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Treosulphan

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Synopsis

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Chemistry

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Also known as: 299-75-2, Treosulphan, Ovastat, Threosulphan, Dihydroxybusulfan, Nsc 39069

Molecular Formula

C₆H₁₄O₈S₂

Molecular Weight

278.3 g/mol

InChI Key

YCPOZVAOBBQLRI-WDSKDSINSA-N

FDA UNII

CO61ER3EPI

Treosulfan is the prodrug of a bifunctional sulfonate alkylating agent with myeloablative, immunosuppressive, and antineoplastic activities. Under physiological conditions, treosulfan converts nonenzymatically to L-diepoxybutane via a monoepoxide intermediate. The monoepoxide intermediate and L-diepoxybutane alkylate DNA at guanine residues and produce DNA interstrand crosslinks, resulting in DNA fragmentation and apoptosis. In escalated doses, this agent also exhibits myeloablative and immunosuppressive activities.

1 2D Structure

Treosulfan

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(2S,3S)-2,3-dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate

2.1.2 InChI

InChI=1S/C6H14O8S2/c1-15(9,10)13-3-5(7)6(8)4-14-16(2,11)12/h5-8H,3-4H2,1-2H3/t5-,6-/m0/s1

2.1.3 InChI Key

YCPOZVAOBBQLRI-WDSKDSINSA-N

2.1.4 Canonical SMILES

CS(=O)(=O)OCC(C(COS(=O)(=O)C)O)O

2.1.5 Isomeric SMILES

CS(=O)(=O)OC[C@@H]([C@H](COS(=O)(=O)C)O)O

2.2 Other Identifiers

2.2.1 UNII

CO61ER3EPI

2.3 Synonyms

2.3.1 MeSH Synonyms

1. L-dihydroxybusulfan

2. L-threitol-1,4-bismethanesulfonate

3. Nsc 39069

4. Treosulfan, ((r*,r*)-(+-))-isomer

5. Treosulfan, (r*,r*)-isomer

6. Treosulfan, (r*,s*)-isomer

7. Treosulfan, (r-(r*,r*))-isomer

2.3.2 Depositor-Supplied Synonyms

1. 299-75-2

2. Treosulphan

3. Ovastat

4. Threosulphan

5. Dihydroxybusulfan

6. Nsc 39069

7. Nsc-39069

8. (2s,3s)-threitol 1,4-bismethanesulfonate

9. Co61er3epi

10. Trecondi

11. L-threitol 1,4-dimethanesulfonate

12. Chebi:82557

13. L-threitol-1,4-bis(methanesulfonate)

14. Treosulfan (inn)

15. Treosulfan [inn]

16. Cb 40067

17. (2s,3s)-2,3-dihydroxybutane-1,4-diyl Dimethanesulfonate

18. Treosulfano

19. Treosulfanum

20. Treosulfanum [inn-latin]

21. Treosulfano [inn-spanish]

22. Ccris 2781

23. Hsdb 6963

24. Einecs 206-081-0

25. Unii-co61er3epi

26. L-threitol, 1,4-bis(methanesulfonate)

27. Threitol, 1,4-dimethanesulfonate, L-(+)-

28. Ovastat (tn)

29. L-threitol, 1,4-bismethanesulfonate

30. Grafapex

31. Graftrevo

32. Kepcondi

33. Trecondyv

34. Treograft

35. Treosulphannsc 39069

36. Treosulfan [hsdb]

37. Treosulfan [iarc]

38. Treosulfan [usan]

39. Threitol, 1,4-dimethanesulfonate, (2s,3s)-

40. Treosulfan [mart.]

41. Treosulfan [who-dd]

42. Treosulfan [usan:inn:ban]

43. Chembl455186

44. Schembl5399430

45. Dtxsid0026173

46. (s-(r*,r*))-1,2,3,4-butanetetrol, 1,4-dimethanesulfonate

47. 1,2,3,4-butanetetrol, 1,4-dimethanesulfonate, (s-(r*,r*))-

48. Who 3103

49. Zinc1671094

50. L-threitol-1,4-bis-methanesulfonate

51. Mfcd02258964

52. S6958

53. L-threitol 1,4-bis(methanesulfonate)

54. Cs-3889

55. Db11678

56. Hy-16503

57. Ps-12126

58. L-threitol 1,4-dimethanesulphonate

59. C19557

60. D07253

61. A912763

62. (2s,3s)-2,3-dihydroxy-4-(methanesulfonyloxy)butyl Methanesulfonate

63. (s)-3-boc-amino-1-diazo-3-(4-benzyloxy)phenyl-2-butanone

64. [(2s,3s)-2,3-dihydroxy-4-methylsulfonyloxybutyl] Methanesulfonate

2.4 Create Date

2006-10-25

3 Chemical and Physical Properties

Molecular Formula	C₆H₁₄O₈S₂
Molecular Weight	278.3 g/mol
XLogP3	-2.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	7
Exact Mass	278.01300975 g/mol
Monoisotopic Mass	278.01300975 g/mol
Topological Polar Surface Area	144 Å²
Heavy Atom Count	16
Formal Charge	0
Complexity	345
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Therapeutic Uses

