(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(11),3,5,7,9,15(20)-heptaene-14,18-dione

• ChemBase ID: 902
• Molecular Formular: C23H23N3O5
• Molecular Mass: 421.44582
• Monoisotopic Mass: 421.16377085
• SMILES: O1Cc2c([C@@](O)(CC)C1=O)cc1n(Cc3c1nc1c(c3)c(CN(C)C)c(O)cc1)c2=O
• Canonical SMILES: CC[C@@]1(O)C(=O)OCc2c1cc1c3nc4ccc(c(c4cc3Cn1c2=O)CN(C)C)O
• InChI: InChI=1S/C23H23N3O5/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/t23-/m0/s1
• InChIKey: UCFGDBYHRUNTLO-QHCPKHFHSA-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^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione; (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
• IUPAC Traditional name: topotecan
• Brand Name: Hycamptamine; Hycamptin; Hycamtin
• Synonyms: TPT; TTC; Topotecanum [INN-Latin]; Topotecane [INN-French]; Topotecan Lactone; Topotecan Hydrochloride; Topotecan Hcl; topotecan; Topotecan; 9-[(dimethylamino)methyl]-10-hydroxy-(20S)-camptothecin hydrochloride hydrate; NSC-609669 hydrochloride hydrate; SKF-104864A hydrochloride hydrate; hycamptamine hydrochloride hydrate; Topotecan hydrochloride hydrate

Database IDs

• CAS Number: 123948-87-8(freebase); 119413-54-6; 123948-87-8
• MDL Number: MFCD00870670
• PubChem SID: 160964365; 46505204
• PubChem CID: 60700

CALCULATED PROPERTIES

JChem

• 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
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.84
• LOG S: -2.69
• Solubility (Water): 8.61e-01 g/l

PROPERTIES

Physical Property

• Solubility: 1 mg/ml; DMSO: ≥20 mg/mL
• Apperance: yellow powder
• Hydrophobicity(logP): 0.8

Safety Information

• Storage Condition: desiccated; protect from light
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 46-48
• Safety Statements: 22-36
• GHS Pictograms: GHS08
• GHS Signal Word: Warning
• GHS Hazard statements: H341
• GHS Precautionary statements: P281
• RID/ADR: UN 2811 6.1/PG 3
• Storage Temperature: -20°C

Product Information

• Purity: ≥98% (HPLC and enzymatic); 95+%
• Empirical Formula (Hill Notation): C23H23N3O5 · xHCl · yH2O

DETAILS

DrugBank - DB01030

• Drug Groups: approved; investigational
• Description: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I. [PubChem]
• Indication: For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.
• Pharmacology: Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.
• Toxicity: The primary anticipated complication of overdosage would consist of bone marrow suppression.
• Affected Organisms: Humans and other mammals
• Biotransformation: Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.
• Half Life: 2-3 hours
• Protein Binding: 35%
• Elimination: Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.
• References: Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. [Pubmed] ; Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. [Pubmed] ; Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Sigma Aldrich - T2705

Biochem/physiol Actions
Topotecan is a topoisomerase I inhibitor and an apoptosis inducer. It is a potent antineoplastic agent.

REFERENCES

• Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. Pubmed
• Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. Pubmed
• Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. Pubmed