of preformed side chain acid and amine components, using diethyl phosphorocyanidate at room temperature. Although designed to be bis- bioreductive prodrugs of DNA cross-linking agents, none of the compounds showed evidence of DNA cross-linking activity, being equally potent against cell lines deficient and proficient in repair of cross-links. However, one of these compounds, N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-4-(2-nitro-1H- imidazolyl)butanamide (10; SN 24699), showed high hypoxic selectivity as a cytotoxin (rising to 200-fold after exposure to the drug for several hours) in the repair-proficient Chinese hamster cell line AA8. This selectivity was greater than observed for the alkylating 2-nitroimidazole (4; RB 6145) (40- fold) or simple mononitroimidazoles (5-25-fold). Investigation of structure- activity relationships for hypoxic selectivity of bis(nitroimidzoles) was restricted by their low aqueous solubility, but a certain minimum separation of the two nitroimidazole units (by more than five atoms) appears desirable. All the compounds radiosensitized hypoxic cells in vitro but were little more potent as radiosensitizers than the corresponding monomeric nitroimidazoles. Compound 10 caused additional cell killing in the KHT tumor when multiple drug doses were administered in combination with a single dose of radiation. It is not yet clear whether this activity reflects hypoxic cell radiosensitization or cytotoxicity toward hypoxic cells, but this new class of bis-bioreductive agent clearly warrants further investigation.

Synthesis of Potential Dual-Acting Radiation Sensitizer Antineoplastic Agents: 2,2-Dimethylphosphoraziridines Containing 2-Nitroimidazoles or Other Electron-Affinic Moieties

In view of the in vivo demonstrated radiation-potentiating activities of several previously studied 2,2-dimethylphosphoraziridines, six new compounds incorporating the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety, together with an electron-affinic grou