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| Targets |
Human telomeric G-quadruplex (ΔTm = 26.6°C at 1 μM); HSP90 promoter G-quadruplex (HSP90A: ΔTm = 33.1°C, HSP90B: ΔTm = 28.6°C at 1 μM) [1]
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| ln Vitro |
3d exhibits potent antiproliferative activity against multiple cancer cell lines, with IC50 values of 10 nM in MIA PaCa-2 (pancreatic), 70 nM in MCF-7 (breast), and 230 nM in WI-38 (normal fibroblasts). In MIA PaCa-2 cells, it induces cellular senescence (50–60% senescent cells at 3–4 nM after 7 days) but does not inhibit telomerase activity even at 10 μM, as confirmed by TRAP-LIG assay.
qPCR analysis reveals dose-dependent transcriptional modulation: significant upregulation of DNA damage response genes (CDKN1A, DDT3, GADD45A/G, PPM1D) and downregulation of telomere maintenance genes (hPOT1, PARP1) at 20–80 nM concentrations after 24 h exposure. FRET melting assays demonstrate high stabilization of human telomeric quadruplex (ΔTm = 26.6°C) and HSP90 promoter quadruplexes (ΔTm = 33.1°C/28.6°C) at 1 μM, with superior quadruplex-vs-duplex selectivity compared to earlier analogues. |
| Enzyme Assay |
FRET-based melting assays were performed using FAM/TAMRA-labeled oligonucleotides (human telomeric sequence: 5′-FAM-d[AGGG(TTAGGG)3]-TAMRA-3′; HSP90 promoter sequences HSP90A/B). Compounds (1 μM final) in 60 mM K+ cacodylate buffer (pH 7.4) were heated from 30°C to 100°C at 0.5°C intervals. Fluorescence was monitored (ex: 450–495 nm; em: 515–545 nm), and ΔTm values calculated from triplicate data.
TRAP-LIG telomerase activity assay: MIA PaCa-2 cell extracts (1 μg protein) were incubated with TS primer, elongated products purified, PCR-amplified with ACX primer, and analyzed via PAGE/SYBR green staining. No telomerase inhibition was observed at ≤10 μM 3d. |
| Cell Assay |
Cell proliferation was assessed by SRB assay. Cells (MIA PaCa-2, MCF-7, A549, WI-38) were treated with 2-fold serial dilutions of 3d for 96 h. Absorbance at 540 nm measured cell viability, and IC50 values were calculated relative to untreated controls.
Senescence detection: MIA PaCa-2 cells treated with 3d (3.3–6.6 nM) for 7 days were fixed, stained with β-galactosidase kit, and senescent (blue) cells counted microscopically. qPCR arrays: Total RNA from 3d-treated MIA PaCa-2 cells (20–160 nM, 24 h) was extracted, reverse-transcribed, and analyzed using pathway-focused arrays (telomere maintenance/DNA damage response). Data normalized to housekeeping genes; fold-changes calculated via ΔΔCT method. |
| References | |
| Additional Infomation |
3d is a di-morpholine-substituted naphthalene diimide designed via structure-based optimization. Crystal structures (PDB: 3UYH) confirm binding to the 3′ G-quartet of parallel human telomeric quadruplex, with morpholine groups maintaining groove interactions via water-mediated H-bonds. It exhibits 10-fold higher potency than the tetra-N-methylpiperazine analogue (4) in pancreatic cancer cells, likely due to reduced cationic character enhancing cellular uptake.
Mechanistically, it disrupts telomere maintenance via POT1 displacement and induces senescence without telomerase inhibition, triggering distinct DNA damage responses. No in vivo or ADME data reported. Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1. [1] |
| Molecular Formula |
C44H66N10O6
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|---|---|
| Molecular Weight |
831.06
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| Exact Mass |
830.5167
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| Elemental Analysis |
C, 63.59; H, 8.01; N, 16.85; O, 11.55
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| CAS # |
1429028-96-5
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| PubChem CID |
135566608
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| Appearance |
Blue to purple solid powder
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| LogP |
-0.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
60
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| Complexity |
1810
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C12=CC(NCCCN3CCN(C)CC3)=C3C4C1=C(C(NCCCN1CCN(C)CC1)=CC=4C(=O)N(CCCN1CCOCC1)C3=O)C(=O)N(CCCN1CCOCC1)C2=O
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| InChi Key |
KOQWCTULEQQTBE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C44H66N10O6/c1-47-15-19-49(20-16-47)9-3-7-45-35-31-33-38-37-34(42(56)53(43(57)39(35)37)13-5-11-51-23-27-59-28-24-51)32-36(46-8-4-10-50-21-17-48(2)18-22-50)40(38)44(58)54(41(33)55)14-6-12-52-25-29-60-30-26-52/h31-32,45,55H,3-30H2,1-2H3
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| Chemical Name |
14-hydroxy-3-[3-(4-methylpiperazin-1-yl)propylamino]-10-[3-(4-methylpiperazin-1-yl)propylimino]-6,13-bis(3-morpholin-4-ylpropyl)-6,13-diazatetracyclo[6.6.2.04,16.011,15]hexadeca-1(14),2,4(16),8,11(15)-pentaene-5,7,12-trione
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| Synonyms |
MM41; 1429028-96-5; MM-41; compound 3d; 4,9-bis((3-(4-methylpiperazin-1-yl)propyl)amino)-2,7-bis(3-morpholinopropyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone; 4,9-Bis{[3-(4-Methylpiperazin-1-Yl)propyl]amino}-2,7-Bis[3-(Morpholin-4-Yl)propyl]benzo[lmn][3,8]phenanthroline-1,3,6,8(2h,7h)-Tetrone; 0DX; CHEMBL2335138; SCHEMBL16048175;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~33.33 mg/mL (~40.11 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2033 mL | 6.0164 mL | 12.0328 mL | |
| 5 mM | 0.2407 mL | 1.2033 mL | 2.4066 mL | |
| 10 mM | 0.1203 mL | 0.6016 mL | 1.2033 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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