(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: 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

NAMES AND DATABASE IDS

Names

• IUPAC name: (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^2,^1^1.0^4,^9.0^1^5,^2^0]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[11.8.0.0^2,^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: camptothecin; (19S)-19-ethyl-19-hydroxy-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
• 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

Database IDs

• CAS Number: 7689-03-4
• MDL Number: MFCD00081076
• Beilstein Number: 631069
• PubChem SID: 160967676; 46507644
• PubChem CID: 24360

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.708908
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 1.2186455
• LogD (pH = 7.4): 1.2202017
• Log P: 1.2202432
• Molar Refractivity: 94.4925 cm^3
• Polarizability: 37.18863 Å^3
• Polar Surface Area: 79.73 Å^2
• Rotatable Bonds: 1
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.91
• LOG S: -2.83
• Solubility (Water): 5.11e-01 g/l

PROPERTIES

Physical Property

• Solubility: Acetonitrile; DMSO; Methanol
• Apperance: Pale Yellow Solid; Yellow powder
• Melting Point: 239-245°C (dec.); 260 °C (dec.)(lit.); 260(dec.)°C
• Hydrophobicity(logP): 1.74 [HANSCH,C ET AL. (1995)]

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• Storage Warning: IRRITANT; Toxic/Keep Cold
• RTECS: UQ0492000
• European Hazard Symbols: Toxic (T)
• UN Number: 1544
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 25
• Safety Statements: 45
• TSCA Listed: false
• GHS Pictograms: GHS06
• GHS Signal Word: Danger
• GHS Hazard statements: H301
• GHS Precautionary statements: P301 + P310
• Personal Protective Equipment: Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges
• RID/ADR: UN 1544 6.1/PG 3

Pharmacology Properties

• Target: Topoisomerase
• Mechanism of Action: Inhibits the DNA enzyme topoisomerase

Product Information

• Purity: ≥90% (sum of enantiomers, HPLC); 95+%; 97.5
• Salt Data: Free Base
• Biological Source: Alkaloid from Camptotheca acuminata, Mappia foetida, Ervatamia heyneana and Ophiorrhiza mungos (Nyssaceae, Rubiaceae, Apocynaceae)
• Application(s): Cytostatic; Severe side effects and rapid hydrol. at physiological pH have inhibited widespread clinical use; Shows anti-HIV and antiprotozoal activity; Shows plant growth regulatory and insect chemosterilant props.; Shows potent antineoplastic activity in exp. animals; Used clinically in China against gastrointestinal tumours
• Empirical Formula (Hill Notation): C20H16N2O4

DETAILS

DrugBank - DB04690

• 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

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.

Protocol

• 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.
• Protocol: 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.
• Protocol: 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

• References: [1] Wall ME, et al. J Am Chem Soc, 1966, 88 (16), 3888–3890.
• References: [2] Luzzio MJ, et al. J Med Chem, 1995, 38(3), 395-401.
• References: [3] Giovanella BC, et al. Cancer Res, 1991, 51(11), 3052-3055.
• References: [4] Hentze H, et al. Hepatology, 2004, 39(5), 1311-1320.
• References: [5] Cheng F, et al. Oncogene, 2011, 30(33), 3599-3611.

Sigma Aldrich - 21376

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

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

• 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.
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• Desai, S.D., et al.: J. Biol. Chem., 272, 24159 (1994)
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• Winterfeldt, E. et al., Angew. Chem., Int. Ed., 1972, 11, 289, (synth)
• Boch, M. et al., Chem. Ber., 1972, 105, 2126, (synth)
• Tang, C. et al., J.A.C.S., 1972, 94, 8615, (synth, uv)
• Sugasawa, T. et al., Chem. Pharm. Bull., 1974, 22, 77, (synth, ir, pmr)
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• Martindale, The Extra Pharmacopoeia, 28th/29th edn., Pharmaceutical Press, 1982, 12515
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• Suffness, M. et al., Alkaloids (N.Y.), 1985, 25, 83, (antineoplastic activity)
• Priel, E., AIDS Res. Hum. Retroviruses, 1991, 7, 65, (anti-HIV activity)
• Ezell, E.L. et al., J. Nat. Prod., 1991, 54, 1645, (pmr, cmr)
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• Comins, D.L. et al., J.A.C.S., 1992, 114, 10971, (synth)