N-acetyl-calicheamicin gamma1
[CAS# 108212-76-6]

Identification

• Classification: API >> Antibiotics
• Name: N-acetyl-calicheamicin gamma1
• Synonyms: [(1R,4Z,8S,13E)-8-[[2-O-[4-(acetylethylamino)-2,4-dideoxy-3-O-methyl-a-L-threo-pentopyranosyl]-4,6-dideoxy-4-[[[2,6-dideoxy-4-S-[4-[(6-deoxy-3-O-methyl-a-L-mannopyranosyl)oxy]-3-iodo-5,6-dimethoxy-2-methylbenzoyl]-4-thio-�-D-ribo-hexopyranosyl]oxy]amino]-�-D-glucopyranosyl]oxy]-1-hydroxy-13-[2-(methyltrithio)ethylidene]-11-oxobicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-10-yl]-Carbamic acid methyl ester
• Molecular Formula: C₅₇H₇₆IN₃O₂₂S₄
• Molecular Weight: 1410.38
• CAS Registry Number: 108212-76-6
• EC Number: 680-674-6
• 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=C\C#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)C(=O)C

Properties

• Solubility: Sparingly Soluble (0.11 g/L) (25 ºC), Calc.^*
• Density: 1.56±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of Refraction: 1.661, Calc.^*

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

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Dander
• Hazard Statements: H300-H302-H310-H315-H319-H330-H335-H341-H351-H361-H372
• Precautionary Statements: P203-P260-P261-P262-P264-P264+P265-P270-P271-P280-P284-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P316-P318-P319-P320-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	1	H310
Acute toxicity	Acute Tox.	4	H302
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	2	H300
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	2	H330
Carcinogenicity	Carc.	2	H351
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Skin irritation	Skin Irrit.	2	H315

Discovory and Applicatios

N-Acetyl-calicheamicin gamma1 is a potent enediyne antitumor antibiotic derived from the bacterium *Micromonospora echinospora*. Discovered in the late 1980s, this molecule belongs to the calicheamicin family, which is known for its exceptional cytotoxicity due to DNA cleavage properties. Its structure features an enediyne core, a sugar moiety, and an N-acetyl group that modulates its biological activity and specificity. The molecule’s discovery represented a milestone in natural product research, with its complex structure offering insight into innovative mechanisms of DNA damage.

N-Acetyl-calicheamicin gamma1 acts by binding to the minor groove of DNA, where it undergoes a triggered cyclization reaction to generate highly reactive diradicals. These diradicals abstract hydrogen atoms from the DNA backbone, leading to strand scission. This mechanism of DNA cleavage is highly efficient and lethal to cells, making it particularly valuable in targeting rapidly proliferating cancer cells. The molecule’s activity is activated under reductive conditions within cells, allowing for precise delivery of cytotoxic effects.

The extraordinary potency of N-acetyl-calicheamicin gamma1 inspired the development of antibody-drug conjugates (ADCs), where the molecule is linked to monoclonal antibodies targeting specific cancer cell antigens. One of the most notable applications is in the drug gemtuzumab ozogamicin, approved for treating acute myeloid leukemia (AML). In this ADC, the antibody targets CD33-positive leukemic cells, delivering N-acetyl-calicheamicin gamma1 directly to the cancerous cells while sparing normal tissue. This approach enhances therapeutic efficacy and minimizes systemic toxicity.

Research into N-acetyl-calicheamicin gamma1 has significantly influenced the field of targeted cancer therapies. Its discovery highlighted the potential of enediyne antibiotics as payloads in ADCs, encouraging further development of similar conjugates. Ongoing investigations aim to improve the stability, specificity, and delivery mechanisms of these conjugates to treat various malignancies more effectively.

Due to its highly potent nature, handling and synthesis of N-acetyl-calicheamicin gamma1 remain challenging. The biosynthetic pathways of calicheamicins are complex, involving multiple enzymes for enediyne core formation and sugar moiety attachment. Advances in genetic engineering and synthetic biology are enhancing the feasibility of producing analogs with tailored properties for therapeutic use.

N-Acetyl-calicheamicin gamma1 exemplifies the power of natural products in modern drug development. Its role in targeted therapies underscores how molecular insights into natural compounds can lead to life-saving treatments, especially for diseases like leukemia. The continued exploration of enediyne antibiotics holds promise for the discovery of new therapeutic agents with high precision and potency.