(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione hydrochloride

• ChemBase ID: 72584
• Molecular Formular: C23H24ClN3O5
• Molecular Mass: 457.90676
• Monoisotopic Mass: 457.14044856
• SMILES: c1(ccc2c(c1CN(C)C)cc1c(n2)c2n(C1)c(=O)c1c(c2)[C@](C(=O)OC1)(CC)O)O.Cl
• Canonical SMILES: CC[C@@]1(O)C(=O)OCc2c1cc1c3nc4ccc(c(c4cc3Cn1c2=O)CN(C)C)O.Cl
• InChI: InChI=1S/C23H23N3O5.ClH/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20;/h5-8,27,30H,4,9-11H2,1-3H3;1H/t23-;/m0./s1
• InChIKey: DGHHQBMTXTWTJV-BQAIUKQQSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^2,^1^1.0^4,^9.0^1^5,^2^0]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione hydrochloride; (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione hydrochloride
• IUPAC Traditional name: topotecan hydrochloride
• Synonyms: (4S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3’,4’,6-7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione Hydrochloride; NSC-609669; SKF-104864A; Hycamtin; NSC 609699; Topotecan Hydrochloride

Database IDs

• CAS Number: 119413-54-6
• PubChem SID: 162037509
• PubChem CID: 60699

CALCULATED PROPERTIES

• Rotatable Bonds: 3
• Lipinski's Rule of Five: true
• Acid pKa: 7.999574
• H Acceptors: 6
• H Donor: 2
• LogD (pH = 5.5): -2.4005558
• LogD (pH = 7.4): -0.9559677
• Log P: -0.35709506
• Molar Refractivity: 115.0161 cm^3
• Polarizability: 44.844234 Å^3
• Polar Surface Area: 103.2 Å^2

PROPERTIES

Physical Property

• Solubility: DMSO; Methanol; Water
• Apperance: Light Yellow-Green Solid
• Melting Point: 213-218°C (dec.)

Safety Information

• Storage Condition: -20°C; Refrigerator

Pharmacology Properties

• Target: Topoisomerase

Product Information

• Purity: 95+%
• Salt Data: Hydrochloride

DETAILS

Selleck Chemicals - S1231

Research Area

• Description: Cancer

Biological Activity

• Description: Topotecan (Hycamtin, NSC 609699) is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM, respectively.
• Targets: MCF-7 Luc cells; DU-145 Luc cells
• IC50: 13 nM; 2 nM ^[1]
• In Vitro: Stronger drug activity of Topotecan is observed for DU-145 Luc and MCF-7 Luc cells. ^[1] Topotecan causes cytotoxicity during the course of DNA replication by stabilizing the covalent complex between topoisomerase I and DNA and preventing the religation of enzyme-linked single-strand DNA break. Topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell clonogenic growth in a dose-dependent fashion. ^[2]
• In Vivo: Animals inoculate s.c. with DU-145 Luc cells and then treated with Topotecan demonstrates significant tumor growth and regression as measured with calipers and luminescent imaging. The correlation coefficient is 0.75 for the control untreated group and 0.93 for the Topotecan-treated group. Similarly, tumor progression and regression are measurable using luminescent imaging for untreated and Topotecan-treated mice inoculated i.p. with MCF-7 Luc cells. ^[1] Topotecan elicited potent antileukemic activity in severe combined immune-deficiency (SCID) mouse models of human poor prognosis ALL. Topotecan markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of humaln leukemia cells at systemic drug exposure levels. ^[2] Gliomas preferentially express TRAIL R2 and that treatment with Topotecan significantly up-regulates its expression. ^[3]
• Clinical Trials: Topotecan plus Pazopanib has entered in a phase II clinical trial in the treatment of ovarian cancer.
• Features: Topotecan is a water-soluble derivative of camptothecin.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: MCF-7 Luc and DU-145 Luc cells
• Concentrations: 0 μg/mL - 0.692 μg/mL
• Incubation Time: 96 hours
• Methods: Topotecan is dissolved in sterile water to a stock concentration of 1 mg/mL, diluted to 6 μg/mL in cultured medium and then serially diluted 1:4 in opaque, white tissue culture-treated microplates to a final volume of 0.1 mL/well. MCF-7 Luc and DU-145 Luc cells are resuspended in 3×10^4 cells/mL in DMEM with high glucose containing 10% FBS and 0.5 mg/mL Geneticin; 100 μL of cells are added in each well. Plates are incubated for 4 days at 37 °C in 95% humidity/5% CO₂. After incubation, 0.05 mL of 0.1 M HEPES buffer (pH 7.9) containing 50 μg/mL D-luciferin is added to each well. After incubation at room temperature for 10 minutes, the culture microplate is measured in a microplate luminometer and a molecular light imager. Results obtained with the microplate luminometer are calculated using no inhibition control wells without exogenous drug and maximum inhibition control wells containing ATP inhibitor. Results for the molecular light imager are similarly calculated using values obtained with a 5 minutes luminescent image.
• Protocol: Animal Study ^[1]
• Animal Models: Mice with MCF-7 Luc or DU-145 Luc cells
• Formulation: PBS
• Doses: 0.25 mg/mL
• Administration: Administered via i.p.

References

• References: [1] Caceres G, et al. Anticancer Drugs. 2003, 14(7), 569-574.
• References: [2] Uckun FM, et al. Blood. 1995. 85(10), 2817-2828.
• References: [3] Ciusani E, et al. J Neurooncol. 2005, 71(1), 19-25.
• References: [4] McCluskey AG, et al. J Nucl Med. 2012, 53(7), 1146-1154.
• References: [5] Romanelli S, et al. Cancer Chemother Pharmacol. 1998, 41(5), 385-390.

Toronto Research Chemicals - T542500

A DNA topoisomerase I inhibitor; semisynthetic analog of Camptothecin. Antineoplastic. Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase 1 inhibitor.

REFERENCES

• Caceres G, et al. Anticancer Drugs. 2003, 14(7), 569-574.
• Uckun FM, et al. Blood. 1995. 85(10), 2817-2828.
• Ciusani E, et al. J Neurooncol. 2005, 71(1), 19-25.
• McCluskey AG, et al. J Nucl Med. 2012, 53(7), 1146-1154.
• Romanelli S, et al. Cancer Chemother Pharmacol. 1998, 41(5), 385-390.
• Beijnen, J.H., et al.: J. Pharm. Biomed. Anal., 8, 789 (1990)
• BeiKingsburg, W.D., et al.: J. Med. Chem., 34, 98 (1990)
• Rowinsky, E.K., et al.: J. Clin. Oncol., 10, 647 (1990)