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Chemistry

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Also known as: 162652-95-1, Javlor, 20',20'-difluoro-3',4'-dihydrovinorelbine, Chebi:90241, 4'-deoxy-20',20'-difluoro-c'-norvincaleukoblastine, 5bf646324k
Molecular Formula
C45H54F2N4O8
Molecular Weight
816.9  g/mol
InChI Key
NMDYYWFGPIMTKO-KLCPSUAYSA-N
FDA UNII
5BF646324K

Vinflunine
Vinflunine is a bi-fluorinated derivative of the semi-synthetic vinca alkaloid vinorelbine with antitubulin, antineoplastic, and antiangiogenic activities. Vinflunine inhibits tubulin assembly without any stablization of assembled microtubules at concentrations comparable to those of other vinca alkaloids such as vincristine, vinblastine and vinorelbine; this effect on microtubule dynamics results in cell cycle arrest in mitosis and apoptosis. Compared to other vinca alkaloids, this agent binds weakly to the vinca-binding site, indicating that vinflunine may exhibit reduced neurotoxicity.
1 2D Structure

Vinflunine

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-4-[(12S,14S,16R)-16-(1,1-difluoroethyl)-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8-tetraen-12-yl]-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
2.1.2 InChI
InChI=1S/C45H54F2N4O8/c1-8-42-14-11-16-51-17-15-43(36(42)51)30-19-31(34(56-5)20-33(30)49(4)37(43)45(55,40(54)58-7)38(42)59-25(2)52)44(39(53)57-6)21-26-18-27(41(3,46)47)23-50(22-26)24-29-28-12-9-10-13-32(28)48-35(29)44/h9-14,19-20,26-27,36-38,48,55H,8,15-18,21-24H2,1-7H3/t26-,27+,36-,37+,38+,42+,43+,44-,45-/m0/s1
2.1.3 InChI Key
NMDYYWFGPIMTKO-KLCPSUAYSA-N
2.1.4 Canonical SMILES
CCC12C=CCN3C1C4(CC3)C(C(C2OC(=O)C)(C(=O)OC)O)N(C5=CC(=C(C=C45)C6(CC7CC(CN(C7)CC8=C6NC9=CC=CC=C89)C(C)(F)F)C(=O)OC)OC)C
2.1.5 Isomeric SMILES
CC[C@@]12C=CCN3[C@@H]1[C@]4(CC3)[C@H]([C@]([C@@H]2OC(=O)C)(C(=O)OC)O)N(C5=CC(=C(C=C45)[C@]6(C[C@@H]7C[C@H](CN(C7)CC8=C6NC9=CC=CC=C89)C(C)(F)F)C(=O)OC)OC)C
2.2 Other Identifiers
2.2.1 UNII
5BF646324K
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Javlor

2.3.2 Depositor-Supplied Synonyms

1. 162652-95-1

2. Javlor

3. 20',20'-difluoro-3',4'-dihydrovinorelbine

4. Chebi:90241

5. 4'-deoxy-20',20'-difluoro-c'-norvincaleukoblastine

6. 5bf646324k

7. Methyl (1r,9r,10s,11r,12r,19r)-11-acetyloxy-4-[(12s,14s,16r)-16-(1,1-difluoroethyl)-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8-tetraen-12-yl]-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate

8. 4'-deoxy-20',20'-difluoro-5'-norvincaleukoblastine

9. 4'-deoxy-20',20'-difluoro-8'-norvincaleukoblastine

10. Vinflunine [inn]

11. Vinflunine [inn:ban]

12. Vinflunina

13. Vinfluninum

14. Unii-5bf646324k

15. L-0070

16. Vinflunine [mi]

17. Vinflunine [mart.]

18. Vinflunine [who-dd]

19. Vinflunine [ema Epar]

20. Chembl2110725

21. Dtxsid30936722

22. Hy-b0628

23. Zinc85537078

24. Db11641

25. C'-norvincaleukoblastine, 4'-deoxy-20',20'-difluoro-

26. 4'-deoxy-20',20'-difluoro-8'-norvincaleucoblastine

27. Methyl (2beta,3beta,4beta,5alpha,12beta,19alpha)-4-(acetyloxy)-15-[(12s,14s,16r)-16-(1,1-difluoroethyl)-12-(methoxycarbonyl)-1,10-diazatetracyclo[12.3.1.0(3,11).0(4,9)]octadeca-3(11),4,6,8-tetraen-12-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3-carboxylate

2.4 Create Date
2006-10-25
3 Chemical and Physical Properties
Molecular Weight 816.9 g/mol
Molecular Formula C45H54F2N4O8
XLogP34.4
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count13
Rotatable Bond Count10
Exact Mass816.39097102 g/mol
Monoisotopic Mass816.39097102 g/mol
Topological Polar Surface Area134 Ų
Heavy Atom Count59
Formal Charge0
Complexity1720
Isotope Atom Count0
Defined Atom Stereocenter Count9
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

For use as a monotherapy in adults with advanced or transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing therapy.


