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Topotecan - CAS 123948-87-8 Catalog number: BADC-00328
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Topotecan has been used as a positive control for the identification and analysis of HIF-1α and VEGF inhibitors in human glioma cells under hypoxic conditions. It has also been used for in vitro apoptosis assays in PA317 cells.
Category
ADCs Cytotoxin
Product Name
Topotecan
CAS
123948-87-8
Catalog Number
BADC-00328
Molecular Formula
C23H23N3O5
Molecular Weight
421.45
Ordering Information
| Catalog Number | Size | Price | Quantity |
|---|---|---|---|
| BADC-00328 | -- | $-- |
Description
Topotecan has been used as a positive control for the identification and analysis of HIF-1α and VEGF inhibitors in human glioma cells under hypoxic conditions. It has also been used for in vitro apoptosis assays in PA317 cells.
Synonyms
(S)-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;Hycamtin; SKF104864; SKF 104864; SKF-104864
IUPAC Name
(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),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
Canonical SMILES
CC[C@@]1(c2cc3n(c(=O)c2COC1=O)Cc4c3nc5ccc(c(c5c4)CN(C)C)O)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
Solubility
Soluble to 2,350 mg/l at 25 °c in water
Melting Point
>155 °C (dec.)
LogP
-0.88
Vapor Pressure
3.52X10-18 mm Hg at 25 °C (est)
UV Spectra
(MeOH) max = 207 ± 2 nm E = 21,484;(MeOH) max = 224 ± 2 nm E = 39,009;(MeOH) max = 269 ± 2 nm E = 22,902;(MeOH) max = 296 ± 2 nm E = 6,783;(MeOH) max = 318 ± 2 nm E = 10,003;(MeOH) max = 332 ± 2 nm E = 13,091;(MeOH) max = 371 ± 2 nm E = 19,267;(MeOH) max = 384 ± 2 nm E = 22,718
Mechanism Of Action
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.
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 (LD50)
The dose-limiting toxicity of topotecan is leukopenia. Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. Case report describes a patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. Topotecan was clastogenic to cultured human lymphocytes with and without metabolic activation.
In Vitro
Topotecan, a topoisomerase I inhibitor, is an anticancer drug widely used in the therapy of lung, ovarian, colorectal, and breast adenocarcinoma. Cells were incubated with different topotecan and thymoquinone concentrations for 24 and 48 hours in order to determine the IC50 for each drug. Combined therapy was then tested with ± 2 values for the IC50 of each drug. The reduction in proliferation was significantly dose- and time-dependent. After determining the best combination (40 µM thymoquinone and 0.6 µM topotecan), cell proteins were extracted after treatment, and the expression levels of B-cell lymphoma 2 and of its associated X protein, proteins p53 and p21, and caspase-9, caspase-3, and caspase-8 were studied by Western blot. Cell cycle analysis and annexin/propidium iodide staining were performed. Both drugs induced apoptosis through a p53-independent mechanism, whereas the expression of p21 was only seen in thymoquinone treatment. Cell cycle arrest in the S phase was detected with each compound separately, while combined treatment only increased the production of fragmented DNA. Both compounds induced apoptosis through the extrinsic pathway after 24 hours; however, after 48 hours, the intrinsic pathway was activated by topotecan treatment only.
In Vivo
Pravastatin and probenecid significantly inhibited the uptake of topotecan hydroxyl acid by rat kidney slices with K(i) values of 10.6 and 8.1 microM, respectively, and p-aminohippurate was weakly inhibitory at high concentrations, whereas excess tetraethylammonium had no effect. The uptake of topotecan hydroxyl acid by oocytes injected with complementary RNA of either rat or human organic anion transporter 3 (rOAT3 or hOAT3) was greater than that of water-injected oocytes. Kinetic analysis showed that the K(m) values for rOAT3 and hOAT3 were 21.9 and 56.5 microM, respectively. Neither rOAT1 nor hOAT1 stimulated topotecan hydroxyl acid transport.
Clinical Trial Information
| NCT Number | Condition Or Disease | Phase | Start Date | Sponsor | Status |
|---|---|---|---|---|---|
| NCT04213937 | Extensive Stage Small Cell Lung Cancer | Phase 2 | 2019-12-30 | Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Recruiting |
| NCT00158886 | Carcinoma, Renal Cell | Phase 1 | 2017-11-14 | GlaxoSmithKline | Terminated |
| NCT00888810 | Cancer | Phase 2 | 2009-04-28 | Centre Francois Baclesse | Terminated (lack of efficacy (intermediate analysis)) |
| NCT01405235 | Recurrent, Persistent or Metastasized Cervical Cancer | Phase 3 | 2012-04-12 | Institut fuer Frauengesundheit | Unknown Verified September 2006 by Institut fuer Frauengesundheit. Recruitment status was Active, not recruiting |
| NCT04799002 | Retinoblastoma | Phase 3 | 2021-03-16 | Sun Yat-sen University | Recruiting |
Appearance
Soild powder
Purity
≥95%
Shelf Life
Stable under recommended storage conditions
Shipping
Room temperature
Pictograms
Irritant; Acute Toxic; Health Hazard
Signal Word
Warning;Danger
1. Mode of binding of camptothecins to double helix oligonucleotides
Stefania Mazzini, Maria Cristina Bellucci, Sabrina Dallavalle, Franca Fraternali and Rosanna Mondelli *. Org. Biomol. Chem. , 2004, 2, 505–513
Actually, the mode of binding of Cpts to DNA in absence of the enzyme is still unclear and the published results on the DNA/Cpt interactions are confusing and contradictory. Cpt was first described as a prototypical Topo-I poison that exhibits little or no binding to either DNA or Topo-I alone. More recently two clinically important Cpt derivatives, topotecan (Tpt) 1 and irinotecan, were shown to be capable of binding with DNA in the absence of Topo-I, but no data on the molecular structure of Cpt/DNA complexes have been published. The results from linear dichroism spectroscopy appear difficult to interpret; binding in the major groove was suggested by some authors, others claimed to have recognized two types of complexes with calf-thymus DNA, and concluded for a binding in the minor groove. Two NMR studies on Tpt/DNA binding have been reported, but the results, based only on chemical shift values, are contradictory. Yao et al. claimed a sequence specificity for duplex DNA containing dT, whereas Yang et al. reported a specific intercalation of topotecan into dGdC rather than dAdT sequences. An intercalation type of binding has also been suggested by Pilch et al.
2. Integrated computational strategies for UV/vis spectra of large molecules in solution
Vincenzo Barone* and Antonino Polimeno. Chem. Soc. Rev., 2007, 36, 1724–1731
Let us consider, for purposes of illustration, an example in which even a semi-quantitative approach (i.e. vertical excitations with a basic non-equilibrium solvent model) provides results of remarkable interest for the individuation of spectroscopic signatures in large molecules of biological interest. Topotecan is the most commonly used agent for the treatment of ovarian carcinoma, and is the only single agent currently approved in the United States for the treatment of small-cell lung cancer recurrent disease, which is among the most lethal malignancies. Since the drug displays a high degree of toxicity also against normal tissues that show enhanced proliferative rates, a deeper understanding of structure–property relationships is of considerable interest. At concentrations low enough to avoid dimer formation, tautomeric forms with charge +1 (see Fig. 3) dominate in the pH range 4–6.
3. Live-cell monitoring of the glutathione-triggered release of the anticancer drug topotecan on gold nanoparticles in serum-containing media
Mira Kim, Kwangsu Ock, Keunchang Cho, Sang-Woo Joo* and So Yeong Lee*. Chem. Commun., 2012, 48, 4205–4207
Topotecan (TOPO) is a camptothecin compound, one of the topoisomerase I inhibitors resulting in the accumulation of single-stranded breaks in DNA. Topotecan (TOPO) has its own fluorescence emission maximum at 530 nm, quite close to the absorption bands of AuNPs. The camptothecin compounds may adsorb onto Au surfaces. Fluorescence appears to be quenched on Au surfaces via nanometal surface energy transfer (NSET), which may be utilized in biomolecular imaging.
4. Cyclometalated gold(III) complexes with N-heterocyclic carbene ligands as topoisomerase Ⅰ poisons
Jessie Jing Yan, Andy Lok-Fung Chow, Chung-Hang Leung, Raymond Wai-Yin Sun, Dik-Lung Ma and Chi-Ming Che*. Chem. Commun., 2010, 46, 3893–3895
To gain insight into the structural basis of the TopoI-linked DNA complex stabilization by 1, we used flexible-ligand docking module of ICM-Pro 3.6–1 molecular software (Molsoft). Analysis of the low energy metal complex conformations revealed that 1 binds to TopoI-linked DNA in a manner similar to the binding by topotecan, a derivative of CPT (Fig. 4), with a calculated binding energy of -9.7 kcal/mol (cf., calculated binding of topotecan = -11.6 kcal/mol). The proposed binding mode of 1 partially overlaps with that of topotecan and there is no hydrogen bond between TopoI and 1, in contrast to the presence of a direct hydrogen bonds between Asp533 and topotecan, and between Arg364 and topotecan, in the TopoI-DNA-topotecan complex.
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