Gimatecan
Gimatecan is an orally bioavailable, semi-synthetic lipophilic analogue of camptothecin, a quinoline alkaloid extracted from the Asian tree Camptotheca acuminate, with potential antineoplastic and antiangiogenic activities. Gimatecan binds to and inhibits the activity of topoisomerase I, stabilizing the cleavable complex of topoisomerase I-DNA, which inhibits the religation of single-stranded DNA breaks generated by topoisomerase I; lethal double-stranded DNA breaks occur when the topoisomerase I-DNA complex is encountered by the DNA replication machinery, DNA replication is disrupted, and the tumor cell undergoes apoptosis. Although the mechanism of its antiangiogenic activity has yet to be full elucidated, this agent may inhibit endothelial cell migration, tumor neovascularization, and the expression of proangiogenic basic fibroblast growth factor (bFGF). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).
1: Zucchetti M, Meco D, Di Francesco AM, Servidei T, Patriarca V, Cusano G, D'Incalci M, Forestieri D, Pisano C, Riccardi R. Antitumor activity and pharmacokinetics of oral gimatecan on pediatric cancer xenografts. Cancer Chemother Pharmacol. 2010 Sep;66(4):635-41. Epub 2009 Dec 20. PubMed PMID: 20091168.
2: Frapolli R, Zucchetti M, Sessa C, Marsoni S, Viganò L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C, Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the inter-patient variability is related to alpha1-acid glycoprotein plasma levels. Eur J Cancer. 2010 Feb;46(3):505-16. Epub 2009 Dec 16. PubMed PMID: 20007015.
3: Pecorelli S, Ray-Coquard I, Tredan O, Colombo N, Parma G, Tisi G, Katsaròs D, Lhommé C, Lissoni AA, Vermorken JB, du Bois A, Poveda A, Frigerio L, Barbieri P, Carminati P, Brienza S, Guastalla JP. Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes. Ann Oncol. 2010 Apr;21(4):759-65. Epub 2009 Nov 11. PubMed PMID: 19906760; PubMed Central PMCID: PMC2844948.
4: Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo A. Determination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metabolite ST1698 in human plasma by high-performance liquid chromatography with fluorimetric detection. J Pharm Biomed Anal. 2009 Oct 15;50(3):507-14. Epub 2009 May 27. PubMed PMID: 19553057.
5: Vekhoff P, Halby L, Oussedik K, Dallavalle S, Merlini L, Mahieu C, Lansiaux A, Bailly C, Boutorine A, Pisano C, Giannini G, Alloatti D, Arimondo PB. Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan. Bioconjug Chem. 2009 Apr;20(4):666-72. PubMed PMID: 19309124.
6: Oostendorp RL, van de Steeg E, van der Kruijssen CM, Beijnen JH, Kenworthy KE, Schinkel AH, Schellens JH. Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos. 2009 Apr;37(4):917-23. Epub 2009 Jan 12. PubMed PMID: 19139163.
7: Zhu AX, Ready N, Clark JW, Safran H, Amato A, Salem N, Pace S, He X, Zvereva N, Lynch TJ, Ryan DP, Supko JG. Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009 Jan 1;15(1):374-81. PubMed PMID: 19118068.
8: Petrangolini G, Tortoreto M, Perego P, Carenini N, De Cesare M, Balsari A, Zunino F, Pratesi G. Combination of metronomic gimatecan and CpG-oligodeoxynucleotides against an orthotopic pancreatic cancer xenograft. Cancer Biol Ther. 2008 Apr;7(4):596-601. Epub 2008 Jan 9. PubMed PMID: 18364568.
9: Marchetti S, Oostendorp RL, Pluim D, van Eijndhoven M, van Tellingen O, Schinkel AH, Versace R, Beijnen JH, Mazzanti R, Schellens JH. In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3307-13. PubMed PMID: 18089724.
