| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 1g | |||
| Other Sizes |
| Targets |
DNA intercalator; topoisomerase II inhibitor (anthrapyrazole family) – designed as a chromophore-modified anthracene-9,10-dione with reduced cardiotoxicity [1]
|
|---|---|
| ln Vitro |
As an intercalating agent, nortopixantrone incorporates into DNA and induces both single- and double-stranded DNA breaks by targeting topoisomerase II. This mechanism of action results in the inhibition of DNA replication and repair, as well as RNA and protein synthesis, ultimately leading to cell death.
|
| ln Vivo |
In preclinical studies, BBR 3438 showed high in vivo antitumor efficacy against both murine and human tumor models with minimal delayed cardiotoxicity. It was more active than losoxantrone (DuP-941) and as active as doxorubicin on murine hematological tumors, and was curative on YC-8 murine lymphoma. It was as active as 5-fluorouracil on MKN45 gastric human carcinoma and more active than 5-fluorouracil and doxorubicin on Hs746T human gastric carcinoma. BBR 3438 also showed unique activity on human prostate cancer. [1]
In a phase II clinical trial in patients with advanced gastric cancer (n=27 evaluable for safety, n=25 evaluable for response), BBR 3438 was administered at 50 mg/m² as a 1-hour intravenous infusion every 4 weeks. No objective tumor remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. The study was closed early due to lack of efficacy (no responses among first 23 patients). [1] |
| Animal Protocol |
Preclinical xenograft studies: BBR 3438 was tested in murine hematological tumors (YC-8 lymphoma) and human gastric carcinoma xenografts (MKN45, Hs746T). No specific dosing details (route, frequency, formulation) were provided. [1]
Clinical trial protocol: Patients with advanced gastric cancer (failed first-line chemotherapy) received BBR 3438 at 50 mg/m² as a 1-hour intravenous infusion on day 1 every 4 weeks. Planned treatment duration was 6 courses. BBR 3438 was supplied as a 1% ready-to-use solution in isotonic saline in vials of 50 mg/5 ml, stored at room temperature. Dose modifications were based on hematological toxicity: for neutropenia grade 4 (neutrophils <500/μl) or febrile neutropenia, 20% dose reduction; for thrombocytopenia ≤20,000/μl or bleeding, 20% dose reduction. Treatment was delayed until recovery to ≤grade 1 toxicity. Cardiac toxicity ≥grade 2 required withdrawal. [1] |
| Toxicity/Toxicokinetics |
In the phase II trial (27 patients, 94 cycles), the main toxicity was neutropenia: grades 3 and 4 in 70.4% of patients (grade 4 in 51.9%). Neutrophil nadir (520/μl) reached after median 15 days; recovery to ≤grade 1 neutropenia took median 13.5 days. Febrile neutropenia occurred in one patient (3.7%). Dose reductions were performed in 6 courses (11% of all courses) and in 6 patients (22.2%). [1]
Non-hematological toxicities: nausea (grades 1/2/3: 22%/26%/7%), vomiting (19%/7%/7%), stomatitis (15%/19%/4%), alopecia (15%/33%/-), fatigue (18%/11%/11%/7%), anorexia (18%/11%/4%/7%). [1] Cardiac safety: Median LVEF at baseline was 67.5% (range 51-87%), at end of cycle 2 was 65% (range 59-98%). No patient had a clinically relevant decrease of LVEF (by >10% or below 50%). No cardiac toxicity was observed. [1] One patient developed microangiopathic hemolytic anemia (hemolytic-uremic syndrome), likely associated with prior mitomycin C treatment, not considered related to study drug. [1] |
| References | |
| Additional Infomation |
BBR 3438 (2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[(2-methylamino)ethyl]amino]indazol[4,3-gh]isoquinolin-6(2H)-one dihydrochloride salt) is a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline-dependent cardiotoxicity and improve efficacy. It was more active than losoxantrone and as active as doxorubicin on murine hematological tumors, and curative on YC-8 murine lymphoma. The drug had no effect on renal and liver functions, clotting activity, electrolyte profiles, vital signs, or ECG parameters up to the highest investigated dose of 64 mg/m². Based on preclinical activity in gastric cancer xenografts, a phase II trial was initiated but showed no clinical antitumor effect in second-line treatment of advanced gastric cancer. The maximum phase of clinical development reached was Phase II. [1]
|
| Molecular Formula |
C20H26CL2N6O2
|
|---|---|
| Molecular Weight |
453.368
|
| Exact Mass |
452.149
|
| Elemental Analysis |
C, 52.99; H, 5.78; Cl, 15.64; N, 18.54; O, 7.06
|
| CAS # |
438244-41-8
|
| Related CAS # |
156090-17-4; 438244-41-8 (HCl);
|
| PubChem CID |
3038511
|
| Appearance |
Typically exists as solid at room temperature
|
| Boiling Point |
684.6ºC at 760 mmHg
|
| Flash Point |
367.8ºC
|
| LogP |
3.207
|
| Hydrogen Bond Donor Count |
6
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
30
|
| Complexity |
535
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
OC1=CC=C(/N=N/C2=CC=CC=C2O)C(O)=C1
|
| InChi Key |
PBBLZEYTDDWEIH-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H24N6O2.2ClH/c1-21-6-7-24-15-2-3-16-18-17(15)20(28)13-4-5-23-12-14(13)19(18)25-26(16)10-8-22-9-11-27;;/h2-5,12,21-22,24,27H,6-11H2,1H3;2*1H
|
| Chemical Name |
14-[2-(2-hydroxyethylamino)ethyl]-10-[2-(methylamino)ethylamino]-4,14,15-triazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2(7),3,5,9,11,13(16)-heptaen-8-one;dihydrochloride
|
| Synonyms |
BBR3438; BBR-3438; Nortopixantrone hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| 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 | 2.2057 mL | 11.0285 mL | 22.0570 mL | |
| 5 mM | 0.4411 mL | 2.2057 mL | 4.4114 mL | |
| 10 mM | 0.2206 mL | 1.1029 mL | 2.2057 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