Therapy of advanced renal cell carcinoma remains difficult. New therapeutic schemes besides cytokine treatment should be evaluated. The following study analyzes the in vitro toxicity of treosulfan on spheroids of 8 primary cultures of renal cell carcinoma cells. these data were compared to the toxicity of vinblastine. All investigations were performed in regard to the P-glycoprotein (Pgp) expression of the cells, which is one of the main causes of multidrug resistance. Four Pgp positive and four Pgp negative spheroids were incubated with the drugs in increasing doses. Toxicity was measured using the MTT toxicity assay as well as trypan blue exclusion. Significantly higher toxicity of treosulfan compared to vinblastine could be demonstrated. In addition, the effects of treosulfan were not related to Pgp expression. These results are encouraging and a phase II study analyzing the efficacy of treosulfan in patients with advanced renal cell carcinoma has been initiated in our institution.

PMID:9738287 Lugler A et al; Urologe A 37 (4): 367-71 (1998)

[Schmidt F et al; J Neurooncol 49 (3): 231-4 (2000)] Treosulfan is a bifunctional alkylating prodrug with activity against various solid tumors. To improve the outcome for patients with recurrent malignant glioma, we assessed the efficacy of intravenous treosulfan (6-10 g/m2 4-weekly) as salvage therapy for patients with recurrent or progressive glioblastoma (GB, n = 14) or anaplastic astrocytoma (AA, n = 2). All patients had prior involved-field radiotherapy and adjuvant nitrosourea-based chemotherapy. A total of 56 cycles were administered. Tumor responses were assessed radiologically and clinically prior to each cycle. All patients were assessable for toxicity, response and survival. There were no complete or partial responses (CR, PR). Two patients progressed after the first cycle, 14 patients had initially stable disease (SD). Median progression-free survival was 3.25 months for the glioblastoma patients. Five patients were progression-free at 6 months (30%), including the 2 anaplastic astrocytoma patients. The 2 anaplastic astrocytoma patients are stable at 22 months. ... Treosulfan has modest activity in patients with recurrent malignant glioma. Further evaluation of treosulfan in chemonaive malignant glioma patients is warranted.

PMID:11212902 Schmidt F et al; J Neurooncol 49 (3): 231-4 (2000)

4.2 Drug Warning

Myelosuppression was the dose-limiting toxicity in this cohort of nitrosourea-pretreated patients.

PMID:11212902 Schmidt F et al; J Neurooncol 49 (3): 231-4 (2000)

Acute non-lymphocytic leukemia occurred in eight women following long-term treatment with Treosulfan (= dihydroxybusulfan) for ovarian carcinoma. The leukemia developed from 21 to 58 months (median 50 months) after the institution of chemotherapy. At the time when the leukemia appeared seven of the patients were in complete, and one in partial, remission as regards the ovarian carcinoma. Seven of the eight cases of acute leukemia occurred in a series of 553 patients treated with Treosulfan for ovarian cancer in the period from 1970 to 1977 and followed closely for a total of 1159 patient-years up to February 1978. As compared with an expected number of 0.04 cases of acute myeloblastic leukemia based on patient-years, the observed seven cases correspond to a 175-times increased risk. Although the cumulative probability of acute non-lymphocytic leukemia among surviving patients at five years using life-table statistics was 7.6%, the survival curve for the 553 patients with ovarian carcinoma was only slightly affected by death from leukemia. The probability of developing acute leukemia in this study was not significantly correlated to the total cumulative dosage of Treosulfan. Cytogenetic studies of the bone marrow performed after the development of acute leukemia showed chromosome abnormalities in all five patients examined, with hypodiploidy and loss of B and C group chromosomes.