Javlor is indicated in monotherapy for the treatment of adult patients with advanced or metastatic transitional-cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen.

Efficacy and safety of vinflunine have not been studied in patients with performance status 2.


5 Pharmacology and Biochemistry
5.1 Pharmacology

The antitumour effects of vinflunine are dependent on concentration and exposure duration of the drug. Vinflunine mediates an anti-mitotic action by inhibiting the microtubule assembly at micromolar concentrations and reducing the rate and extent of microtubule growing events. _In vivo_, vinflunine displays a significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition. Compared with other vinca alkaloids, vinflunine is a less-potent inductor of drug resistance _in vitro_.


5.2 ATC Code

L01CA05


L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01C - Plant alkaloids and other natural products

L01CA - Vinca alkaloids and analogues

L01CA05 - Vinflunine


5.3 Absorption, Distribution and Excretion

Absorption

Vinflunine displays a linear pharmacokinetic profile in the range of administered doses (from 30 mg/m^2 to 400 mg/m^2) in cancer patients.


Route of Elimination

Fecal excretion accounts for 2/3 of the total elimination of vinflunine and its metabolites and the remaining 1/3 of their elimination indicates urinary excretion.


Volume of Distribution

The terminal volume of distribution is large, 2422 676 L (about 35 l/kg), suggesting extensive distribution into tissues. The ratio between plasma and whole blood concentrations of 0.80 0.12.


Clearance

The total blood clearance was 40 L/h according to a population pharmacokinetic analysis in 372 patients. The inter- and intra-individual variability was low, with the coefficient of variation approximately 25% and 8%, respectively.


5.4 Metabolism/Metabolites

The metabolites of influnine are mostly cytochrome P450 3A4, but 4-O-deacetylvinflunine (DVFL) may be slowly formed by multiple esterases. DVFL is the main metabolite and is the only metabolite that retains pharmacological activity.


5.5 Biological Half-Life

The mean terminal half-life is approximately 40 h. The half life of the main metabolite, DVFL, is approximately 120 hours.


5.6 Mechanism of Action

Microtubules are a major component of the cytoskeleton that have a critical role in maintenance of cell shape, mobility, adhesion and intracellular integrity. They also play a role in the formation of the mitotic spindle and chromosomal segregation to the daughter cells at mitosis. Via GTP hydrolysis at the -tubulin subunit and polymerization of tubulin into linear polymers, microtubules, or macromolecular filaments composed of tubulin heterodimers, are formed via a mechanism of nucleation-elongation. At the onset of mitosis, the interphase microtubule network disassembles into the tubulin. The tubulin reassembles into a new population of mitotic spindle microtubules that further undergo rapid successions of lengthening and shortening until they are attached to the newly duplicated sister chromatids at their centromeres. The dynamic behaviour of microtubules are characterized by two mechanical process: dynamic instability indicating repeated switches of growth and shortening at the ends, and microtubule treadmilling that involves the fast-growing (+) end of the microtubule accompanied by a net loss of the opposite slow-growing (-) end. Microtubule treadmilling plays a critical role in mitosis by generating the forces for separation of the chromosomes in the mitotic spindle from centrosome and kinetochores. In both cancer and normal cells, vinflunine binds to tubulin at or near to the vinca binding sites at -tubulin. It is proposed that in similarity to other vinca alkaloids, vinflunine is most likely to bind to -tubulin subunit at the interdimer interface. Via direct binding to tubulin, vinflunine inhibits microtubule polymerization and induces a G2+M arrest, or a mitotic arrest. Vinflunine disrupts the dynamic function of microtubules by suppressing treadmilling and slowing the microtubule growth rate while increasing growth duration. Ultimately, mitotic accumulation at the metaphase/anaphase transition results in cell apoptosis.


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