Calicheamicins, isolated from Micromonospora echinospora ssp. calichensis, combine unprecedented and extraordinary chemical and biological properties.  This includes activity in the biochemical prophage induction assay at concentrations <1 pM, high antibacterial activity, and extreme potency against various leukemia and solid neoplasms such as colon cancer and melanoma with optimal doses of 0.15-5 ug/kg. [1]

Calicheamicin-γ, as well as other enediyne antibiotics, belongs to a group of the most effective chemotherapeutic agents.  Their effectiveness is due to the unique structure and sophisticated mechanism of action by which they destroy double-stranded DNA.  The compound is a highly potent anti-tumor antibiotic that cleaves DNA with a high degree of specificity, causes sequence-selective double-strand cuts.[2]

Structural regions
Calicheamicin-γ contains two distinct structural regions. The larger of the two consists of an extended sugar residue comprising four monosaccharide units and one hexasubstituted benzene ring which are joined together through a highly unusual series of glycosidic, thioester, and hydroxylamine linkages.[3]

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Researchers note that the specific calicheamicin γ–DNA-binding process depends not only on the base sequence of the double helix but also on its structure and flexibility of the compound [4]

As part of the unique mechanism of action, aryloligosaccharide deliver the molecule to its target where it tightly binds in the minor groove of double-helical DNA and displays high specificity for sequences including  5′-TCCT-3′ and 5′-TTTT-3‘ through significant hydrophobic interactions and other forces. This binding is thought to be facilitated by substantial preorganization of the oligosaccharide into a rigid, ex-tended conformation.

A significant portion of the sequence selectivity for 5′-TCCT-3′ arises from a favorable interaction between the large and polarizable iodo substituent of the hexasubstituted aromatic ring and the exocyclic amino substituents of the two guanines in the 3′-AGGA-5′ tract.[3]

Second region
The second region of calicheamicin-γ is its aglycon, a rigid, highly functionalized bicyclic core which acts as the “payload” of the molecule. The enediyne functionality of the molecule is locked within a rigid 10-membered bridged ring awaiting activation to undergo the Bergman reaction (also known as Bergman cyclization or Bergman cycloaromatization).[3]

Figure 1.0: Mechanism of Action of Calicheamicin. Calicheamicins are a group of enediyne antitumor antibiotics. Calicheamicins target DNA and cause strand scission. [1]

Also forming part of the aglycon is a trisulfide which serves as the so-called trigger. Once the molecule is in the vicinity of DNA, a series of chemical reactions unfold leading to DNA cleavage.

A nucleophile (e.g. glutathione) attacks the central sulfur atom of the trisulfide group. This causes the formation of thiolate or thiol which adds intramolecularly to the adjacent α, β-unsaturated ketone embedded within the framework of the aglycon. This reaction, converting a regional bridgehead position to a tetragonal center, causes a significant change in structural geometry which imposes a great deal of strain on the 10-membered ring.

The strain is completely relieved by the enediyne undergoing an rearrangement reaction analogous to the Bergman reaction, generating a highly reactive benzenoid diradical (1,4-didehydrobenzene).[3]

The calicheamicin diradical then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, the duplex DNA, at the C-5′ position of the cytidine in 5′-TCCT-3′ and the C-4′ position of the nucleotide three base pairs removed on the 3′ side of the complementary strand.  This leads to scission or cleavage of both strands of DNA.[3]

References:
[1] Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996 May 24;39(11):2103-17.<br>
[2] Gredicak M, Jerić I. Enediyne compounds – new promises in anticancer therapy. Acta Pharm. 2007 Jun;57(2):133-50.
[3] Nicolaou KC, Smith AL, Yue EW. Chemistry and biology of natural and designed enediynes .Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5881-8.

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ADC Review, Journal of Antibody-drug Conjugates (ISSN 2327-0152) launched in 2013, is designed to serve the needs of a diverse community of individuals including academia, life sciences, pharma, (basic, translational and clinical) research, clinicians/physicians, along with regulatory affairs, government authorities and representatives from payers, and policy makers. The Journal’s content includes peer reviewed research, commentaries, news features, discussions, editorials and blogs on topics relevant to a broad international readership. The Journal also offers a knowledge center (called ADC University) offering the latest and most relevant information about Antibody-drug Conjugates (ADCs), BiSpecific Antibodies, Site Specific Antibody Drug Conjugates, Small Molecule Drug Conjugates (SMDC), and Engineered Antibody Fragments. The purpose of the Journal is to present this information in an understandable and a useful format for all stakeholders.