Title: Doxorubicin
CAS Registry Number: 23214-92-8
CAS Name: (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione
Additional Names: 14-hydroxydaunomycin
Manufacturers' Codes: NSC-123127; FI-106
Molecular Formula: C27H29NO11
Molecular Weight: 543.52
Percent Composition: C 59.66%, H 5.38%, N 2.58%, O 32.38%
Literature References: Anthracycline antibiotic; interferes with topoisomerase II function. Isoln from Streptomyces peucetius var caesius: F. Arcamone et al., ZA 6802378; eidem, US 3590028 (1968, 1971 both to Farmitalia); eidem, Biotechnol. Bioeng. 11, 1101 (1969). Structural studies: F. Arcamone et al., Tetrahedron Lett. 10, 1007 (1969). Synthesis from daunomycin, q.v.: eidem, Chim. Ind. (Milan) 51, 834 (1969). Biochemical comparison with daunomycin: Wang et al., Proc. Am. Assoc. Cancer Res. 12, No. 62, 77 (1971). In acid environment doxorubicin breaks up into adriamycinone and daunosamine: A. Di Marco et al., Cancer Chemother. Rep. Part 1 53, 33 (1969). Pharmacokinetic and chemotherapeutic studies: E. Arena et al., Arzneim.-Forsch. 21, 1258 (1971). LC/MS/MS determn of doxorubicin and metabolites: R. D. Arnold et al., J. Chromatogr. B 808, 141 (2004). Toxicity study: C. Bertazzoli et al., Experientia 26, 389 (1970). Comprehensive description: A. Vigevani, M. J. Williamson, Anal. Profiles Drug Subs. 9, 245-274 (1980). Book: Doxorubicin, F. Arcamone, Ed. (Academic Press, New York, 1981) 369 pp. Review of clinical development: R. H. Blum, S. K. Carter, Ann. Intern. Med. 80, 249-259 (1974); of efficacy in cancer therapy: H. L. Davis, T. E. Davis, Cancer Treat. Rep. 63, 809-815 (1979); of clinical pharmacokinetics: P. A. J. Speth et al., Clin. Pharmacokinet. 15, 15-31 (1988); of mechanism of cardiotoxicity: R. D. Olson, P. S. Mushlin, FASEB J. 4, 3076-3086 (1990); of mechanism of action: G. Aubel-Sadron, D. Londos-Gagliardi, Biochimie 66, 333-352 (1984); D. A. Gewirtz, Biochem. Pharmacol. 57, 727-741 (1999); of liposomal formulations: D. N. Waterhouse et al., Drug Saf. 24, 903-920 (2001).
Derivative Type: Hydrochloride
CAS Registry Number: 25316-40-9
Trademarks: Adriacin (Pfizer); Adriblastina (Pfizer); Adriamycin (Pfizer)
Molecular Formula: C27H29NO11.HCl
Molecular Weight: 579.98
Percent Composition: C 55.91%, H 5.21%, N 2.42%, O 30.34%, Cl 6.11%
Properties: Red crystalline solid, mp 205° (dec). [a]D20 +248±2° (c = 0.1 in methanol). Absorption max (methanol): 233, 253, 290, 477, 495, 530 nm (e 38150, 25500, 8400, 13050, 13000, 7200). Apparent partition coefficient (1-octanol/Tris buffer pH 7.0): 0.52. Readily sol in water, normal saline, methanol, acetonitrile, THF. Practically insol in acetone, benzene, chloroform, ethyl ether and petr ether. Aq solns are yellow-orange at acid pHs, orange-red at neutral pHs and violet-blue at pH >9. LD50 i.v. in mice: 21.1 mg/kg (Bertazzoli, 1970).
Melting point: mp 205° (dec)
Optical Rotation: [a]D20 +248±2° (c = 0.1 in methanol)
Log P: partition coefficient (1-octanol/Tris buffer pH 7.0): 0.52
Absorption maximum: Absorption max (methanol): 233, 253, 290, 477, 495, 530 nm (e 38150, 25500, 8400, 13050, 13000, 7200)
Toxicity data: LD50 i.v. in mice: 21.1 mg/kg (Bertazzoli, 1970)
Derivative Type: Liposomal complex of the citrate
CAS Registry Number: 111266-55-8 (doxorubicin citrate)
Trademarks: Myocet (Elan)
Literature References: Doxorubicin citrate encapsulated in liposome carriers composed of egg phosphatidylcholine and cholesterol. Review of development and clinical efficacy in breast cancer: G. Batist et al., Expert Opin. Pharmacother. 3, 1739-1751 (2002).
Derivative Type: Liposomal complex of the hydrochloride
Trademarks: Caelyx (Schering-Plough); Doxil (Ortho Biotech)
Literature References: Doxorubicin HCl encapsulated in liposome carriers composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, fully hydrogenated soy phosphatidylcholine, and cholesterol. Review of pharmacology and toxicology: P. K. Working, A. D. Dayan, Hum. Exp. Toxicol. 15, 752-785 (1996); of clinical experience in solid and hematological malignancies and AIDS-related Kaposi's sarcoma: M. Sharpe et al., Drugs 62, 2089-2126 (2002); of pharmacokinetics: A. Gabizon et al., Clin. Pharmacokinet. 42, 419-436 (2003).
Properties: LD50 in mice: 38.3±7.2 mg/kg (Working, Dayan).
Toxicity data: LD50 in mice: 38.3±7.2 mg/kg (Working, Dayan)
CAUTION: Doxorubicin hydrochloride is reasonably anticipated to be a human carcinogen: Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-8.
Therap-Cat: Antineoplastic.
Keywords: Antineoplastic; Antibiotics and Analogs; Anthracyclines; Topoisomerase II Inhibitor. |