1020149-73-8

Basic information

• Product Name: SGI-1027
• Synonyms: SGI-1027;N-[4-[(2-Amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)benzamide;DNA Methyltransferase Inhibitor II;Benzamide, N-[4-[(2-amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)-;N-[4-[(2-Amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)benzamide SGI-1027;SGI-1027 N-[4-[(2-Amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)benzamide;N-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide
• CAS NO: 1020149-73-8
• Molecular Formula: C₂₇H₂₃N₇O
• Molecular Weight: 461.51782
• EINECS: -0
• Product Categories: Inhibitors
• Mol File: 1020149-73-8.mol

Chemical Properties

• Melting Point: >280℃
• Appearance: /
• Density: 1.387±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: Soluble in DMSO (up to 35 mg/ml)
• PKA: 13.31±0.70(Predicted)
• Stability: Stable for 2 years as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: SGI-1027(CAS DataBase Reference)
• NIST Chemistry Reference: SGI-1027(1020149-73-8)
• EPA Substance Registry System: SGI-1027(1020149-73-8)

Safety Data

• Hazardous Substances Data: 1020149-73-8(Hazardous Substances Data)

Usage

Uses

Used in Cancer Treatment:
SGI-1027 is used as a therapeutic agent for the treatment of cancer due to its ability to inhibit DNA methyltransferase, which plays a crucial role in the regulation of gene expression and is often dysregulated in cancer cells. Treatment with SGI-1027 results in selective degradation of DNMT1, leading to the reexpression of silenced tumor suppressor genes and disruption of the MKK3-MYC complex, thereby inhibiting MYC transcriptional activity in colon and breast cancer cells.
Used in Research:
SGI-1027 is used as a research tool to investigate the role of DNMTs in epigenetic events, as it provides valuable insights into the molecular mechanisms underlying gene regulation and the development of cancer.
Used in Combination Therapy:
SGI-1027 is used in combination with conventional chemotherapeutic drugs, such as doxorubicin, to enhance chemo-sensitivity and efficacy in resistant cases. This synergistic effect can improve the overall treatment outcome for patients with neuroblastoma and other cancer types.
Used in Drug Development:
SGI-1027 serves as a starting point for the development of novel drug delivery systems and therapeutic strategies targeting DNA methylation, which could potentially lead to more effective and targeted cancer treatments.

Features

Potential for use in epigenetic cancer therapy.

In vitro

SGI-1027 inhibits DNA methylation by directly inhibiting DNMTs, and results in selective degradation of DNMT1 in a wide variety of human cancer cell lines. SGI-1027 exhibits minimal or no cytotoxic effect in rat hepatoma H4IIE cells.? SGI-1027 (0-100 μM) exhibits a moderate pro-apoptotic effect on U937 human leukemia cell line with no relevant changes on the cell cycle.

Biochem/physiol Actions

SGI-1027 is a DNA methyltransferase (DNMT) inhibitor with IC50 values of 6-13 μM for DNMT3B, DNMT3A and DNMT1. SGI-1027 directly inhibits DNMT activity by competing with the cofactor, S-adenosylmethionine (SAM) in the methylation reaction. SGI-1027 treatment of cancer cell lines induced degradation of DNMT1, but not DNMT3A or DNMT3B, and in RKO cells caused re-expression of the silenced tumor supressor genes p16, MLH1 and TIMP3.

References

Datta et al. (2009), A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation; Cancer Res., 69 4277 Penter et al. (2015) A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma; Target Oncol., 10 523 Yang et al. (2021), Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer; Bioorg. Chem., 45 116324

Upstream product

• 1020087-05-1 N-[4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl]-4-nitrobenzamide 
• 611-35-8 4-chloroquinoline 
• 5600-21-5 2-amino-6-methyl-4-chloropyrimidine 
• 94-09-7 p-aminoethylbenzoate 
• 20719-43-1 N⁴-(4-aminophenyl)-6-methyl-2,4-diamino-pyrimidine 
• 133041-90-4 4-(quinolin-4-ylamino)benzoic acid 
• 100-01-6 4-nitro-aniline 
• 20719-42-0 6-methyl-N⁴-(4-nitrophenyl)-2,4-diamino-pyrimidine 
• 58519-43-0 ethyl 4-((quinolin-4-yl)amino)benzoate 

Relevant articles and documents

Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

Synthetic approaches to DNMT inhibitor SGI-1027 and effects on the U937 leukemia cell line

The known DNMT inhibitor SGI-1027 4 has been synthesized using as key steps Pd-catalyzed Ar-N bond formation reactions performed in a sequential or convergent manner. In the former approach, a by-product, which corresponds to the incorporation of two units of 4-chloroquinoline, was also isolated. The biological effects of compound 4 in the U937 human leukemia cell line are also described.