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| Targets |
Human telomeric G-quadruplex [1]; telomerase/telomere;
BRACO-19 selectively binds to conserved G-quadruplex (GQ) motifs in the Human Adenovirus (HAdV) genome, specifically PGQ-AV-C3 (Kd = 0.28 × 10⁻⁶ M), PGQ-AV-D2 (Kd = 0.34 × 10⁻⁶ M), and PGQ-AV-E3 (Kd = 0.28 × 10⁻⁶ M) [2] |
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| ln Vitro |
Strong GQ-binding ligand braco-19 triHClide binds to HAdV GQ, stabilizes it, and causes HAdV swelling to stop [2]. Nuclear hTERT expression is Braco-19 triHClide is a potent GQ-binding ligand that resonates with HAdV GQ, stabilizing it and causing HAdV swelling to burst [2]. Significant reduction of nuclear hTERT expression is seen with Braco-19 triHClide (1 μM; 24 hours). On the other hand, unusual mitoses were noted in conjunction with widespread cytoplasmic hTERT staining [1]. AdV in eGFP-transfected HEK 293 cells is lowered by braco-19 trihydrochloride (0–40 μM; 24 hours) using quantitative sampling. Band intensity decreases in a concentration-dependent manner with Braco-19 trihydrochloride (0-150 μM; 24 hours) [2].
BRACO-19 inhibits proliferation in UXF1138L uterine carcinoma cells (IC50 = 2.5 μM, IC100 = 5 μM) in 5-day SRB assays. At subcytotoxic concentrations (1 μM), it induces telomere shortening (0.4 kb after 15 days) and replicative senescence, evidenced by morphological changes and β-galactosidase-positive cells. Immunohistochemistry reveals nuclear hTERT expression loss within 24 hours at 1 μM, with residual cytoplasmic staining. Atypical mitoses and enlarged nuclei indicate telomere dysfunction. TRAP assays confirm telomerase inhibition. Triple staining shows cytoplasmic colocalization of hTERT and ubiquitin after 24-hour treatment (1–10 μM), suggesting ubiquitin-mediated degradation of displaced hTERT.[1] BRACO-19 stabilizes HAdV G-quadruplex structures, increasing their melting temperature (ΔTm) by 13.1°C (PGQ-AV-C3), 27.77°C (PGQ-AV-D2), and 11.7°C (PGQ-AV-E3) in circular dichroism (CD) melting assays. Stabilization occurs via π-π stacking interactions, confirmed by NMR proton broadening.[2] In Taq polymerase stop assays, BRACO-19 (0–150 μM) dose-dependently inhibits DNA synthesis at GQ sites (e.g., PGQ-AV-C3/D2/E3), evidenced by reduced full-length product intensity on gels. Mutant controls show no inhibition.[2] BRACO-19 (20–40 μM) reduces adenovirus proliferation in HEK 293 cells by 65% (20 μM) and 70% (40 μM) via GFP/mTFP reporter assays, confirming GQ-mediated antiviral activity.[2] |
| ln Vivo |
The BRACO-19 triHCl (hydrogen or i.p.; 2 or 5 mg/kg; 3 weeks) medication regimen was consistently ineffective, and because of the large tumor burden and chronic nature of the i.p., animals had to be euthanized prior to the study's completion. In early-stage xenografts, the BRACO-19 product qdx5 efficiently suppressed tumor growth; however, it was ineffective in late-stage xenografts [1]. Significant single-agent tumor resistance activity was demonstrated under BRACO-19 trihydrochloride (i.p.; 2 mg/kg; 3 weeks; starting 6 days post-graft withdrawal of UXF1138LX), and animals in this group showed regression (5 of 12 tumors) [1].
In early-stage UXF1138LX xenografts (median volume 68 mm³), chronic i.p. administration of BRACO-19 (2 mg/kg/day, 5 days/week for 3 weeks) achieves 95.9% tumor growth inhibition (T/C = 4.1%, P = 0.018) with partial regressions (5/12 tumors regressed completely). Oral dosing (5 mg/kg twice weekly) is ineffective (T/C = 73%). Immunohistochemistry of treated xenografts shows reduced nuclear hTERT expression, increased cytoplasmic hTERT, and atypical mitotic figures (anaphase bridges, tripolar divisions), indicating telomere uncapping.[1] |
| Enzyme Assay |
TRAP telomerase assay: UXF1138L cell extracts incubated with TS primer for elongation, followed by PCR amplification with ACX primer. Products separated by PAGE and detected via SYBR green staining.[1]
Isothermal Titration Calorimetry (ITC) was performed in 80 mM KCl phosphate buffer at 25°C. BRACO-19 (200 μM) was titrated into GQ DNA (PGQ-AV-C3/D2/E3; 20 μM). Data fitted to a two-site model revealed exothermic binding (Kd = 0.28–0.34 × 10⁻⁶ M), while mutants showed negligible affinity.[2] Taq polymerase stop assays used ³²P-labeled primer and GQ templates (10 nM) in Tris-HCl (pH 7.4). Reactions with 0–125 mM KCl showed polymerase arrest at GQ sites. BRACO-19 addition (0–150 μM) intensified arrest, visualized via 15% denaturing PAGE.[2] |
| Cell Assay |
Cell Viability Assay [1]
