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MedKoo Cat#: 202130 | Name: Palifosfamide-Tris
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Palifosfamide, also known as ZIO201, is a synthetic mustard compound with potential antineoplastic activity. An active metabolite of ifosfamide covalently linked to the amino acid lysine for stability, palifosfamide irreversibly alkylates and cross-links DNA through GC base pairs, resulting in irreparable 7-atom inter-strand cross-links; inhibition of DNA replication and cell death follow. Unlike ifosfamide, this agent is not metabolized to acrolein or chloroacetaldehyde, metabolites associated with bladder and CNS toxicities. In addition, because palifosfamide does not require activation by aldehyde dehydrogenase, it may overcome the tumor resistance seen with ifosfamide.

Chemical Structure

Palifosfamide-Tris
Palifosfamide-Tris
CAS#1070409-31-2 (tris salt)

Theoretical Analysis

MedKoo Cat#: 202130

Name: Palifosfamide-Tris

CAS#: 1070409-31-2 (tris salt)

Chemical Formula: C8H22Cl2N3O5P

Exact Mass: 0.0000

Molecular Weight: 342.15

Elemental Analysis: C, 28.08; H, 6.48; Cl, 20.72; N, 12.28; O, 23.38; P, 9.05

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Related CAS #
1070409-31-2 (tris salt); 31645-39-3 (free acid)
Synonym
ZIO201; ZIO-201; ZIO 201; IPAM; NSC 297900; NSC-297900; NSC297900; isophosphoramide mustard; Palifosfamide. Palifosfamide tris salt; Trade name: Zymafos.
IUPAC/Chemical Name
2-amino-2-(hydroxymethyl)propane-1,3-diol;bis(2-chloroethylamino)phosphinic acid
InChi Key
PGLRCMRTUIMSFQ-UHFFFAOYSA-N
InChi Code
InChI=1S/C4H11Cl2N2O2P.C4H11NO3/c5-1-3-7-11(9,10)8-4-2-6;5-4(1-6,2-7)3-8/h1-4H2,(H3,7,8,9,10);6-8H,1-3,5H2
SMILES Code
ClCCNP(NCCCl)(O)=O.OCC(CO)(N)CO
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
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not soluble in water.
Shelf Life
>5 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Palifosfamide (ZIO-201) is currently developed by ZIOPHARM Oncology, Inc. It is  a proprietary stabilized metabolite of ifosfamide. Ifosfamide has been shown to be effective in high doses in treating testicular cancer, sarcoma and lymphoma. Ifosfamide-based treatment generally represents the standard of care for sarcoma; however, it is not approved by the FDA in this indication. Ifosfamide metabolites include acrolein and chloroacetaldehyde, both highly toxic.  Preclinical studies have shown that palifosfamide has activity in leukemia and solid tumor cancers. These studies also indicate that palifosfamide has a better safety profile than ifosfamide, likely because the toxic metabolites of ifosfamide, acrolein and chloroacetaldehyde are not present in palifosfamide. We believe the administration of palifosfamide may avoid many of the toxicities of ifosfamide without compromising the activity of the drug. see ZIOPHARM's website:  http://www.ziopharm.com/clinical_zio201.php.        
Product Data
Product Data
Instruction
View handling instruction
Biological target:
Palifosfamide, also known as ZIO201, is a synthetic mustard compound with potential antineoplastic activity.
In vitro activity:
The cytotoxic effect of palifosfamide lysine was studied in osteosarcoma (OS), Ewing's sarcoma (ES) and rhabdomyosarcoma (RMS) cell lines using the MTT assay. Palifosfamide lysine was cytotoxic against all the cell lines tested with the IC(50) ranging from 0.5 to 1.5 microg/ml except for OS222, which had an IC(50) of 7 microg/ml. Reference: Cancer Chemother Pharmacol. 2009 Sep;64(4):733-40. https://pubmed.ncbi.nlm.nih.gov/19224214/
In vivo activity:
The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague-Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over control. Reference: Anticancer Drugs. 2012 Feb;23(2):173-84. https://pubmed.ncbi.nlm.nih.gov/22027537/

