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Details

Stereochemistry ABSOLUTE
Molecular Formula C23H23N3O5
Molecular Weight 421.4458
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOPOTECAN

SMILES

CC[C@@]1(O)C(=O)OCC2=C1C=C3N(CC4=C3N=C5C=CC(O)=C(CN(C)C)C5=C4)C2=O

InChI

InChIKey=UCFGDBYHRUNTLO-QHCPKHFHSA-N
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

HIDE SMILES / InChI

Molecular Formula C23H23N3O5
Molecular Weight 421.4458
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

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. Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. Topotecan is used 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. Topotecan is sold under the trade name Hycamtin.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
1028.0 nM [IC50]
3.16 µM [IC50]
0.448 µM [IC50]
1.1 µM [IC50]
33.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
HYCAMTIN
Primary
HYCAMTIN

Cmax

ValueDoseCo-administeredAnalytePopulation
9.29 ng/mL
4 mg single, oral
TOPOTECAN plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
61 ng × h/mL
4 mg single, oral
TOPOTECAN plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
5.23 h
4 mg single, oral
TOPOTECAN plasma
Homo sapiens

Funbound

ValueDoseCo-administeredAnalytePopulation
65%
TOPOTECAN plasma
Homo sapiens

Doses

AEs

PubMed

Sample Use Guides

In Vivo Use Guide
Ovarian cancer and small cell lung cancer: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course. Cervical cancer: 0.75 mg/m2 by intravenous infusion over 30 minutes on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m2 on Day 1
Route of Administration: Intravenous
In Vitro Use Guide
In DC3F hamster lung fibroblasts, 2.5 uM topotecan caused redistribution of topo I to nonnucleolar regions of the nucleus.
Substance Class Chemical
Record UNII
7M7YKX2N15
Record Status Validated (UNII)
Record Version