Cell Types: HEK 293 Cell Tested Concentrations: 20 μM; 40 μM Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated low cytotoxicity and diminished eGFP fluorescence. Cell proliferation: UXF1138L cells (2,000/well) treated with 0.1–10 μM BRACO-19 for 5 days. Viability assessed by sulforhodamine B (SRB) staining (515 nm absorbance). Senescence: Cells treated with 0.1–1 μM BRACO-19 for 15 days, fixed, and stained for β-galactosidase activity (blue pigmentation). hTERT/ubiquitin colocalization: Cells treated with 1–10 μM BRACO-19 for 24 hours, triple-stained with anti-hTERT (TRITC), anti-ubiquitin (FITC), and DAPI. Fluorescence microscopy analyzed colocalization (yellow-orange in merged images). Telomere length: Genomic DNA isolated after 15-day treatment (1 μM), digested with HinfI/RsaI, and analyzed by Southern blot using telomere-specific probes.[1] HEK 293 cells infected with AdV-eGFP (MOI = 3) were treated with BRACO-19 (0–40 μM) in DMEM + 2% FBS. Fluorescence (GFP/mTFP) quantified at 12–24 h post-infection via microscopy/flow cytometry showed dose-dependent viral suppression (30–70% at 20–40 μM).[2] Cytotoxicity assays confirmed BRACO-19 had low toxicity in HEK 293 cells at effective concentrations (≤40 μM).[2] |
| Animal Protocol |
Animal/Disease Models: Establishment of UXF1138LX xenografts in nude mice [1]
Doses: 2 mg/kg Route of Administration: intraperitoneal (ip) injection; 3 weeks; Results starting 6 days after UXF1138LX fragment transplantation: showing partial tumor regression, optimal T/ on day 28 C was 4.1%, equivalent to 95.9% tumor growth inhibition compared to the control. Xenograft efficacy: UXF1138LX tumor fragments implanted s.c. in nude mice. Treatment initiated at early-stage (median 68 mm³) or advanced-stage (130–200 mm³). BRACO-19 dissolved in PBS, administered: - i.p.: 2 mg/kg/day, 5 consecutive days/week for 3 weeks. - p.o.: 5 mg/kg, twice weekly for 2 weeks. Tumor volumes measured twice weekly; %T/C calculated from relative tumor volumes.[1] |
| References |
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| Additional Infomation |
BRACO-19 is a hydrochloride. It contains a N,N'-(9-{[4-(dimethylamino)phenyl]amino}acridine-3,6-diyl)bis(3-pyrrolidin-1-ylpropanamide).
BRACO-19 is a trisubstituted acridine G-quadruplex ligand that displaces telomerase from telomeric ends, inducing rapid uncapping and ubiquitin-mediated hTERT degradation. Effective only in tumors with short telomeres (e.g., UXF1138L: 2.7 kb). Oral bioavailability is low; i.p. delivery required for efficacy. Mechanism involves G-quadruplex stabilization → hTERT displacement → telomere dysfunction (atypical mitoses) → senescence/apoptosis. No ADME/toxicity data reported. [1] BRACO-19 is a trisubstituted acridine derivative that stabilizes viral G-quadruplexes, disrupting replication. It previously showed antiviral activity against HIV-1 and HSV by similar mechanisms.[2] This study identifies HAdV GQs as druggable targets; BRACO-19 represents a prototype for anti-adenoviral therapeutics targeting genomic secondary structures.[2] |
| Molecular Formula |
C35H46CL3N7O2
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|---|---|
| Molecular Weight |
703.144444942474
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| Exact Mass |
701.277
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| Elemental Analysis |
C, 59.79; H, 6.59; Cl, 15.12; N, 13.94; O, 4.55
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| CAS # |
1177798-88-7
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| Related CAS # |
Braco-19;351351-75-2
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| PubChem CID |
10349800
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| Appearance |
Yellow to brown solid powder
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
47
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| Complexity |
870
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.Cl.Cl.O=C(CCN1CCCC1)NC1C=CC2C(C=1)=NC1C=C(C=CC=1C=2NC1C=CC(=CC=1)N(C)C)NC(CCN1CCCC1)=O
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| InChi Key |
MJAPNWJRLLDPAB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H43N7O2.3ClH/c1-40(2)28-11-7-25(8-12-28)38-35-29-13-9-26(36-33(43)15-21-41-17-3-4-18-41)23-31(29)39-32-24-27(10-14-30(32)35)37-34(44)16-22-42-19-5-6-20-42;;;/h7-14,23-24H,3-6,15-22H2,1-2H3,(H,36,43)(H,37,44)(H,38,39);3*1H
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| Chemical Name |
N-[9-[4-(dimethylamino)anilino]-6-(3-pyrrolidin-1-ylpropanoylamino)acridin-3-yl]-3-pyrrolidin-1-ylpropanamide;trihydrochloride
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| Synonyms |
BRACO19 hydrochloride; 1177798-88-7; BRACO 19 trihydrochloride; braco-19 trihydrochloride; Braco-19 (trihydrochloride); BRACO 19 3HCl; BRACO-19 (hydrochloride); N-[9-[4-(dimethylamino)anilino]-6-(3-pyrrolidin-1-ylpropanoylamino)acridin-3-yl]-3-pyrrolidin-1-ylpropanamide;trihydrochloride; N,N'-[9[[4-(Dimethylamino)phenyl]amino]-3,6-acridinediyl]bis-1-pyrrolidinepropanamideTrihydrochloride; BRACO 19; BRACO19 HCl; BRAC-O19
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
H2O : ~22 mg/mL (~31.29 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 | 1.4222 mL | 7.1110 mL | 14.2219 mL | |
| 5 mM | 0.2844 mL | 1.4222 mL | 2.8444 mL | |
| 10 mM | 0.1422 mL | 0.7111 mL | 1.4222 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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