Calicheamicin: Difference between revisions

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| verifiedrevid = 477002679
| verifiedrevid = 477002679
| IUPAC_name = 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==Calicheamicin==
'''Calicheamicin''' is a potent [[antibiotic]] and [[antitumor]] agent belonging to the class of [[enediynes]]. It is produced by the bacterium ''[[Micromonospora echinospora]]'' and is known for its ability to cleave [[DNA]] with high specificity and efficiency. Calicheamicin is one of the most potent cytotoxic agents known and has been utilized in the development of [[antibody-drug conjugates]] for targeted cancer therapy.
===Structure===
Calicheamicin is characterized by its unique molecular structure, which includes an enediyne core. This core is responsible for its DNA-cleaving activity. The molecule also contains a trisulfide linkage and a sugar moiety, which contribute to its binding affinity and specificity for DNA. The enediyne core undergoes a Bergman cyclization to form a highly reactive diradical species that abstracts hydrogen atoms from the DNA backbone, leading to strand scission.
===Mechanism of Action===
The mechanism of action of calicheamicin involves its binding to the minor groove of DNA, followed by activation of the enediyne core. Upon activation, the enediyne undergoes a cycloaromatization reaction, generating a diradical species. This diradical abstracts hydrogen atoms from the deoxyribose sugar in the DNA backbone, resulting in double-strand breaks. These breaks are lethal to cells, making calicheamicin an effective cytotoxic agent.
===Clinical Applications===
Calicheamicin has been utilized in the development of [[gemtuzumab ozogamicin]], an antibody-drug conjugate used in the treatment of [[acute myeloid leukemia]] (AML). In this conjugate, calicheamicin is linked to an antibody that targets the CD33 antigen on leukemia cells, allowing for targeted delivery of the cytotoxic agent. This targeted approach minimizes damage to normal cells and enhances the therapeutic index of the drug.
===Challenges and Research===
Despite its potent activity, the clinical use of calicheamicin is limited by its toxicity and the development of resistance. Research is ongoing to develop new formulations and delivery methods to improve its therapeutic window. Efforts are also being made to engineer calicheamicin derivatives with improved selectivity and reduced side effects.
==Related Pages==
* [[Enediyne]]
* [[Antibody-drug conjugate]]
* [[Acute myeloid leukemia]]
* [[DNA]]
* [[Antibiotic]]
{{Antibiotics}}
{{Chemotherapy}}
[[Category:Antibiotics]]
[[Category:Chemotherapy]]
[[Category:Enediynes]]

Revision as of 00:38, 19 February 2025

A potent antitumor antibiotic


{{Drugbox | verifiedfields = changed | verifiedrevid = 477002679 | IUPAC_name = 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Calicheamicin

Calicheamicin is a potent antibiotic and antitumor agent belonging to the class of enediynes. It is produced by the bacterium Micromonospora echinospora and is known for its ability to cleave DNA with high specificity and efficiency. Calicheamicin is one of the most potent cytotoxic agents known and has been utilized in the development of antibody-drug conjugates for targeted cancer therapy.

Structure

Calicheamicin is characterized by its unique molecular structure, which includes an enediyne core. This core is responsible for its DNA-cleaving activity. The molecule also contains a trisulfide linkage and a sugar moiety, which contribute to its binding affinity and specificity for DNA. The enediyne core undergoes a Bergman cyclization to form a highly reactive diradical species that abstracts hydrogen atoms from the DNA backbone, leading to strand scission.

Mechanism of Action

The mechanism of action of calicheamicin involves its binding to the minor groove of DNA, followed by activation of the enediyne core. Upon activation, the enediyne undergoes a cycloaromatization reaction, generating a diradical species. This diradical abstracts hydrogen atoms from the deoxyribose sugar in the DNA backbone, resulting in double-strand breaks. These breaks are lethal to cells, making calicheamicin an effective cytotoxic agent.

Clinical Applications

Calicheamicin has been utilized in the development of gemtuzumab ozogamicin, an antibody-drug conjugate used in the treatment of acute myeloid leukemia (AML). In this conjugate, calicheamicin is linked to an antibody that targets the CD33 antigen on leukemia cells, allowing for targeted delivery of the cytotoxic agent. This targeted approach minimizes damage to normal cells and enhances the therapeutic index of the drug.

Challenges and Research

Despite its potent activity, the clinical use of calicheamicin is limited by its toxicity and the development of resistance. Research is ongoing to develop new formulations and delivery methods to improve its therapeutic window. Efforts are also being made to engineer calicheamicin derivatives with improved selectivity and reduced side effects.

