Development of a Safe and Efficient Two-Step Synthesis for Preparing 1-Bromoacetyl-3,3-dinitroazetidine, a Novel Clinical Anticancer Candidate

Straessler, Nicholas A.; Lesley, Michael W.; Cannizzo, Louis F.

doi:10.1021/op2003216

Cited by 18 publications

(11 citation statements)

References 22 publications

(51 reference statements)

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“…Like its closest chemical relative, the propellant, 1,3,3 trinitroazetidine (TNAZ) [5], (Figure 1(a)), RRx-001 is a readily synthesized [6], highly ring-strained nitroalkane possessing geminal dinitro groups. In RRx-001, also known by its chemical acronym, ABDNAZ, the dinitroazetidine scaffold from TNAZ displays a sulfhydryl-selective α-bromoacetyl functionality [7] ( Figure 1(b)) that forms stable adducts with reduced glutathione, a conserved cysteine 93 beta residue of hemoglobin, and, to a lesser extent, cysteine, via displacement of the bromide atom [8].…”

Section: Chemical Structurementioning

confidence: 99%

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

Oronsky

Paulmurugan

Foygel

et al. 2016

Expert Opinion on Investigational Drugs

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Section: Chemical Structurementioning

confidence: 99%

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

Oronsky

Paulmurugan

Foygel

et al. 2016

Expert Opinion on Investigational Drugs

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“…RRx-001 was obtained from ATK Aerospace Systems [ 10 ]. The synthesis and characterization of RRx-001 is reported in detail elsewhere [ 8 – 12 ].…”

Section: Methodsmentioning

confidence: 99%

Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

Ning

Sekar

Scicinski³

et al. 2015

Oncotarget

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making.

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“…The present reaction afforded the corresponding azetidine 11c in 76% yield as a 3.4:1 mixture of diastereomers . To complete the preparation of 3c , oxidative nitration of 11c was carried out with aqueous sodium hydroxide, sodium nitrite, potassium ferricyanide, and sodium persulfate in water, and the desired product 3c was obtained in 44% yield …”

Section: Resultsmentioning

confidence: 99%

Synthesis of Enantiopure 2‐Alkyl‐1,3,3‐Trinitroazetidines

Lee

Chang

et al. 2019

Bulletin Korean Chem Soc

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Enantiopure 2-alkyl-1,3,3-trinitroazetidines 4 were efficiently synthesized by the nitrolysis of enantiopure 2-alkyl-3,3-dinitro-1-tosylazetidines 3 using an excess of fuming nitric acid in CHCl 3 at ambient temperature. In addition, elaboration of (S)-2-(2-methoxyethyl)-1,3,3-trinitroazetidine (4c) was successfully performed to synthesize a variety of enantiopure 2-alkyl-1,3,3-trinitroazetidines 5-7. The advantage of this strategy is that 2-alkyl-1,3,3-trinitroazetidines can be synthesized either asymmetrically or racemically depending on the presence or absence of chirality in N-sulfinyl aldimines 2 used as the starting material. Furthermore, the sensitivity measurement results of racemic 2-methyl-1,3,3-trinitroazetidine (racemic 4a) showed that the introduction of an alkyl substituent at the C2 position of 1,3,3-trinitroazetidine had a significant effect on the sensitivity of the resulting 2-alkyl-1,3,3-trinitroazetidine.

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Development of a Safe and Efficient Two-Step Synthesis for Preparing 1-Bromoacetyl-3,3-dinitroazetidine, a Novel Clinical Anticancer Candidate

Cited by 18 publications

References 22 publications

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

Synthesis of Enantiopure 2‐Alkyl‐1,3,3‐Trinitroazetidines

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