Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone – A novel class of compounds with potent activity against acute myeloid leukemia cells

Carter-Cooper, Brandon; Fletcher, Steven; Ferraris, Dana; Choi, Eun Yong; Kronfli, Dahlia; Dash, Smaraki; Truong, Phuc; Sausville, Edward A.; Lapidus, Rena G.; Emadi, Ashkan

doi:10.1016/j.bmcl.2016.11.045

Cited by 9 publications

(7 citation statements)

References 25 publications

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“…In the search for new anti-HIV agents, Carter-Cooperet al synthesized a novel series of amino dimeric naphthoquinones with reportedly good anti-integrase and cytotoxic activity against a panel of leukemia cancer cell lines [114]. Trying to increase their antitumoral properties, they made some modifications to the original structures that led to a series of bis-aziridinyl compounds.…”

Section: Main Textmentioning

confidence: 99%

The diverse mechanisms and anticancer potential of naphthoquinones

et al. 2019

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Cancer is one of the leading causes of death around the world and although the different clinical approaches have helped to increase survival rates, incidence is still high and so its mortality. Chemotherapy is the only approach which is systemic, reaching cancer cells in all body tissues and the search for new potent and selective drugs is still an attractive field within cancer research. Naphthoquinones, natural and synthetic, have garnered much attention in the scientific community due to their pharmacological properties, among them anticancer action, and potential therapeutic significance. Many mechanisms of action have been reported which also depend on structural differences among them. Here, we describe some of the most relevant mechanisms of action reported so far for naphthoquinones and highlight novel targets which are being described in the literature. Furthermore, we gather some of the most impressive efforts done by researchers to harness the anticancer properties of these compounds through specifically designed structural modifications.

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Section: Main Textmentioning

confidence: 99%

The diverse mechanisms and anticancer potential of naphthoquinones

et al. 2019

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“…The IC 50 values (μM) of 3-bromo-3′-hydroxyl-dimeric 1,4-naphthoquinone (BiQ1) against AML cell lines MOLM-14, THP1, and one primary AML cells from patients, as well as normal bone marrow cells were 5.5 ± 0.8, 4.2 ± 1.9, 0.4 and 14.5, respectively [55]. Bis-aziridinyl dimeric naphthoquinone containing two nitrogen mustard alkylating groups was synthesized to improve the potency and bioavailability of dimeric naphthoquinones [56]. This compound showed a potent anti-leukemic activity (IC 50 range 0.18–2 μM) against three AML cell lines and four primary AML cells from patients [56].…”

Section: Resultsmentioning

confidence: 99%

“…Bis-aziridinyl dimeric naphthoquinone containing two nitrogen mustard alkylating groups was synthesized to improve the potency and bioavailability of dimeric naphthoquinones [56]. This compound showed a potent anti-leukemic activity (IC 50 range 0.18–2 μM) against three AML cell lines and four primary AML cells from patients [56]. Of note, the patient-derived AML cells had a heterogeneous cytogenetic and molecular mutation profile.…”

Section: Resultsmentioning

confidence: 99%

“…Of note, the patient-derived AML cells had a heterogeneous cytogenetic and molecular mutation profile. In addition to inducing a decrease in cell survival and viability, exposure to the bis-aziridinyl dimeric naphthoquinone at concentrations relative to the respective IC 50 values for 24 h resulted in a marked reduction in clonogenic activity—an in vitro assay to assess the capability of a single AML cell in the population to generate a colony—the quintessential anti-cancer in vitro assay [56]. Dimeric naphthoquinones had favorable therapeutic indices as demonstrated by their more potent IC 50 values in AML cells compared to normal hematopoietic cells.…”

Section: Resultsmentioning

confidence: 99%

“…A few studies tested the tolerability and safety of naphthoquinone derivatives in vivo as wells as their anti-AML activity [4,24,35,40,56]. Plumbagin dosed 2 mg/kg via intraperitoneal injection, IP) daily for three weeks significantly reduced tumor volume in NB4 tumor xenograft in NOD/SCID mice; 153 mm 3 in plumbagin versus 194 mm 3 in control after one week of treatment and approximately 65% tumor volume reduction at the completion of the study [24].…”

Section: Resultsmentioning

confidence: 99%

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Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics

et al. 2019

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Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.

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Electrochemical behavior of 1,2-dihydroxyanthraquinone dianion in aprotic solvents-DMSO and DMF: understanding the hydrogen bonding phenomena and protonation effect in biochemical systems

Tariq

Ullah

2020

SN Appl. Sci.

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In this work, we report, the electrochemical properties of 1,2-dihydroxyanthraquinone through cyclic voltammetry (CV) and square wave voltammetry (SWV) in two aprotic solvents-DMSO and DMF. It is investigated that 1,2-dihydroxyanthraquinone undergoes two single-electron reduction processes. The first electron transfer process corresponds to formation of anion radical while the second electron transfer corresponds to dianion of 1,2-dihydroxyanthraquinone. Concentration effect and scan rate effect on CV of 1,2-dihydroxyanthraquinone is also studied. Effect of different alcohols (hydrogen-bonding agents) and organic acids (protonating agents) on the CVs and SWVs of 1,2-dihydroxyanthraquinone is also investigated. It is found that addition of alcohols shifts the peak potential of the dianion towards less negative potential whereas addition of organic acids) inhabits the formation of dianion. Furthermore, it is also observed that methanol has strong hydrogen-bonding interaction with 1,2-dihydroxyanthraquinone as compared to ethanol and propanol. The hydrogen bonding equilibrium constant and hydrogen-bonding rate constants are evaluated from the shift in CV curves using Gupta and Linchtiz equation. It is inferred that the anion radical has a very weak hydrogen bonding interaction with alcohols as compared to dianion.

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Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone – A novel class of compounds with potent activity against acute myeloid leukemia cells

Cited by 9 publications

References 25 publications

The diverse mechanisms and anticancer potential of naphthoquinones

The diverse mechanisms and anticancer potential of naphthoquinones

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics

Electrochemical behavior of 1,2-dihydroxyanthraquinone dianion in aprotic solvents-DMSO and DMF: understanding the hydrogen bonding phenomena and protonation effect in biochemical systems

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