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Chemistry

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Also known as: 132682-98-5, D 19575, Glufosfamide [inn], Glucosylifosfamide mustard, D-19575, 1w5n8szd9a
Molecular Formula
C10H21Cl2N2O7P
Molecular Weight
383.16  g/mol
InChI Key
PSVUJBVBCOISSP-SPFKKGSWSA-N
FDA UNII
1W5N8SZD9A

Glufosfamide
Glufosfamide is a compound consisting of the mustard agent ifosforamide conjugated to glucose, with potential alkylating activity. Glufosfamide is cleaved by glucosidases in tumor cells and forms ifosforamide. In turn, ifosforamide alkylates and forms DNA crosslinks, thereby inhibiting DNA replication and subsequent cell growth. The glucose moiety may enhance this agent's uptake by tumor cells.
1 2D Structure

Glufosfamide

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(2S,3R,4S,5S,6R)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol
2.1.2 InChI
InChI=1S/C10H21Cl2N2O7P/c11-1-3-13-22(19,14-4-2-12)21-10-9(18)8(17)7(16)6(5-15)20-10/h6-10,15-18H,1-5H2,(H2,13,14,19)/t6-,7-,8+,9-,10+/m1/s1
2.1.3 InChI Key
PSVUJBVBCOISSP-SPFKKGSWSA-N
2.1.4 Canonical SMILES
C(CCl)NP(=O)(NCCCl)OC1C(C(C(C(O1)CO)O)O)O
2.1.5 Isomeric SMILES
C(CCl)NP(=O)(NCCCl)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O
2.2 Other Identifiers
2.2.1 UNII
1W5N8SZD9A
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Beta-d-glc-ipm

2. Beta-d-glucosyl-ifosfamide Mustard

3. Beta-d-glucosylisophosphoramide Mustard

4. D 19575

5. D-19575

6. Glucosyl-ifosfamide Mustard

2.3.2 Depositor-Supplied Synonyms

1. 132682-98-5

2. D 19575

3. Glufosfamide [inn]

4. Glucosylifosfamide Mustard

5. D-19575

6. 1w5n8szd9a

7. Glucosyl-ifosfamide Mustard

8. Beta-d-glucopyranose, 1-(n,n'-bis(2-chloroethyl)phosphorodiamidate)

9. Glucosylifostamide Mustard

10. Glc-ipm

11. Beta-d-glucopyranose, 1-[n,n'-bis(2-chloroethyl)phosphorodiamidate]

12. N,n'-bis(2-chloroethyl)phosphorodiamidic Acid Beta-d-glucopyranosyl Ester

13. Glufosfamide,b-d-glucopyranose,1-(n,n-bis(2-chloroethyl)phosphorodiamidate)-

14. Hsdb 7024

15. Unii-1w5n8szd9a

16. (2s,3r,4s,5s,6r)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol

17. Beta-d-glucopyranose 1-(n,n'-bis(2-chloroethyl)phosphorodiamidate

18. Glufosfamide [mi]

19. Glufosfamide [hsdb]

20. Schembl18241

21. Glufosfamide [mart.]

22. Glufosfamide [who-dd]

23. Chembl2107143

24. Dtxsid001031222

25. Zinc3918137

26. Db06177

27. Hy-16232

28. Cs-0006254

29. 682g985

30. Q15711735

31. .beta.-d-glucopyranose, 1-(n,n'-bis(2-chloroethyl))phosphorodiamidate

2.4 Create Date
2005-08-08
3 Chemical and Physical Properties
Molecular Weight 383.16 g/mol
Molecular Formula C10H21Cl2N2O7P
XLogP3-2
Hydrogen Bond Donor Count6
Hydrogen Bond Acceptor Count9
Rotatable Bond Count9
Exact Mass382.0463434 g/mol
Monoisotopic Mass382.0463434 g/mol
Topological Polar Surface Area141 Ų
Heavy Atom Count22
Formal Charge0
Complexity369
Isotope Atom Count0
Defined Atom Stereocenter Count5
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

... To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. ... Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. ... The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. ... The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.

PMID:11032596 Briasoulis E, et al; J Clin Oncol 18 (20): 3535-3544 (2000)


4.2 Drug Indication

Investigated for use/treatment in pancreatic cancer, solid tumors, breast cancer, colorectal cancer, brain cancer, lung cancer, ovarian cancer, and sarcoma.


5 Pharmacology and Biochemistry
5.1 Biological Half-Life

... /A study was conducted/ to determine the maximum tolerated dose (MTD)... and the pharmacokinetics of 6 hr infusion of glufosfamide ... a novel alkylating agent with the potential to target the glucose transporter system. Twenty-one patients (10 women, 11 men; median age 56 yr) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/sq m. /The drug/ was admin very three weeks as a two step (fast/slow) iv infusion over a 6 hr period. All patients went under pharmacokinetic sampling at the first course. The MTD was 6,000 mg/sq m. ... Pharmacokinetics indicated linearity of the area the time-versus-concentration curve against dose over the dose range studied and a short elimination half life. ...

PMID:11032596 Briasoulis E, et al; J Clin Oncol 18 (20): 3535-44 (2000)


5.2 Mechanism of Action

Beta-D-glucosyl-ifosfamide mustard (D 19575, glc-IPM, INN = glufosfamide) is a new agent for cancer chemotherapy. Its mode of action, which is only partly understood, was investigated at the DNA level. In the breast carcinoma cell line MCF7 glufosfamide inhibited both the synthesis of DNA and protein in a dose-dependent manner, as shown by the decreased incorporation of (3)H-methyl-thymidine into DNA and (14)C-methionine into protein of these cells. Treatment of MCF7 cells with 50 microM glufosfamide was sufficient to trigger poly(ADP-ribose) polymerase (PARP) activation, as revealed by immunofluorescence analysis. Both CHO-9 cells, which are O6-methylguanine-DNA methyltransferase (MGMT)-deficient, and an isogenic derivative, which has a high level of MGMT, showed the same cytotoxic response to beta-D-glc-IPM, indicating that the O6 position of guanine is not the critical target for cytotoxicity. By contrast, a sharp decrease in survival of cross-link repair deficient CL-V5 B cells was observed already at concentrations of 0.1 mM beta-D-glc-IPM, whereas the wild-type V79 cells showed a 90% reduction in survival only after treatment with 0.5 mM of this compound. The therapeutically inactive beta-L-enantiomer of glufosfamide also showed genotoxic effects in the same assays but at much higher doses. This was probably due to small amounts of ifosfamide mustard formed under the conditions of incubation. The results indicate that the DNA crosslinks are the most critical cytotoxic lesions induced by beta-D-glc-IPM.

PMID:10682676 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363326 Seker H, et al; Br J Cancer 82 (3): 629-634 (2000)


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