Related Pages


Types of antibacterials
Antibacterials that inhibit protein synthesis (J01A, J01B, J01F, J01G, QJ01XQ)
30S
50S
Oxazolidinone (initiation inhibitors)
Peptidyl transferase
MLS (transpeptidation/translocation)
Antibacterials active on the cell wall and envelope (J01C-J01D)
β-lactams
(inhibit synthesis
of peptidoglycan
layer of bacterial
cell wall by binding
to and inhibiting
PBPs, a group of
D-alanyl-D-alanine
transpeptidases)
Penicillins (Penams)
Narrow
spectrum
Extended
spectrum
Carbapenems / Penems
Cephems
Cephalosporins
Cephamycins
Carbacephems
1st generation
2nd generation
3rd generation
4th generation
5th generation
Monobactams
β-lactamase inhibitors
Polypeptides
Lipopeptides
- Insert into bacterial cell wall causing perforation and depolarization: Daptomycin - Surfactin
Other
- Inhibits PG elongation and crosslinking: Ramoplanin§
Intracellular
- Inhibit PG subunit synthesis and transport: NAM synthesis inhibition (Fosfomycin)

- DADAL/AR inhibitors (Cycloserine)

- bactoprenol inhibitors (Bacitracin)
Other
- Hydrolyze NAM-NAG

- - lysozyme - Tyrothricin - - Gramicidin - - Tyrocidine - Isoniazid#

- Teixobactin


Antibacterials that inhibit nucleic acid (J01E, J01M)
Antifolates
(inhibit bacterial
purine metabolism,
inhibiting DNA/RNA synthesis)

DHFR inhibitors - 2,4-Diaminopyrimidine (Brodimoprim - Iclaprim - Ormetoprim - Pyrimethamine - Tetroxoprim - Trimethoprim)
Sulfonamides (DHPS inhibitors)
Short-acting - Sulfisomidine - Sulfamethizole - Sulfadimidine (Sulfamethazine - Sulfadimerazine - Sulfadimezine) - Sulfapyridine (Sulfasalazine) - Sulfafurazole (Acetyl sulfisoxazole) - Sulfanilamide (Prontosil) - Sulfathiazole (Phthalylsulfathiazole - Succinylsulfathiazole) - Sulfathiourea

Intermediate-acting - Sulfamethoxazole - Sulfadiazine - Sulfamoxole

Long-acting - Sulfadimethoxine - Sulfadoxine - Sulfalene - Sulfametomidine - Sulfametoxydiazine - Sulfamethoxypyridazine - Sulfaperin - Sulfamerazine - Sulfaphenazole - Sulfamazone

Other/ungrouped - Mafenide - Sulfacetamide - Sulfaclozine - Sulfadicramide - Sulfaguanidine - Sulfametrole - Sulfanitran

Combinations - Trimethoprim/sulfamethoxazole - Ormetoprim/sulfadimethoxine - Pyrimethamine/dapsone - Pyrimethamine/sulfadoxine

Other DHPS inhibitors - Acediasulfone - Dapsone - Solasulfone - Sulfoxone

Quinolones
(inhibit topoisomerase/DNA gyrase)

1st Generation - Cinoxacin - Flumequine - Nalidixic acid - Oxolinic acid - Pipemidic acid - Piromidic acid - Rosoxacin

Fluoroquinolones
2nd Gen - Ciprofloxacin - Ofloxacin - Enoxacin - Fleroxacin - Lomefloxacin - Nadifloxacin - Levonadifloxacin - Alalevonadifloxacin - Norfloxacin - Pefloxacin - Rufloxacin

3rd Gen - Levofloxacin - Balofloxacin - Grepafloxacin - Pazufloxacin - Sparfloxacin - Temafloxacin - Tosufloxacin

4th Gen - Besifloxacin - Delafloxacin - Gatifloxacin - Finafloxacin - Gemifloxacin - Moxifloxacin - Clinafloxacin - Garenoxacin - Prulifloxacin - Sitafloxacin - Trovafloxacin - Alatrofloxacin

Veterinary use - Danofloxacin - Difloxacin - Enrofloxacin - Ibafloxacin - Marbofloxacin - Orbifloxacin - Pradofloxacin - Sarafloxacin

Newer non-fluorinated - Nemonoxacin - Ozenoxacin Related (DNA gyrase) - Aminocoumarins (Novobiocin)

Anaerobic DNA inhibitors

Nitroimidazole derivatives - Secnidazole

RNA synthesis inhibitors

Rifamycins - Rifampicin - Rifabutin - Rifapentine - Rifaximin - Rifalazil
Lipiarmycins - Fidaxomicin


Antibacterials: others (J01X, D06AX)
Other/ungrouped




Chemotherapy‏‎
Basics
Types
Administration
Side Effects
Supportive Care
This Chemotherapy related article is a stub.
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