Rubitecan

Rubitecan (INN, marketing name Orathecin) is an oral topoisomerase inhibitor, developed by SuperGen (now Astex Pharmaceuticals, Inc.; a member of the Otsuka Group).

Rubitecan
Clinical data
Trade namesOrathecin
Other names9-Nitrocamptothecin
9-NC
9-nitro-20(S)-camptothecin
Camptogen
(19S)-19-Ethyl-19-hydroxy-10-nitro-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
Routes of
administration		Oral (capsules)
ATC code
  • None
Legal status
Legal status
  • Application withdrawn
Pharmacokinetic data
Bioavailability25–30% (rubitecan and 9-AC; in dogs)
Protein binding97% (rubitecan), 65% (9-AC)
MetabolismProbably CYP-dependent
Metabolites9-Aminocamptothecin (9-AC)
Elimination half-life15–18 hours (rubitecan), 18–22 hours (9-AC)
ExcretionBile and feces (major proportion), urine (the minor one)[1]
Identifiers
IUPAC name
  • (4S)-4-Ethyl-4-hydroxy-11-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H15N3O6
Molar mass393.355 g·mol−1
3D model (JSmol)
SMILES
  • CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=CC5=C(C=CC=C5[N+](=O)[O-])N=C4C3=C2)O
InChI
  • InChI=1S/C20H15N3O6/c1-2-20(26)13-7-16-17-10(8-22(16)18(24)12(13)9-29-19(20)25)6-11-14(21-17)4-3-5-15(11)23(27)28/h3-7,26H,2,8-9H2,1H3/t20-/m0/s1 N
  • Key:VHXNKPBCCMUMSW-FQEVSTJZSA-N N
 NY (what is this?)  (verify)

History

On January 27, 2004, SuperGen announced that it has completed the submission of an NDA for rubitecan to the US FDA,[2] and was accepted for filing in March 2004.[3]

In January 2005, and under the direction of then-CEO James Manuso, SuperGen withdrew the NDA for rubitecan, based on feedback indicating that the current data package would not be sufficient to gain US approval,[4] and in January 2006, the Marketing Authorization Application (MAA) filed with the European Medicines Agency (EMA) was also withdrawn.[5]

The name Rubitecan is a portmanteau of SuperGen's founder, Dr. Joseph Rubinfeld, and the chemical name 9-Nitrocamptothecin.

Synthesis

Large scale production of Rubitecan has encountered problems. The direct nitration of camptothecin results in regioselectivity problems. One way that has been used to synthesize Rubitecan is to nitrate 10-hydroxycamptothecin then remove the hydroxyl functional group.[6]

Use as Anti-Cancer Drug

Rubitecan is a compound used extensively in cancer research. Rubitecan is an effective drug against pancreatic cancer and other solid tumors. One major problem is the lack of oral bioavailability due to low permeability and poor water solubility. One study shows 9-NC-SD through Soluplus1-based solid dispersion system is a much more effective delivery method than free 9-NC.[7]

References
  1. "Withdrawal Assessment Report for Orathecin (rubitecan). Applicant: EuroGen Pharmaceuticals, Ltd" (PDF). European Medicines Agency. 30 November 2007. pp. 4–8. Retrieved 15 July 2016.
  2. "SuperGen completes submission of New Drug Application (NDA) for Orathecin as an oral treatment for pancreatic cancer". Drugs.com. Retrieved 2008-03-25.
  3. "SuperGen's New Drug Application for Orathecin (rubitecan) capsules accepted by FDA for filing". Drugs.com. Retrieved 2008-03-25.
  4. "SuperGen Announces Withdrawal of Orathecin NDA". Drugs.com. Retrieved 2008-03-25.
  5. "Press release from the EMEA website regarding withdrawal of Orathecin MAA" (PDF). Archived from the original (PDF) on 2007-06-11. Retrieved 2008-03-25.
  6. Chen Z, Fu Q (2006). "A Practical Regiospecific Synthesis of 9-Nitrocamptothecin". Synthesis. 2006 (12): 1940–1942. doi:10.1055/s-2006-942359.
  7. Lian X, Dong J, Zhang J, Teng Y, Lin Q, Fu Y, Gong T (December 2014). "Soluplus(®) based 9-nitrocamptothecin solid dispersion for peroral administration: preparation, characterization, in vitro and in vivo evaluation". International Journal of Pharmaceutics. 477 (1–2): 399–407. doi:10.1016/j.ijpharm.2014.10.055. PMID 25445521.


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