(10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1(9),2,7-trien-12-one

• ChemBase ID: 653
• Molecular Formular: C29H32O13
• Molecular Mass: 588.55658
• Monoisotopic Mass: 588.18429108
• SMILES: O([C@H]1[C@@H]2[C@@H]([C@@H](c3c1cc1OCOc1c3)c1cc(OC)c(O)c(OC)c1)C(=O)OC2)[C@@H]1O[C@H]2[C@@H](O[C@@H](OC2)C)[C@H](O)[C@H]1O
• Canonical SMILES: COc1cc(cc(c1O)OC)[C@H]1[C@H]2C(=O)OC[C@@H]2[C@@H](c2c1cc1OCOc1c2)O[C@@H]1O[C@@H]2CO[C@H](O[C@H]2[C@@H]([C@H]1O)O)C
• InChI: InChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25-,26-,27-,29+/m1/s1
• InChIKey: VJJPUSNTGOMMGY-MRVIYFEKSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^3,^7.0^1^1,^1^5]hexadeca-1(9),2,7-trien-12-one; (10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1(9),2,7-trien-12-one; (10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^3,^7.0^1^1,^1^5]hexadeca-1,3(7),8-trien-12-one; (10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1,3(7),8-trien-12-one
• IUPAC Traditional name: etoposide
• Brand Name: Eposin; Etopophos; Lastet; Toposar; Vepesid; Vepesid J; Zuyeyidal
• Synonyms: (5R,5aR,8aR,9S)-9-[[4,6-O-(1R)-Ethylidene-β-D-glucopyranosyl]oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one; EPEG; P 16-213; Vepesid J; Zuyeyidal; (-)-Etoposide; Etoposidum [INN-Latin]; trans-Etoposide; Etoposide; 4′-Demethylepipodophyllotoxin 9-(4,6-O-ethylidene-β-D-glucopyranoside); VP-16-213; Etoposide; EPA; Demethyl-epiodophyllotoxin ethylidene glucoside; Eposin; Vepesid; VP-16; Toposar

Database IDs

• CAS Number: 33419-42-0
• EC Number: 251-509-1
• MDL Number: MFCD00869325
• PubChem SID: 46505434; 160964116; 24278178
• PubChem CID: 36462

CALCULATED PROPERTIES

JChem

• Acid pKa: 9.329948
• H Acceptors: 12
• H Donor: 3
• LogD (pH = 5.5): 1.1603667
• LogD (pH = 7.4): 1.155394
• Log P: 1.1604304
• Molar Refractivity: 139.0212 cm^3
• Polarizability: 55.93246 Å^3
• Polar Surface Area: 160.83 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 0.73
• LOG S: -2.78
• Solubility (Water): 9.78e-01 g/l

PROPERTIES

Physical Property

• Solubility: 58.7 mg/L; DMSO: soluble30 mg/mL; Methanol
• Apperance: white powder; White Solid
• Melting Point: 236-251 °C(lit.); 254-256°C
• Hydrophobicity(logP): 1
• pKa: 9.8

Safety Information

• Storage Condition: -20°C; -20°C Freezer, Under Inert Atmosphere; Room Temperature (15-30°C)
• RTECS: KC0190000
• European Hazard Symbols: Toxic (T); Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 45-22; R:22-45-36/37/38
• Safety Statements: 53-45; S:28-29-36/37/39-45-53
• GHS Pictograms: GHS07; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H302-H350
• GHS Precautionary statements: P201-P308 + P313
• Personal Protective Equipment: Eyeshields, full-face particle respirator type N100 (US), Gloves, respirator cartridge type N100 (US), type P1 (EN143) respirator filter, type P3 (EN 143) respirator cartridges

Pharmacology Properties

• Target: Topoisomerase
• Gene Information: human ... ABCB1(5243), CYP3A4(1576), TOP2A(7153)mouse ... Abcb1a(18671), Abcb1b(18669)rat ... Top2a(360243)

Product Information

• Purity: ≥98%
• Salt Data: Free Base
• Biological Source: synthetic

DETAILS

DrugBank - DB00773

• Drug Groups: approved
• Description: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [PubChem]
• Indication: For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.
• Pharmacology: Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.
• Toxicity: Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine.
• Absorption: Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50%.
• Half Life: 4-12 hours
• Protein Binding: 97%
• Elimination: Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide.
• Clearance: * 33 - 48 mL/min [IV administration]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1225

Research Area: Cancer
Biological Activity:
Two subclones of the OCI/AML-2 cell line, etoposide-sensitive (ES) and etoposide-resistant (ER) were used to investigate whether the Fas pathway is involved in etoposide-induced apoptosis in acute myeloblastic leukemia (AML). Both of the studied subclones expressed the Fas receptor (FasR), but only the ER cell line expressed the Fas ligand (FasL). Etoposide caused an increase in the mean fluorescence intensity of FasR in both subclones, and an induction of FasL in the ES subclone. However, no change in the numbers of apoptotic cells induced by etoposide was observed when FasR was blocked by an antagonist anti-Fas antibody, nor was an agonist anti-Fas antibody alone cytotoxic to the subclones or enhanced the cytotoxic effect of etoposide. [1]Etoposide phosphate is rapidly absorbed and converted to etoposide. Bioavailability averages 68% at doses up to 150 mg/m2/day. [3]

Sigma Aldrich - E1383

Biochem/physiol Actions
Etoposide is an antitumor agent that complexes with topoisomerase II and DNA to enhance double-strand and single-strand cleavage of DNA and reversibly inhibit religation. Blocks the cell cycle in in S-phase and G2-phase of the cell cycle; induces apoptosis in normal and tumor cell lines; inhibits synthesis of the oncoprotein Mdm2 and induces apoptosis in tumor lines that overexpress Mdm2.

Toronto Research Chemicals - E933750

A DNA topoisomerase II inhibitor. Semi-synthetic derivative of podophyllotoxin, related structurally to Teniposide. Antineoplastic.

REFERENCES

• Siitonen T et al. Leuk Res. 2000 Apr;24(4):281-8
• Burden, D.A., et al.: J. Biol. Chem., 271, 29238 (1996)
• Joel, S., et al.: Cancer Treat. Rev., 22, 179 (1996)