(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-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)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate

• ChemBase ID: 642
• Molecular Formular: C33H38N4O6
• Molecular Mass: 586.67802
• Monoisotopic Mass: 586.27913496
• SMILES: O(C(=O)N1CCC(N2CCCCC2)CC1)c1cc2c(c3Cn4c(c3nc2cc1)cc1[C@@](O)(CC)C(=O)OCc1c4=O)CC
• Canonical SMILES: CC[C@@]1(O)C(=O)OCc2c1cc1c3nc4ccc(cc4c(c3Cn1c2=O)CC)OC(=O)N1CCC(CC1)N1CCCCC1
• InChI: InChI=1S/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1
• InChIKey: UWKQSNNFCGGAFS-XIFFEERXSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-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)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate; (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-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)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate
• IUPAC Traditional name: irinotecan; (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-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)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate
• Brand Name: CP0; Camptosar; IRINOTECAN, CPT-11
• Synonyms: Irinotecan Hydrochloride; Irinotecan Hydrochloride Trihydrate; Irinotecan Hcl; Irinotecanum [INN-Latin]; irinotecan; Irinotecan; Camptosar; Camptetin; Campto; Topotecin; Irinotecan

Database IDs

• CAS Number: 97682-44-5; 100286-90-6
• PubChem SID: 46505871; 160964105
• PubChem CID: 60838

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.713039
• H Acceptors: 6
• H Donor: 1
• LogD (pH = 5.5): -0.6070732
• LogD (pH = 7.4): 0.7157881
• Log P: 2.776473
• Molar Refractivity: 161.3303 cm^3
• Polarizability: 63.005684 Å^3
• Polar Surface Area: 112.51 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 3.94
• LOG S: -3.74
• Solubility (Water): 1.07e-01 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Soluble
• Hydrophobicity(logP): 3.2

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: topoisomerase
• Mechanism of Action: Topoisomerase I inhibitor

Product Information

• Salt Data: Free Base
• Application(s): Antineoplastic agent; Use is in colon cancer

DETAILS

DrugBank - DB00762

• Drug Groups: approved; investigational
• Description: Irinotecan is an antineoplastic enzyme inhibitor primarily used in the treatment of colorectal cancer. It is a derivative of camptothecin that inhibits the action of topoisomerase I. Irinotecan prevents religation of the DNA strand by binding to topoisomerase I-DNA complex, and causes double-strand DNA breakage and cell death.
• Indication: For the treatment of metastatic colorectal cancer (first-line therapy when administered with 5-fluorouracil and leucovorin). Also used in combination with cisplatin for the treatment of extensive small cell lung cancer. Irinotecan is currently under investigation for the treatment of metastatic or recurrent cervical cancer.
• Pharmacology: Irinotecan is an antineoplastic enzyme inhibitor primarily used in the treatment of colorectal cancer. Irinotecan is a semisynthetic derivative of camptothecin. Camptothecins interact specifically with topoisomerase I, an enzyme in the cell nucleus that regulates DNA topology and facilitates nuclear processes such as DNA replication, recombination, and repair. During these processes, topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks, allowing single DNA strands to pass through the break. The 3'-DNA terminus of the broken DNA strands bind covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After the DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the chemically unaltered topoisomers that allow transcription to proceed. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either Irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks. The precise contribution of SN-38 to the activity of irinotecan in humans is not known. Irinotecan is cell cycle phase-specific (S-phase).
• Toxicity: Gastrointestinal complications, such as nausea, vomiting, abdominal cramping, diarrhea, and infection.
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic
• Absorption: 100%
• Half Life: 6-12 hours
• Protein Binding: 30%-68%
• Elimination: The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).
• References: Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004 Apr 15;22(8):1382-8. Epub 2004 Mar 8. [Pubmed] ; O'Dwyer PJ, Catalano RB: Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol. 2006 Oct 1;24(28):4534-8. [Pubmed] ; Ramesh M, Ahlawat P, Srinivas NR: Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. Biomed Chromatogr. 2010 Jan;24(1):104-23. [Pubmed] ; Chabot GG: Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet. 1997 Oct;33(4):245-59. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1198

