Calicheamicin gamma 1
[CAS# 108212-75-5]

Identification

• Classification: API >> Antibiotics
• Name: Calicheamicin gamma 1
• Synonyms: LL-E 33288 gamma1-I; S-[(2R,3S,4S,6S)-6-[[(2R,3S,4S,5R,6R)-5-[(2S,4S,5S)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2S,5Z,9R,13Z)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-methyloxan-3-yl]amino]oxy-4-hydroxy-2-methyloxan-3-yl] 4-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-4-methoxy-6-methyloxan-2-yl]oxy-5-iodo-2,3-dimethoxy-6-methylbenzenecarbothioate
• Molecular Formula: C₅₅H₇₄IN₃O₂₁S₄
• Molecular Weight: 1368.35
• CAS Registry Number: 108212-75-5
• EC Number: 813-745-9
• SMILES: CCN[C@H]1CO[C@H](C[C@@H]1OC)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2O[C@H]3C#C/C=CC#C[C@@]4(CC(=O)C(=C3/C4=C/CSSSC)NC(=O)OC)O)C)NO[C@H]5C[C@@H]([C@@H]([C@H](O5)C)SC(=O)C6=C(C(=C(C(=C6OC)OC)O[C@H]7[C@@H]([C@@H]([C@H]([C@@H](O7)C)O)OC)O)I)C)O)O

Properties

• Solubility: Practically insoluble (0.021 g/L) (25 °C), Calc.^*
• Density: 1.57±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.662, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08 Danger
• Risk Statements: H302-H341-H361-H372
• Safety Statements: P203-P260-P264-P270-P280-P301+P317-P318-P319-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Germ cell mutagenicity	Muta.	2	H341
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

Calicheamicin gamma 1, a potent antitumor antibiotic, was discovered in the late 1970s by researchers at Wyeth-Ayerst Laboratories (now Pfizer Inc.). The discovery originated from soil samples collected in Texas, USA, containing the bacterium Micromonospora echinospora subspecies calichensis. Through a series of bioassays, calicheamicin gamma 1 was isolated and identified as the active compound responsible for its remarkable cytotoxic properties against cancer cells. Its discovery marked a significant breakthrough in the search for novel anticancer agents.

Calicheamicin gamma 1 has shown exceptional efficacy in the treatment of hematologic malignancies, particularly acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It exerts its antitumor activity by inducing DNA cleavage through double-strand breaks, leading to apoptosis in cancer cells. As a key component of antibody-drug conjugates (ADCs), calicheamicin gamma 1 is conjugated to monoclonal antibodies targeting tumor-specific antigens, delivering cytotoxic payloads selectively to cancer cells while sparing healthy tissues. Calicheamicin gamma 1 serves as the cytotoxic payload in several FDA-approved ADCs, including gemtuzumab ozogamicin (Mylotarg) for the treatment of CD33-positive AML and inotuzumab ozogamicin (Besponsa) for relapsed or refractory B-cell precursor ALL. ADCs harness the specificity of monoclonal antibodies to target cancer cells, enabling precise delivery of calicheamicin gamma 1 to tumor sites and minimizing off-target effects, thereby enhancing therapeutic efficacy and reducing systemic toxicity. While most prominently used in hematologic malignancies, ongoing research explores the potential of calicheamicin gamma 1-based ADCs in the treatment of solid tumors. Preclinical and clinical studies are investigating novel ADCs targeting various tumor-associated antigens in solid tumors such as breast cancer, lung cancer, and ovarian cancer. These investigational therapies hold promise for expanding the therapeutic options available for patients with refractory or metastatic solid tumors. Beyond its anticancer properties, calicheamicin gamma 1 has demonstrated antibacterial activity against certain gram-positive bacteria. Research efforts continue to explore its potential applications in antibacterial therapies, particularly in combination with other antibiotics or as part of novel treatment strategies for multidrug-resistant bacterial infections.

References

2024. Tunable and Photoactivatable Mimics of Calicheamicin γ1 for DNA Cleavage. Journal of the American Chemical Society.
DOI: 10.1021/jacs.4c07754

2014. Identification and Characterization of a Methionine Γ‐Lyase in the Calicheamicin Biosynthetic Cluster of Micromonospora echinospora. Chembiochem: A European Journal of Chemical Biology.
DOI: 10.1002/cbic.201402489

1988. Calicheamicin Γ 1 I: an Antitumor Antibiotic That Cleaves Double-Stranded DNA Site Specifically. Science (New York, N.Y.).
DOI: 10.1126/science.3240341