Preparing Stock Solutions

The following data is based on the product molecular weight 342.15 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Hingorani P, Zhang W, Piperdi S, Pressman L, Lin J, Gorlick R, Kolb EA. Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma. Cancer Chemother Pharmacol. 2009 Sep;64(4):733-40. doi: 10.1007/s00280-008-0922-4. Epub 2009 Feb 18. PMID: 19224214. 2. Jones B, Komarnitsky P, Miller GT, Amedio J, Wallner BP. Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs. 2012 Feb;23(2):173-84. doi: 10.1097/CAD.0b013e32834d73a6. PMID: 22027537.
In vitro protocol:
1. Hingorani P, Zhang W, Piperdi S, Pressman L, Lin J, Gorlick R, Kolb EA. Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma. Cancer Chemother Pharmacol. 2009 Sep;64(4):733-40. doi: 10.1007/s00280-008-0922-4. Epub 2009 Feb 18. PMID: 19224214.
In vivo protocol:
1. Jones B, Komarnitsky P, Miller GT, Amedio J, Wallner BP. Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs. 2012 Feb;23(2):173-84. doi: 10.1097/CAD.0b013e32834d73a6. PMID: 22027537.
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The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma. Eur J Cancer. 2017 Oct;84:257-261. doi: 10.1016/j.ejca.2017.07.043. Epub 2017 Aug 23. PMID: 28841543. 5: Jalal SI, Lavin P, Lo G, Lebel F, Einhorn L. Carboplatin and Etoposide With or Without Palifosfamide in Untreated Extensive-Stage Small-Cell Lung Cancer: A Multicenter, Adaptive, Randomized Phase III Study (MATISSE). J Clin Oncol. 2017 Aug 10;35(23):2619-2623. doi: 10.1200/JCO.2016.71.7454. Epub 2017 Jun 12. PMID: 28605291. 6: Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, Jones RL, Elias AD, Choy E, Alcindor T, Keedy VL, Reed DR, Taub RN, Italiano A, Garcia Del Muro X, Judson IR, Buck JY, Lebel F, Lewis JJ, Maki RG, Schöffski P. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol. 2016 Nov 10;34(32):3898-3905. doi: 10.1200/JCO.2016.67.6684. Epub 2016 Sep 30. PMID: 27621408. 7: Skarbek C, Lesueur LL, Chapuis H, Deroussent A, Pioche Durieu C, Daville A, Caron J, Rivard M, Martens T, Bertrand JR, Le Cam E, Vassal G, Couvreur P, Desmaele D, Paci A. Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies: synthesis and proof of concept. J Med Chem. 2015 Jan 22;58(2):705-17. doi: 10.1021/jm501224x. Epub 2014 Dec 23. PMID: 25494842. 8: Opydo-Chanek M, Mazur L, Stojak M. In vitro cytotoxicity testing of new generation oxazaphosphorines against human histiocytic lymphoma cells. Indian J Exp Biol. 2013 Aug;51(8):615-22. PMID: 24228385. 9: Cytarska J, Misiura K, Filip-Psurska B, Wietrzyk J. Acyloxymethyl esters of isophosphoramide mustard as new anticancer prodrugs. Acta Pol Pharm. 2013 May- Jun;70(3):481-7. PMID: 23757939. 10: Jones B, Komarnitsky P, Miller GT, Amedio J, Wallner BP. Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs. 2012 Feb;23(2):173-84. doi: 10.1097/CAD.0b013e32834d73a6. PMID: 22027537. 11: Jung D, Lin L, Jiao H, Cai X, Duan JX, Matteucci M. Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys. Cancer Chemother Pharmacol. 2012 Mar;69(3):643-54. doi: 10.1007/s00280-011-1741-6. Epub 2011 Oct 1. PMID: 21964906. 12: Chen N, Hanly L, Rieder M, Yeger H, Koren G. The effect of N-acetylcysteine on the antitumor activity of ifosfamide. Can J Physiol Pharmacol. 2011 May;89(5):335-43. doi: 10.1139/y11-028. Epub 2011 May 24. PMID: 21609276. 13: Jung S, Kasper B. Palifosfamide, a bifunctional alkylator for the treatment of sarcomas. IDrugs. 2010 Jan;13(1):38-48. PMID: 20024846. 14: Patzer L, Hernando N, Ziegler U, Beck-Schimmer B, Biber J, Murer H. Ifosfamide metabolites CAA, 4-OH-Ifo and Ifo-mustard reduce apical phosphate transport by changing NaPi-IIa in OK cells. Kidney Int. 2006 Nov;70(10):1725-34. doi: 10.1038/sj.ki.5001803. Epub 2006 Sep 27. PMID: 17003823. 15: Sun YM, Chen XY, Zhong DF. [Identification of glufosfamide metabolites in rats]. Yao Xue Xue Bao. 2006 Jun;41(6):513-7. Chinese. PMID: 16927824. 16: Sun Y, Chen X, Xu H, Guan Z, Zhong D. Stability of glufosfamide in phosphate buffers and in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Mar 7;832(2):224-30. doi: 10.1016/j.jchromb.2006.01.001. Epub 2006 Feb 7. PMID: 16455312. 17: Germann N, Urien S, Rodgers AH, Ratterree M, Struck RF, Waud WR, Serota DG, Bastian G, Jursic BS, Morgan LR. Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide. Cancer Chemother Pharmacol. 2005 Feb;55(2):143-51. doi: 10.1007/s00280-004-0894-y. Epub 2004 Sep 14. PMID: 15592722. 18: Springer JB, Chang YH, Koo KI, Colvin OM, Colvin ME, Dolan ME, Delaney SM, Flowers JL, Ludeman SM. 1,3- vs 1,5-intramolecular alkylation reactions in isophosphoramide and phosphoramide mustards. Chem Res Toxicol. 2004 Sep;17(9):1217-26. doi: 10.1021/tx030051k. PMID: 15377155. 19: Misiura K, Szymanowicz D, Wietrzyk J, Opolski A. Phosphate prodrugs of isophosphoramide mustard. Acta Pol Pharm. 2003 Mar-Apr;60(2):109-12. PMID: 13678316. 20: Ludeman SM, Gamcsik MP. Mechanisms of resistance against cyclophosphamide and ifosfamide: can they be overcome without sacrificing selectivity? Cancer Treat Res. 2002;112:177-97. doi: 10.1007/978-1-4615-1173-1_9. PMID: 12481717.