Idarubicin , 伊达比星

4-Demethoxydaunomycin (4DMXD) is a drug that belongs to the class of anthracyclines. It is structurally similar to idarubicin and daunorubicin, but it has a different mechanism of action. 4DMXD inhibits DNA synthesis by binding to nuclear DNA, which may be the result of competitive inhibition with deoxycytidine kinase. This drug has been shown to have cytotoxic effects on mouse tumor cells in vitro and leukemia cells in vivo. It also has anti-inflammatory properties and can inhibit prostaglandin synthesis. 4DMXD is currently being studied for potential use in the treatment of various types of cancer, including myelogenous leukemias, lymphomas, and other cancers such as prostate cancer.

Idarubicin is an anthracycline antibiotic that has been used for nearly 40 years as a potent chemotherapy agent in malignancies such as acute myeloid leukemia (AML). Besides its well-known chemotherapeutic activities, idarubicin has shown promise in other fields of research including cardiology, neurology, and molecular biology.

This review aims to summarize and critically analyze the chemical, biological, and toxicological properties of idarubicin, its synthesis and characterization, analytical techniques, various applications, and current limitations. Additionally, it offers recommendations for future research in this fascinating field.

Definition and Background

Idarubicin is a second-generation anthracycline antibiotic isolated from the culture broth of Streptomyces peucetius. It is a derivative of daunorubicin and is structurally related to doxorubicin. Idarubicin is an intercalating agent that binds to DNA, blocking DNA synthesis and leading to cell cycle arrest and apoptosis. Due to its potent anticancer activity, idarubicin is used as a standard chemotherapeutic agent in various chemotherapy regimens for AML and other malignancies.

Synthesis and Characterization

Idarubicin is synthesized by semi-synthesis from daunorubicin, which is extracted from a bacterium Streptomyces peucetius.

Analytical Methods

High-performance liquid chromatography (HPLC) is the most common method used for the quantification of idarubicin in biological fluids and tissues. It offers excellent sensitivity, specificity, and accuracy.

Biological Properties

Idarubicin possesses potent anticancer activity against various tumor cell lines both in vitro and in vivo. Its mechanism of action involves intercalation into DNA, inhibiting DNA and RNA synthesis, and inducing oxidative stress and apoptotic cell death. Additionally, idarubicin has shown potential in treating other medical conditions such as heart failure and neurodegenerative diseases.

Toxicity and Safety in Scientific Experiments

Idarubicin has been associated with various significant adverse events such as cardiotoxicity, myelosuppression, and gastrointestinal toxicity. The severity and incidence of these adverse events depend on the dose and duration of the treatment regimen.

Applications in Scientific Experiments

Besides its well-known anticancer activity, idarubicin has shown promise in other fields of research such as treating heart failure, Alzheimer's disease, and other neurodegenerative disorders.

Current State of Research

Several recent studies have explored the potential of idarubicin in treating various medical conditions. One study in rats suggested that idarubicin could reduce ventricular remodeling and improve cardiac function in chronic heart failure models. Additionally, experimental evidence also suggests the potential for idarubicin to improve cognitive function in Alzheimer's disease models.

Future Directions

Several potential applications of idarubicin have been identified, and significant interest exists in the scientific community to explore these new avenues for research. Some of the promising future directions include:

1. Development of idarubicin derivatives that could improve its therapeutic profile and reduce its toxicity.

2. Investigation of idarubicin's potential use in treating other conditions such as viral infections, autoimmune diseases, and chronic pain.

3. Exploration of idarubicin's mechanism of action on cancer stem cells, which could have significant implications for cancer treatment.

4. Identification of novel drug combinations with idarubicin that could enhance its anticancer activity and reduce its side effects.

5. Deployment of idarubicin in nanoscale drug delivery systems that could improve its pharmacokinetics and biodistribution.

6. Development of idarubicin-based imaging agents for the early detection of cancer and other medical conditions.

7. Investigation of idarubicin's mechanism of action on other biological targets, such as G-protein coupled receptors (GPCRs).

8. Exploration of idarubicin's anti-inflammatory properties and their potential use in treating a wide range of inflammatory conditions.

Limitations

The major limitations of idarubicin include its toxicity, selectivity for cancer cells, and the emergence of drug resistance. Additionally, further research is required to elucidate the precise mechanisms of idarubicin's anticancer and other therapeutic activities.

Conclusion

In conclusion, idarubicin is a potent and well-established chemotherapeutic agent with broad anticancer activity. Recent evidence suggests that idarubicin may have potential in other fields of research, including cardiology, neurology, and molecular biology. Although the clinical application of idarubicin is limited by dose-dependent toxicity and drug resistance, several promising future directions exist that could expand and enhance the use of this fascinating compound.

Title: Idarubicin

CAS Registry Number: 58957-92-9

CAS Name: (7S,9S)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione

Additional Names: (1S,3S)-3-acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl-3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranoside; 4-demethoxydaunomycin; 4-demethoxydaunorubicin; DMDR

Manufacturers' Codes: IMI-30; NSC-256439

Molecular Formula: C26H27NO9

Molecular Weight: 497.49

Percent Composition: C 62.77%, H 5.47%, N 2.82%, O 28.94%

Literature References: Orally active anthracycline; analog of daunorubicin, q.v. Prepn: B. Patelli et al. DE 2525633; eidem, US 4046878 (1976, 1977 both to Soc. Farmac. Ital.); and antitumor activity: F. Arcamone et al., Cancer Treat. Rep. 60, 829 (1976). Total synthesis for larger scale preparation: M. J. Broadhurst et al., Chem. Commun. 1982, 158. Synthesis of optically pure isomers: Y. Kimura et al., Bull. Chem. Soc. Jpn. 59, 423 (1986). Metabolism and biodistribution in rats: G. Zini et al., Cancer Chemother. Pharmacol. 16, 107 (1986). HPLC determn in plasma: S. S. N. De Graaf et al., J. Chromatogr. 491, 501 (1989). Clinical pharmacokinetics: H. C. Gillies et al., Br. J. Clin. Pharmacol. 23, 303 (1987). Clinical evaluation of cardiac toxicity: F. Villani et al., Eur. J. Cancer Clin. Oncol. 25, 13 (1989). Reviews of pharmacology and antitumor efficacy: A. M. Casazza, Cancer Treat. Rep. 63, 835-844 (1979); F. Ganzina et al., Invest. New Drugs 4, 85-105 (1986). Symposium on clinical experience in acute leukemias: Semin. Oncol. 17, Suppl. 2, 1-36 (1989).

Derivative Type: Hydrochloride

CAS Registry Number: 57852-57-0

Trademarks: Idamycin (Pharmacia & Upjohn); Zavedos (Pharmacia & Upjohn)

Molecular Formula: C26H27NO9.HCl

Molecular Weight: 533.95

Percent Composition: C 58.48%, H 5.29%, N 2.62%, O 26.97%, Cl 6.64%

Properties: Orange crystalline powder, mp 183-185° (Arcamone); also reported as mp 172-174° (Broadhurst). [a]D20 +205° (c = 0.1 in methanol) (Arcamone); also reported as [a]D20 +188° (c = 0.10 in methanol) (Kimura).

Melting point: mp 183-185° (Arcamone); mp 172-174° (Broadhurst)

Optical Rotation: [a]D20 +205° (c = 0.1 in methanol) (Arcamone); [a]D20 +188° (c = 0.10 in methanol) (Kimura)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Antibiotics and Analogs; Anthracyclines; Topoisomerase II Inhibitor.