Doxorubicin HCl, 盐酸多柔比星

Doxorubicin hydrochloride is an inhibitor of topoisomerase II with anti-neoplastic activity and belongs to the class of anthracyclines. Its is cytotoxic, and interferes with the topoisomerase II-mediated repair of DNA causing accumulation of mutations. Doxorubicin also leads to the generation of reactive oxygen species (ROS), which further damage DNA as well as proteins and membranes. Doxorubicin is used as a chemotherapy treatment for various types of cancer, including breast cancer, lung cancer, ovarian cancer, and leukaemia. However, the compound presents with a risk of developing cardiomyopathy as well as drug resistance.

Doxorubicin Hydrochloride (DOX) is an anthracycline antibiotic that has been extensively researched because of its potent anticancer activity. DOX is one of the most commonly used chemotherapy drugs for the treatment of several types of cancers, including breast cancer, ovarian cancer, and leukemia. Since its discovery in the 1960s, DOX has been widely used as an effective anticancer drug, and its mechanisms of action have been extensively studied. In this paper, we provide comprehensive coverage of DOX by discussing its definition and background, physical and chemical properties, synthesis, characterization, analytical methods, biological properties, toxicity, safety in scientific experiments, applications in scientific experiments, current state of research, potential implications in various fields of research and industry, limitations, and future directions.

Definition and Background:

DOX is an anthracycline antibiotic derived from Streptomyces peucetius var. caesius, which was first discovered in the 1960s. DOX is a hydrochloride salt of doxorubicin, a bright red crystalline powder that is highly soluble in water. The chemical formula for DOX is C27H29NO11.HCl, with a molecular weight of 579.98 g/mol.

Physical and Chemical Properties:

DOX belongs to the anthracycline family and has a broad range of physical and chemical properties. DOX is a highly fluorescent compound that can be excited by ultraviolet light. It is also known for its potent red color, which is due to the presence of its anthraquinone moiety. DOX has a melting point of 214-215°C, and it is soluble in a variety of solvents, including water, ethanol, and methanol. DOX has a pKa of 8.3 and is protonated under acidic conditions.

Synthesis and Characterization:

The synthesis of DOX involves several steps, starting with the fermentation of Streptomyces peucetius var. caesius. After fermentation, the DOX analogs are isolated and purified before further chemical modifications. The final step involves the conversion of DOX analogs into DOX hydrochloride salt for clinical use. DOX can be characterized by various analytical techniques, including UV-Vis spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry.

Analytical Methods:

Various analytical methods have been developed to quantify DOX and its metabolites in biological samples. These analytical methods include high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), liquid chromatography-mass spectrometry (LC-MS), and fluorescence-based assays.

Biological Properties:

DOX exerts its anticancer activity by interfering with DNA synthesis and repair. Moreover, DOX prevents cell proliferation by inducing cellular apoptosis. DOX has also been shown to inhibit angiogenesis, which is critical for tumor growth and invasion. The biological properties of DOX contribute to its widespread use in various chemotherapy regimens.

Toxicity and Safety in Scientific Experiments:

DOX has several side effects, which limit its use in clinical and scientific research. These side effects include cardiotoxicity, myelosuppression, and gastrointestinal toxicity. DOX has also been linked to the development of secondary malignancies, such as leukemia and sarcomas. Therefore, it is essential to measure the toxicity and safety of DOX to assess its efficacy in cancer treatment.

Applications in Scientific Experiments:

DOX has been extensively researched for its applications in scientific experiments. DOX has been shown to be an effective chemotherapeutic agent against various types of cancers, including breast, lung, and bladder cancer. DOX has also been used to evaluate drug delivery systems and imaging agents for cancer diagnosis and treatment. Moreover, DOX has been used to generate animal models of cancer to study the mechanisms of tumor development and progression.

Current State of Research:

The current state of research on DOX is focused on improving its delivery and reducing its toxicity. Novel drug delivery systems have been developed to enhance the efficacy of DOX while reducing its side effects. For example, liposomal formulations of DOX have been developed for targeted drug delivery to tumor tissues. Moreover, research is ongoing to develop novel imaging agents for the non-invasive detection of tumors.

Potential Implications in Various Fields of Research and Industry:

DOX has the potential to be used in several fields of research and industry. DOX can be used as a tool for the development of new cancer therapeutics and drug delivery systems. Moreover, DOX can be used as a diagnostic and prognostic tool for the detection and monitoring of cancer. Additionally, DOX has potential applications in the production of dyes, paints, and plastics.

Limitations:

Despite its widespread use, DOX has several limitations, including dose-dependent toxicity, drug resistance, and limited efficacy in certain types of cancers. Therefore, novel drug delivery systems and combination therapies are needed to improve the efficacy of DOX in cancer treatment.

Future Directions:

Several future directions have been proposed for the development and use of DOX. These include:

1. Development of targeted drug delivery systems for more efficient treatment of cancer.

2. Development of imaging agents for non-invasive detection and monitoring of cancer.

3. Combination therapy with other chemotherapeutic agents for improved efficacy in cancer treatment.

4. Study of the molecular mechanisms underlying DOX resistance to identify new therapeutic targets for cancer treatment.

5. Development of new formulations of DOX to reduce its toxicity and improve its efficacy.

6. Use of DOX in stem cell research to enhance differentiation and proliferation.

Conclusion:

DOX is an anthracycline antibiotic that has been widely used as a potent anticancer drug. DOX has several physical and chemical properties that are critical for its efficacy and safety in clinical and scientific research. Although DOX has several limitations, novel drug delivery systems and combination therapies offer exciting opportunities for improving its efficacy and reducing its toxicity. DOX has broad implications in various fields of research and industry, and future directions for its use and development are promising.

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.