PMID:7351000 Pedersen-Bjergaard J et al; Cancer 45 (1): 19-29 (1980)

Treosulfan and busulphan are similar molecules, the former used in the treatment of ovarian cancer and the latter in chronic myelogenous leukaemia. We have used both in the differential staining cytotoxicity (DiSC) assay for in vitro drug sensitivity testing to aid in the choice of chemotherapy for individual patients. It was observed that occasionally the viability of control cells in one assay box was reduced compared with control cells in other boxes from the same assay. Treosulfan was suspected as the cause because cells throughout the microtitre box containing treosulfan had reduced viability in 28/62 (45%) experiments and in 9 of these, total kill of all cells in the box was observed. We tested the hypothesis that a metabolite of treosulfan might be the cause of this airborne cytotoxicity, and found that whilst 10 mg ml-1 of either methane sulphonic acid or tetrahydrofuran had no airborne cytotoxic effect, 1 mg ml-1 diepoxybutane killed over 95% of cells in all tubes in the same box. Treosulfan is another chemical (cf. azide, mafosfamide and possibly other cytotoxic agents) that can cause airborne cytotoxicity.

PMID:7531465 Bosanquet AG, Burlton AR; cytotechnology 16 (2): 131-6 (1994)

4.3 Drug Indication

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and non malignant diseases, and in paediatric patients older than one month with malignant diseases.

5 Pharmacology and Biochemistry

5.1 MeSH Pharmacological Classification

Antineoplastic Agents, Alkylating

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)

5.2 ATC Code

L01AB02

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01A - Alkylating agents

L01AB - Alkyl sulfonates

L01AB02 - Treosulfan

5.3 Absorption, Distribution and Excretion

In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. ... The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 + or - 0.18 (mean + or - SD) using the values AUC oral = 82.1 + or- 39.4 ug/ml hr and AUC i.v. = 85.4 + or - 30.3 ug/ml hr. The peak plasma concentration cmax (29 + or - 14 ug/ml vs 65 + or - 23 ug/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 + or - 0.34 hr. The terminal half-life of treosulfan was about 1.8 hr. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 hr (range 6-26%). ... A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

Hilger RA et al; Cancer Chemother Pharmacol 45 (6): (2000)

5.4 Mechanism of Action

The anti-tumour drug treosulfan (L-threitol 1,4-bismethanesulphonate, Ovastat) is a prodrug for epoxy compounds by converting non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions. The present study supports the hypothesis that this conversion of treosulfan is required for cytotoxicity in vitro. DNA alkylation and interstrand cross-linking of plasmid DNA is observed after treosulfan treatment, but this is again produced via the epoxide species. Alkylation occurs at guanine bases with a sequence selectivity similar to other alkylating agents such as the nitrogen mustards. In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h. Incubation of K562 cells with preformed epoxides shows faster and more efficient DNA cross-linking.

PMID:9888467 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362201 Hartley JA et al; Br J Cancer 79 (2): 264-6 (1999)

API SUPPLIERS

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Fermion Oy

Finland

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Supriya Lifescience

India

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MEDAC GESELLSCHAFT FUR KLINISCHE S...

Germany

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SALSBURY CHEMICALS INC

U.S.A

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Emcure Pharmaceuticals

India

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Fermion Oy

Finland

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DMF Number : 34570

Submission : 2020-06-29

Status : Active

Type : II

02

Medac Gesellschaft Fur Klinische Spe...

Germany

Antibody Engineering

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Salsbury Labs

U.S.A

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Fermion Oy

Finland

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About the Company : Fermion is fully owned subsidiary of Orion Corporation & headquartered in Espoo, Finland. Together with Orion we are a fully integrated CDMO & offer services covering both APIs & F...

Fermion is fully owned subsidiary of Orion Corporation & headquartered in Espoo, Finland. Together with Orion we are a fully integrated CDMO & offer services covering both APIs & Formulations. API portfolio consists of >30 generic APIs & >10 NCEs & 2 mfg. sites as well as R&D facilities are all located in Finland. Fermion has invested & expanded capabilities in the production of HPAPIs. Drug product CMO services include hormonal & non-hormonal semi-solids, cytotoxic oral solids & packaging. We have 3 mfg. sites & one packaging center for drug products at Orion.

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Supriya Lifescience

India

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About the Company : Supriya Lifescience Ltd. specializes in API manufacturing, focusing on therapeutic segments like antihistamines, anti-allergic drugs, vitamins, anaesthetics and anti-asthmatics. Su...

Supriya Lifescience Ltd. specializes in API manufacturing, focusing on therapeutic segments like antihistamines, anti-allergic drugs, vitamins, anaesthetics and anti-asthmatics. Supriya follows industry standards and constantly improves to deliver quality products. Its facility is 47,000 square meters with dedicated areas for warehouse, QA, QC, R&D, production and finished products. The current capacity is 550 KL, with plans to expand to over 1000 KL by 2024. Supriya has 14 active USDMFs, 8 active CEPs, strong R&D and compliant facilities worldwide. Supriya works with innovators, generic companies, and as a CMO.

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