10: Gounder MK, Nazar AS, Saleem A, Pungaliya P, Kulkarni D, Versace R, Rubin EH. Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan. Invest New Drugs. 2008 Jun;26(3):205-13. Epub 2007 Oct 18. PubMed PMID: 17943230
2: Frapolli R, Zucchetti M, Sessa C, Marsoni S, Viganò L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C, Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the inter-patient variability is related to alpha1-acid glycoprotein plasma levels. Eur J Cancer. 2010 Feb;46(3):505-16. Epub 2009 Dec 16. PubMed PMID: 20007015.
3: Pecorelli S, Ray-Coquard I, Tredan O, Colombo N, Parma G, Tisi G, Katsaròs D, Lhommé C, Lissoni AA, Vermorken JB, du Bois A, Poveda A, Frigerio L, Barbieri P, Carminati P, Brienza S, Guastalla JP. Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes. Ann Oncol. 2010 Apr;21(4):759-65. Epub 2009 Nov 11. PubMed PMID: 19906760; PubMed Central PMCID: PMC2844948.
4: Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo A. Determination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metabolite ST1698 in human plasma by high-performance liquid chromatography with fluorimetric detection. J Pharm Biomed Anal. 2009 Oct 15;50(3):507-14. Epub 2009 May 27. PubMed PMID: 19553057.
5: Vekhoff P, Halby L, Oussedik K, Dallavalle S, Merlini L, Mahieu C, Lansiaux A, Bailly C, Boutorine A, Pisano C, Giannini G, Alloatti D, Arimondo PB. Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan. Bioconjug Chem. 2009 Apr;20(4):666-72. PubMed PMID: 19309124.
6: Oostendorp RL, van de Steeg E, van der Kruijssen CM, Beijnen JH, Kenworthy KE, Schinkel AH, Schellens JH. Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos. 2009 Apr;37(4):917-23. Epub 2009 Jan 12. PubMed PMID: 19139163.
7: Zhu AX, Ready N, Clark JW, Safran H, Amato A, Salem N, Pace S, He X, Zvereva N, Lynch TJ, Ryan DP, Supko JG. Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009 Jan 1;15(1):374-81. PubMed PMID: 19118068.
8: Petrangolini G, Tortoreto M, Perego P, Carenini N, De Cesare M, Balsari A, Zunino F, Pratesi G. Combination of metronomic gimatecan and CpG-oligodeoxynucleotides against an orthotopic pancreatic cancer xenograft. Cancer Biol Ther. 2008 Apr;7(4):596-601. Epub 2008 Jan 9. PubMed PMID: 18364568.
9: Marchetti S, Oostendorp RL, Pluim D, van Eijndhoven M, van Tellingen O, Schinkel AH, Versace R, Beijnen JH, Mazzanti R, Schellens JH. In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3307-13. PubMed PMID: 18089724.
10: Gounder MK, Nazar AS, Saleem A, Pungaliya P, Kulkarni D, Versace R, Rubin EH. Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan. Invest New Drugs. 2008 Jun;26(3):205-13. Epub 2007 Oct 18. PubMed PMID: 17943230
| Chemical | |
|---|---|
| CAS Num | 292618-32-7 |
| Chemical Formula | C25H25N3O5 |
| Molecular Weight | 447.4831 |
| IUPAC Chemical Name | (4S)-11-((E)-((1,1-Dimethylethoxy)imino)methyl)-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano(3',4' |
| Exact Mass | 447.17942 |
| Elemental Analysis | C, 67.10; H, 5.63; N, 9.39; O, 17.88 |
| Synonym | Code names |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C1[C@](O)(CC)C2=C(CO1)C(N3CC4=C(/C=N/OC(C)(C)C)C5=CC=CC=C5N=C4C3=C2)=O |
| Biological | |
| Targets and Effects | N/A |
| Pathways | Apoptosis |
| Physical | |
| Appearance | Solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years) |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >5 years if stored properly |
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