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1. (+)-(7s,9s)-9-acetyl-9-amino-7-((2-deoxy-beta-d-erythro-pentopyranosyl)oxy)-6,11-dihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione Hydrochloride
2. (7s,9s)-9-acetyl-9-amino-7-((2-deoxy-beta-d-erythro-pentopyranosyl)oxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione Hydrochloride
3. Amrubicin Hydrochloride
4. Sm 5887
5. Sm-5887
1. 110267-81-7
2. 93n13lb4z2
3. Amrubicin [inn]
4. (+-)-(7s,9s)-9-acetyl-9-amino-7-((2-deoxy-beta-d-erythro-pentopyranosyl)oxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione
5. (7s,9s)-9-acetyl-9-amino-7-(((2s,4s,5r)-4,5-dihydroxytetrahydro-2h-pyran-2-yl)oxy)-6,11-dihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione
6. Amrubicin [usan:inn]
7. Amrubicina
8. Amrubicine
9. Amrubicinum
10. Unii-93n13lb4z2
11. Amrubicin Api
12. (7s,9s)-9-acetyl-9-amino-7-[(2s,4s,5r)-4,5-dihydroxyoxan-2-yl]oxy-6,11-dihydroxy-8,10-dihydro-7h-tetracene-5,12-dione
13. (7s,9s)-9-acetyl-9-amino-7-{[(2s,4s,5r)-4,5-dihydroxytetrahydro-2h-pyran-2-yl]oxy}-6,11-dihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione
14. Amrubicin [mi]
15. Amrubicin (usan/inn)
16. Amrubicin [usan]
17. Amrubicin(sm-5887)
18. Amrubicin [mart.]
19. Amrubicin [who-dd]
20. Schembl9140
21. Chembl1186894
22. Ex-a161
23. Chebi:135779
24. Hy-b0067
25. Zinc3780800
26. Db06263
27. Ac-31129
28. D08854
29. W-60403
30. Q4748723
31. W-200813
32. (1s,3s)-3-acetyl-3-amino-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2-deoxy-beta-d-erythro-pentopyranoside
33. 5,12-naphthacenedione, 9-acetyl-9-amino-7-((2-deoxy-beta-d-erythro-pentopyranosyl)oxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-, (7s,9s)-
| Molecular Weight | 483.5 g/mol |
|---|---|
| Molecular Formula | C25H25NO9 |
| XLogP3 | 0.9 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 3 |
| Exact Mass | 483.15293138 g/mol |
| Monoisotopic Mass | 483.15293138 g/mol |
| Topological Polar Surface Area | 177 Ų |
| Heavy Atom Count | 35 |
| Formal Charge | 0 |
| Complexity | 881 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 5 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Covalently Bonded Unit Count | 1 |
Investigated for use/treatment in lung cancer.
The _anthracycline glycoside_ group of antibiotics, which includes amrubicin, represent a group of potent anticancer agents with potent activity against both solid tumors and hematological malignancies. They are the principal subjects of a large number of studies for the treatment of adult and childhood neoplastic diseases. Amrubicin is a 9-aminoanthracycline derivative and promotes cell growth inhibition by stabilizing protein DNA complexes followed by double-stranded DNA breaks, which are mediated by topoisomerase-II enzyme. Anthracyclines have been observed to have a variety molecular effects (for example, DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase II cleavable complexes). Amrubicin shows decreased DNA intercalation when compared with doxorubicin. The decreased DNA interaction likely influences the intracellular distribution because amrubicin and its metabolite, _amrubicinol_. Amrubicin showed 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution shown by doxorubicin (another anthracycline drug). The cell growth inhibitory effects of amrubicin appear to be mainly due to the inhibition of topoisomerase II.
Antineoplastic Agents
Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)
L - Antineoplastic and immunomodulating agents
L01 - Antineoplastic agents
L01D - Cytotoxic antibiotics and related substances
L01DB - Anthracyclines and related substances
L01DB10 - Amrubicin
Absorption
Peak plasma concentrations of the active metabolite _amrubicinol_ were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC. In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values.
Route of Elimination
In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.
Volume of Distribution
Moderate volume of distribution (1.4 times total body water).
Clearance
The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow).
The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)P450 reductase and nicotinamide adenine dinucleotide [phosphate] (NAD[P]H)-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study. Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing. These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.
20-30 h In a study of dogs, Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations observed immediately after dosing followed by and half-lives (t1/2) SD of 0.06 0.01 and 2.0 0.3 hours, respectively.
As an anthracycline, amrubicin has antimitotic and cytotoxic activity through a variety of mechanisms of action. Amrubicin is found to form complexes with DNA via intercalation between base pairs, and it inhibits topoisomerase II enzyme activity by stabilizing the DNA-topoisomerase II complex, which prevents the re-ligation portion of the ligation-religation reaction that topoisomerase II normally catalyzes. Topoisomerase II is an enzyme located in the nucleus that regulates DNA structure through double-strand breakage and re-ligation, therefore modulating DNA replication and transcription. Inhibition of the enzyme leads to inhibition of DNA replication and halt cell growth with an arrest of the cell cycle occurring at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be through stabilization of the cleavable DNAtopo II complex, ending in re-ligation failure and DNA strand breakage. DNA damage triggers activation of caspase-3 and -7 and cleavage of the enzyme PARP (Poly ADP ribose polymerase), leading to apoptosis and a loss of mitochondrial membrane potential. Amrubicin, like all anthracyclines, intercalates into DNA and produces reactive oxygen free radicals via interaction with NADPH, which causes cell damage. Compared with doxorubicin, another member of the anthracycline drug class, amrubicin binds DNA with a 7-fold lower affinity and therefore, higher concentrations of amrubicin are necessary to promote DNA unwinding.
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