Research Area

• Description: Solid tumours

Biological Activity

• Description: Irinotecan (Camptosar, Campto, CPT-11) is a topoisomerase I inhibitor for LoVo cells and HT-29 cells with IC50 of 15.8 μM and 5.17 μM, respectively.
• Targets: LoVo cells; HT-29 cells
• IC50: 15.8 μM; 5.17 μM ^[1]
• In Vitro: Irinotecan is activated to SN-38 by carboxylesterases to become able to interact with its target, topoisomerase I. Irinotecan induces similar amounts of cleavable complexes at its IC50 in LoVo cells and HT-29 cell lines. SN-38 induces a concentration-dependent formation of cleavable complexes, which is not significantly different in LoVo cells and HT-29 cell lines. Cell accumulation of Irinotecan is markedly different, reaching consistently higher levels in HT-29 cells than in LoVo cells. ^[1] The lactone E-ring of Irinotecan and SN-38 hydrolyses reversibly in aqueous solutions, and the interconversion between the lactone and carboxylate forms is dependent on pH and temperature. Liver is primarily responsible for the activation of Irinotecan to SN-38. At equal concentrations of Irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production is higher than that formed from Irinotecan in both tumour and normal tissue. ^[2] Irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. ^[3] Irinotecan is significantly more active in SCLC than in NSCLC cell lines, whereas no significant difference between histological types is observed with SN-38. ^[4]
• In Vivo: In COLO 320 xenografts, Irinotecan induces a maximum growth inhibition of 92%. ^[5] A single dose of Irinotecan significantly increases amounts of topoisomerase I covalently bound to DNA in stomach, duodenum, colon and liver. Concomitantly, the Irinotecan-treated group shows significantly higher amounts of DNA strand breaks in colon mucosa cells compared to the control group. ^[6]
• Clinical Trials: Irinotecan has entered in a phase II clinical trial in the treatment of non-small cell lung cancer.
• Features: Irinotecan is a prodrug that is used to treat metastatic colorectal cancer.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: LoVo and HT-29 cells
• Concentrations: 0 μM -100 μM
• Incubation Time: 48 hours
• Methods: Exponentially growing cells (LoVo and HT-29 cells) are seeded in 20 cm^2 Petri dishes with an optimal cell number for each cell line (2 × 10^4 for LoVo cells, 10^5 for HT-29 cells). They are treated 2 days later with increasing concentrations of Irinotecan or SN-38 for one cell doubling time (24 hours for LoVo cells, 40 hours for HT-29 cells). After washing with 0.15 M NaCl, the cells are further grown for two doubling times in normal medium, detached from the support with trypsin-EDTA and counted in a hemocytometer. The IC50 values are then estimated as the Irinotecan or SN-38 concentrations responsible for 50% growth inhibition as compared with cells incubated without Irinotecan or SN-38.
• Protocol: Animal Study ^[5]
• Animal Models: Female nude mice with COLO 320 and WiDr xenografts
• Formulation: 0.9% NaCl
• Doses: 20 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Pavillard V, et al. Cancer Chemother Pharmacol. 2002, 49(4), 329-335.
• References: [2] Tobin P, et al. Br J Clin Pharmacol. 2006, 62(1), 122-129.
• References: [3] Shingyoji M, et al. Cancer Sci. 2004, 95(6), 537-540.
• References: [4] van Ark-Otte J, et al. Br J Cancer. 1998, 77(12), 2171-2176.
• References: [5] Jansen WJ, et al. Int J Cancer. 1997, 70(3):335-340.
• References: [6] Na YS, et al. Cancer Chemother Pharmacol. 2011, 68(2), 389-398.
• References: [7] Wagner LM, et al. Pediatr Blood Cancer. 2007, 48(2), 132-139.

REFERENCES

• Chabot GG: Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet. 1997 Oct;33(4):245-59. Pubmed
• Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004 Apr 15;22(8):1382-8. Epub 2004 Mar 8. Pubmed
• O'Dwyer PJ, Catalano RB: Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol. 2006 Oct 1;24(28):4534-8. Pubmed
• Ramesh M, Ahlawat P, Srinivas NR: Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. Biomed Chromatogr. 2010 Jan;24(1):104-23. Pubmed
• Pavillard V, et al. Cancer Chemother Pharmacol. 2002, 49(4), 329-335.
• Tobin P, et al. Br J Clin Pharmacol. 2006, 62(1), 122-129.
• Shingyoji M, et al. Cancer Sci. 2004, 95(6), 537-540.
• van Ark-Otte J, et al. Br J Cancer. 1998, 77(12), 2171-2176.
• Jansen WJ, et al. Int J Cancer. 1997, 70(3):335-340.
• Na YS, et al. Cancer Chemother Pharmacol. 2011, 68(2), 389-398.
• Wagner LM, et al. Pediatr Blood Cancer. 2007, 48(2), 132-139.
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