Quarfloxin
(Synonyms: CX-3543) 目录号 : GC37051
Quarfloxin (CX-3543) 是一种具有抗肿瘤活性的氟喹诺酮类衍生物，其靶向抑制RNA pol I的活性，在神经母细胞瘤中的IC50 值在纳摩尔级别。Quarfloxin 干扰核糖体DNA中核蛋白与G-四重DNA结构的相互作用。
Cas No.:865311-47-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Quarfloxin (CX-3543), a fluoroquinolone derivative with antineoplastic activity, targets and inhibits RNA pol I activity, with IC50 values in the nanomolar range in neuroblastoma cells. Quarfloxin disrupts the interaction between the nucleolin protein and a G-quadruplex DNA structure in the ribosomal DNA (rDNA) template[1]. RNA pol I[1].
Quarfloxin (CX-3543) effectively inhibits the growth of neuroblastoma cells in vitro. MNA (or high c-Myc) and wt-TP53 cell lines are found to be more sensitive to Quarfloxin. Quarfloxin and induces DNA damage, p53 signaling, cell death, and cell cycle arrest in neuroblastoma cell lines[1].
[1]. Hald ØH, et al. Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma. Oncogene. 2018 Dec 12.
| Cas No. | 865311-47-3 | SDF | |
| 别名 | CX-3543 | ||
| Canonical SMILES | O=C(C1=CN2C3=C(C(N4CC(C5=NC=CN=C5)CC4)=C(F)C=C3C1=O)OC6=CC7=CC=CC=C7C=C26)NCC[C@H]8N(C)CCC8 | ||
| 分子式 | C35H33FN6O3 | 分子量 | 604.67 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6538 mL | 8.269 mL | 16.5379 mL |
| 5 mM | 0.3308 mL | 1.6538 mL | 3.3076 mL |
| 10 mM | 0.1654 mL | 0.8269 mL | 1.6538 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)
Bioorg Med Chem Lett 2022 Dec 1;77:129016.PMID:36195286DOI:10.1016/j.bmcl.2022.129016.
CX-3543 (Quarfloxin) and CX-5461 (Pidnarulex) were originally derived from a group of fluoroquinolones that were shown to have dual topoisomerase II (Top2) and G-quadruplex (G4) interactions, and QQ58 was the starting structure for their design. Quarfloxin was initially shown to inhibit c-MYC mRNA expression. Studies at Cylene Pharmaceuticals showed that the primary mechanism of action of Quarfloxin is due to displacement of nucleolin from quadruplexes on the non-template strand of rDNA, causing rapid redistribution of nucleolin from nucleoli, inhibition of rRNA synthesis, and apoptotic death in cancer cells. At Cylene a follow-up compound to Quarfloxin, named Pidnarulex (CX-5461), was optimized for targeting RNA Pol 1. Significantly, in more recent work published in Proc Natl Acad Sci USA and Cell in 2020 and in eLIFE and Nat Comm in 2021, it has been shown that the real molecular target for Pidnarulex is Top2 at transcribed regions containing G4s, rather than RNA Pol 1. These results support the original design strategy published in Mol Cancer Ther in 2001, which was to rationally design a G4-targeting drug (QQ58) starting from a fluoroquinolone duplex-targeting Top2 poison (A-62176) that had good drug-like properties. A very important breakthrough was realized when homologous recombination (HR) was found to be important in the repair of DNA damage caused by G4-interactive compounds, suggesting that a synthetic lethal approach might be useful in identifying cancer patients sensitive to these agents. Through use of an unbiased screen, this mechanistic insight was shown to directly apply to Cylene compounds, which were found to induce DNA damage and to be dependent on BRCA1/2-mediated HR and the DNA-PK-mediated nonhomologous end-joining (NHEJ) pathway for damage repair. To evaluate how this mechanistic insight involving a synthetic lethal approach might be applied clinically, a recent Canadian Phase I clinical trial with Pidnarulex in breast and ovarian cancer patients with known BRCA1/2 germline mutations was carried out. Because of the G4 stabilizer function of Pidnarulex, patient populations that responded well to this compound were identified: they are cancer patients with BRCA1/2 deficiency or deficiency in other DNA damage response pathways. Clinically observed resistance to Pidnarulex resulted from reversion to WT BRCA2 and PALB2 ("partner and localizer of BRCA2," because it partners with another gene, called BRCA2), thus providing strong evidence for the underlying synthetic lethal hypothesis proposed for G4-targeting compounds that cause DNA damage.
G-quadruplex, Friend or Foe: The Role of the G-quartet in Anticancer Strategies
Trends Mol Med 2020 Sep;26(9):848-861.PMID:32467069DOI:10.1016/j.molmed.2020.05.002.
The clinical applicability of G-quadruplexes (G4s) as anticancer drugs is currently being evaluated. Several G4 ligands and aptamers are undergoing clinical trials following the notable examples of Quarfloxin and AS1411, respectively. In this review, we summarize the latest achievements and breakthroughs in the use of G4 nucleic acids as both therapeutic tools ('friends', as healing anticancer drugs) and targets ('foes', within the harmful cancer cell), particularly using aptamers and quadruplex-targeted ligands, respectively. We explore the recent research on synthetic G4 ligands toward the discovery of anticancer therapeutics and their mechanism of action. Additionally, we highlight recent advances in chemical and structural biology that enable the design of specific G4 aptamers to be used as novel anticancer agents.
G-quadruplex structures in the human genome as novel therapeutic targets
Molecules 2013 Oct 8;18(10):12368-95.PMID:24108400DOI:10.3390/molecules181012368.
G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex‑stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of MYC, KIT, or KRAS resulted in the down-regulation of the corresponding oncogene either in gene reporter assays or in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as novel therapeutic targets.
Targeting MYC Expression through G-Quadruplexes
Genes Cancer 2010 Jun;1(6):641-649.PMID:21113409DOI:10.1177/1947601910377493.
In this review, the authors describe a novel mechanism for control of MYC expression that involves a four-stranded DNA structure, termed a G-quadruplex, amenable to small molecule targeting. The DNA element involved in this mechanism, the nuclease hypersensitive element III(1) (NHE III(1)), is just upstream of the P1 promoter and is subjected to dynamic stress (negative superhelicity) resulting from transcription. This is sufficient to convert the duplex DNA to a G-quadruplex on the purine-rich strand and an i-motif of the pyrimidine-rich strand, which displaces the activating transcription factors to silence gene expression. Specific proteins have been identified, NM23-H2 and nucleolin, that resolve and fold the G-quadruplex to activate and silence MYC expression, respectively. Inhibition of the activity of NM23-H2 molecules that bind to the G-quadruplex silences gene expression, and redistribution of nucleolin from the nucleolus to the nucleoplasm is expected to inhibit MYC. The authors also describe the mechanism of action of Quarfloxin, a first-in-class G-quadruplex-interactive compound that involves the redistribution of nucleolin from the nucleolus to the nucleoplasm. G-quadruplexes have been best known as test-tube oddities for more than four decades. However, during the past decade, they have emerged as likely players in a number of important biological processes, including transcriptional control. Only time will tell if these odd DNA structures will assume the role of an established receptor class, but it is clear from the scientific literature that there is a dramatic increase in interest in this little-known area in the past few years.
G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets
Antimicrob Agents Chemother 2018 Feb 23;62(3):e01828-17.PMID:29311059DOI:10.1128/AAC.01828-17.
G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including Quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including Quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum but that Quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that Quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs.