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7689-03-4 molecular structure
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(19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione

ChemBase ID: 4244
Molecular Formular: C20H16N2O4
Molecular Mass: 348.35204
Monoisotopic Mass: 348.111007
SMILES and InChIs

SMILES:
O=c1c2COC(=O)[C@](c2cc2n1Cc1cc3c(nc21)cccc3)(O)CC
Canonical SMILES:
CC[C@@]1(O)C(=O)OCc2c1cc1c3nc4ccccc4cc3Cn1c2=O
InChI:
InChI=1S/C20H16N2O4/c1-2-20(25)14-8-16-17-12(7-11-5-3-4-6-15(11)21-17)9-22(16)18(23)13(14)10-26-19(20)24/h3-8,25H,2,9-10H2,1H3/t20-/m0/s1
InChIKey:
VSJKWCGYPAHWDS-FQEVSTJZSA-N

Cite this record

CBID:4244 http://www.chembase.cn/molecule-4244.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
(19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione
(19S)-19-ethyl-19-hydroxy-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)-19-ethyl-19-hydroxy-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
IUPAC Traditional name
camptothecin
(19S)-19-ethyl-19-hydroxy-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
Synonyms
(S)-4-Ethyl-4-hydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
(S)-(+)-Camptothecin
(4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
CPT
D-camptothecin
(+)-camptothecin
(+)-camptothecine
(s)-(+)-camptothecin
(s)-camptothecin
20(S)-Camptothecin
21,22-Secocamptothecin-21-oic acid lactone
Camptothecine
Camptothecin
(S)-(+)-Camptothecin
(S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
Camptothecin
CAS Number
7689-03-4
MDL Number
MFCD00081076
Beilstein Number
631069
PubChem SID
160967676
46507644
PubChem CID
24360

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem ALOGPS 2.1
Acid pKa 11.708908  H Acceptors
H Donor LogD (pH = 5.5) 1.2186455 
LogD (pH = 7.4) 1.2202017  Log P 1.2202432 
Molar Refractivity 94.4925 cm3 Polarizability 37.18863 Å3
Polar Surface Area 79.73 Å2 Rotatable Bonds
Lipinski's Rule of Five true 
Log P 1.91  LOG S -2.83 
Solubility (Water) 5.11e-01 g/l 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
Acetonitrile expand Show data source
DMSO expand Show data source
Methanol expand Show data source
Apperance
Pale Yellow Solid expand Show data source
Yellow powder expand Show data source
Melting Point
239-245°C (dec.) expand Show data source
260 °C (dec.)(lit.) expand Show data source
260(dec.)°C expand Show data source
Hydrophobicity(logP)
1.74 [HANSCH,C ET AL. (1995)] expand Show data source
Storage Condition
-20°C expand Show data source
-20°C Freezer expand Show data source
Storage Warning
IRRITANT expand Show data source
Toxic/Keep Cold expand Show data source
RTECS
UQ0492000 expand Show data source
European Hazard Symbols
Toxic Toxic (T) expand Show data source
UN Number
1544 expand Show data source
MSDS Link
Download expand Show data source
Download expand Show data source
Download expand Show data source
German water hazard class
3 expand Show data source
Hazard Class
6.1 expand Show data source
Packing Group
3 expand Show data source
Risk Statements
25 expand Show data source
Safety Statements
45 expand Show data source
TSCA Listed
false expand Show data source
GHS Pictograms
GHS06 expand Show data source
GHS Signal Word
Danger expand Show data source
GHS Hazard statements
H301 expand Show data source
GHS Precautionary statements
P301 + P310 expand Show data source
Personal Protective Equipment
Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges expand Show data source
RID/ADR
UN 1544 6.1/PG 3 expand Show data source
Target
Topoisomerase expand Show data source
Mechanism of Action
Inhibits the DNA enzyme topoisomerase expand Show data source
Purity
≥90% (sum of enantiomers, HPLC) expand Show data source
95+% expand Show data source
97.5 expand Show data source
Salt Data
Free Base expand Show data source
Certificate of Analysis
Download expand Show data source
Biological Source
Alkaloid from Camptotheca acuminata, Mappia foetida, Ervatamia heyneana and Ophiorrhiza mungos (Nyssaceae, Rubiaceae, Apocynaceae) expand Show data source
Application(s)
Cytostatic expand Show data source
Severe side effects and rapid hydrol. at physiological pH have inhibited widespread clinical use expand Show data source
Shows anti-HIV and antiprotozoal activity expand Show data source
Shows plant growth regulatory and insect chemosterilant props. expand Show data source
Shows potent antineoplastic activity in exp. animals expand Show data source
Used clinically in China against gastrointestinal tumours expand Show data source
Empirical Formula (Hill Notation)
C20H16N2O4 expand Show data source

DETAILS

DETAILS

DrugBank DrugBank Selleck Chemicals Selleck Chemicals Sigma Aldrich Sigma Aldrich TRC TRC
DrugBank - DB04690 external link
Item Information
Drug Groups experimental
Description An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase, type I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [PubChem]
Indication Investigated for the treatment of cancer.
Pharmacology Camptothecin demonstrated strong anticancer activity in preliminary clinical trials but also low solubility and adverse drug reaction. Camptothecin is believed to be a potent topoisomerase inhibitor that interferes with the essential function of topoisomerase in DNA replication.
Toxicity Acute oral toxicity (LD50) in mouse: 50.1 mg/kg
Affected Organisms
Humans and other mammals
References
Wall ME, Wani MC: Camptothecin and taxol: from discovery to clinic. J Ethnopharmacol. 1996 Apr;51(1-3):239-53; discussion 253-4. [Pubmed]
Kepler JA, Wani MC, McNaull JN, Wall ME, Levine SG: Plant antitumor agents. IV. An approach toward the synthesis of camptothecin. J Org Chem. 1969 Dec;34(12):3853-8. [Pubmed]
External Links
Wikipedia
Selleck Chemicals - S1288 external link
Research Area
Description Cancer
Biological Activity
Description Camptothecin (Camptohecine, 20-(S)-Camptothecin, CPT, NSC100880) is a specific inhibitor of DNA topoisomerase I (Topo I) with IC50 of 0.68 μM.
Targets DNA topoisomerase I (topo I)
IC50 0.68 μM [2]
In Vitro Camptothecin, a plant alkaloid orignially isolated from Camptotheca acuminate in 1966. [1] Camptothecin is noted to halt cells during the S phase of mitosis. Camptothecin displays nanomolar potency in cytotoxicity against many human tumor cell lines, including HT29, LOX, SKOV3, and SKVLB, with IC50 values ranging from 37 nM to 48 nM. [2]In combination with TNF, Camptothecin induces apoptosis in primary mouse hepatocytes, with an IC50 value of 13 μM. Camptothecin also abrogated the TNF-induced NF-κB Activation, as well as the expression of TNF-receptor associated factor 2 (TRAF2), X-linked inhibitor of apoptosis protein (X-IAP), and FLICE-inhibitory protein (FLIP). [4]In HCT116 cells, Camptothecin (5 μM) induces proteasome-mediated degradation of mixed lineage leukemia 5 (MLL5) protein, which leads to phosphorylation of p53 at Ser392. [5]Due to the low solubility and adverse effects of Camptothecin, various Camptothecin analogues have been developed, and two of them, topotecan and irinotecan, has been approved by FDA and are used in cancer chemotherapy.
In Vivo Camptothecin (8 mg/kg) displays complete growth inhibition and regression in mice xenografts of various tumors, including colon, lung, breast, stomach, and ovary tumors. [3]In mice, combinations of Camptothecin (50 mg/kg) and TNF (5 and 7 μg/kg), but not Camptothecin alone, induces liver damage. [4]
Clinical Trials Investigations of Camptothecin and its analogues in multiple Phase I–III clinical trials for various cancers have been completed.
Features
Protocol
Kinase Assay [2]
Topoisomerase I Cleavable Complex Assay Topoisomerase I is isolated from calf thymus and is devoid of topoisomerase II. All reactions are carried out in 10 mL volumes of reaction buffer (50 mM Tris-HCl, pH 7.5, 100 mM KCl, 0.5 mM EDTA, and 30 pg/mL BSA) in microtiter plates. Camptothecin is dissolved in DMSO at 10 mg/mL and serially diluted in 96-well microtiter plates to which the 32P end-labeled pBR322 DNA and topoisomerase enzyme are added. The reaction mixture is incubated at room temperature for 30 min and then the reaction stopped by adding 2 mL of a mixture of sodium dodecyl sulfate and proteinase K (1.6% and 0.14 mg/mL final concentrations, respectively). The plates are heated at 50 °C for 30 min, 10 mL of standard stop mixture containing 0.45 N NaOH is added in order to generate single-stranded DNA, and the samples are electrophoresed in 1.5% agarose gels in TBE buffer. Gels are blotted on nitrocellulose paper, dried, and exposed to X-ray film. The units of cleavage are calculated from the autoradiographs and plotted against the log drug concentration. The IC50 values are then obtained.
Cell Assay [2]
Cell Lines U87MG, A549 and H838 cells
Concentrations 0.17 nM–10 mM
Incubation Time 48 hours
Methods Tumor cells are plated in 100 μL of medium in 96-well microtiter plates at a density of 1500 to 4000 cells per well and allowed to adhere overnight. Cells are incubated with Camptothecin for 48 hours and then with fresh medium for 48 hours. Camptothecin at each concentration is added in quadruplicate. Following a 4-hour incubation of treated cells with MTT, the reduced dye product is extracted from the cells with 0.2 mL of DMSO followed by 50 μL of Sorensen's buffer. The plates are shaken briefly, and the absorbance at 570 nm is read and quantitated. Curves are fitted to the MTT assay data using a four-parameter logistic equation.
Animal Study [3]
Animal Models Nude mice (NIH-I high fertility strain) bearing xenografts of CASE, SW48, DOY, SPA, and CLO cells
Formulation Finely grounded and dispersed in intralipid 20% at 1 mg/mL by sonication
Doses 0–8 mg/kg
Administration Administered via i.m. or i.v. injection
References
[1] Wall ME, et al. J Am Chem Soc, 1966, 88 (16), 3888–3890.
[2] Luzzio MJ, et al. J Med Chem, 1995, 38(3), 395-401.
[3] Giovanella BC, et al. Cancer Res, 1991, 51(11), 3052-3055.
[4] Hentze H, et al. Hepatology, 2004, 39(5), 1311-1320.
[5] Cheng F, et al. Oncogene, 2011, 30(33), 3599-3611.
Sigma Aldrich - 21376 external link
Other Notes
Eukaryotic DNA topoisomerase I poison. Used to study the interaction of topo I with DNA1,2; DNA topoisomerases, review3
Toronto Research Chemicals - C175150 external link
Antitumor alkaloid. Binds irreversible to the DNA-topoisomerase I complex, inhibiting the reassociation of DNA after cleavage by topoisomerase I and traps the enzyme in a covalent linkage with DNA. A cytotoxic antitumor agent.

REFERENCES

REFERENCES

From Suppliers Google Scholar IconGoogle Scholar PubMed iconPubMed Google Books IconGoogle Books
  • • Wall ME, Wani MC: Camptothecin and taxol: from discovery to clinic. J Ethnopharmacol. 1996 Apr;51(1-3):239-53; discussion 253-4. Pubmed
  • • Kepler JA, Wani MC, McNaull JN, Wall ME, Levine SG: Plant antitumor agents. IV. An approach toward the synthesis of camptothecin. J Org Chem. 1969 Dec;34(12):3853-8. Pubmed
  • • Wall ME, et al. J Am Chem Soc, 1966, 88 (16), 3888–3890.
  • • Luzzio MJ, et al. J Med Chem, 1995, 38(3), 395-401.
  • • Giovanella BC, et al. Cancer Res, 1991, 51(11), 3052-3055.
  • • Hentze H, et al. Hepatology, 2004, 39(5), 1311-1320.
  • • Cheng F, et al. Oncogene, 2011, 30(33), 3599-3611.
  • • Potmesil, M., et al.: Cancer Res., 54, 1431 (1994)
  • • Desai, S.D., et al.: J. Biol. Chem., 272, 24159 (1994)
  • • Fan, Y., et al.: J. Med. Chem., 41, 2216 (1994)
  • • Kaufmann, S.H., et al.: Biochim. Biophys. Acta, 1400, 195 (1994)
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  • • Winterfeldt, E. et al., Angew. Chem., Int. Ed., 1972, 11, 289, (synth)
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  • • Martindale, The Extra Pharmacopoeia, 28th/29th edn., Pharmaceutical Press, 1982, 12515
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  • • Earl, R.A., J.A.C.S., 1983, 105, 6991, (synth)
  • • Ihara, M. et al., J.O.C., 1983, 48, 3150, (synth)
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