How a sugar unit is defined? I am trying to understand the structure of calicheamicins, and it is noted that They consist of an enediyne headpiece and a modified carbohydrate tail consisting of four sugar units and an unusually substituted aromatic ring. I can understand in the picture where sugar unit is referred, but I would like a general definition. Thank you
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1$\begingroup$ The sugar unit features a linear chain of carbon carbon bonds. Distinct units are usually connected by glycosidic bonds (which may be hydrolyzed without breaking carbon carbon bonds). $\endgroup$ – Karsten Theis May 11 at 11:36
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1$\begingroup$ A sugar unit is a monosaccharide, the Wikipedia entry is a good introduction en.wikipedia.org/wiki/Monosaccharide $\endgroup$ – Waylander May 11 at 13:53
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Calicheamicins are natural products, which were isolated from the fermentation broth of Micromonospora echinospora subsp. calichensis. These antibiotics exhibited significant activity against Gram-positive and Gram-negative bacteria in vitro. Calicheamicin $\gamma_1$ (Ref.1) demonstrated antitumor activity against P388 leukemia and B16 melanoma in vitro (Ref.2).
The structure of Calicheamicin $\gamma_1$ contains biologically active part of bicycloring system, which is described in the following diagram:
The rest of the structure contains four modified sugar units and one aromatic nucleus. The sugar 1 unit is a 6-deoxy-4-aminohexose unit (that's why it is called a modified sugar). Its anomeric oxygen (hemiacetyl $\ce{OH}$) bound to the $\ce{C}$9 position of the endiyne unit in $\beta$-linkage. The sugar 2 unit is a 2,6-dideoxy-4-thiohexose unit, hence it is also a modified sugar. This linkage is unusual among other sugar linkages in natural origin. The inkage is a hydroxyl amine bond ($\ce{-NH-O-}$) without eliminating $\beta$-$\ce{OH}$ of 2nd sugar unit. According to proposed biosynthetic pathway, these two sugars have been added to endiyne unit in first and second steps of the pathway:
The third step of the biosynthesis is addition of the aromatic nucleus (5-iodo-4-hydroxy-2,3-methoxy-6-methylbenzoate unit) to 4-thial group of sugar 2 as a thioester bond. The forth and fifth additions of other sugar units can be alternative. Nonetheless, one sugar (a 6-deoxy-3-O-methylhexose unit) attached to the free 4-phenolic $\ce{OH}$ group of aromatic nucleus in $\alpha$-linkage. The last sugar unit is attached with its $\alpha$-$\ce{OH}$ of the anomeric center to the free 2-$\ce{OH}$ group of the first sugar in $2 \rightarrow 1$ linkage. The unusual about this sugar is it is a pentose (a 2-deoxy-3-O-methyl-4-N-ethylaninopentose unit) instead of hexose among other three.
You can find a good description of mechanism of action of Calicheamicin $\gamma_1$ in Ref.3.
I hope this is what you want to know about this molecule.
References:
- May D. Lee, Theresa S. Dunne, Marshall M. Siegel, Conway C. Chang, George O. Morton, Donald B. Borders, “Calichemicins, a Novel Family of Antitumor Antibiotics. 1. Chemistry and Partial Structure of Calichemicin $\gamma_1$,” J. Am. Chem. Soc. 1987, 109(11), 3464-3466 (https://doi.org/10.1021/ja00245a050).
- W. M. Maiese, M. P. Lechevalier, H. A. Lechevalier, J. Korshalla, N. Kuck, A.Fantini, M.J. Wildey, J. Thomas, M. Greenstein, “Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties,” The Journal of Antibiotics 1989, 42(4), 558-563 (DOI: 10.7164/antibiotics.42.558).
- Miklós Simonyi, ”The Concept of Chiral Conformers and its Significance in Molecular Pharmacology,” In Advances in Drug Research: Volume 30; Bernard Testa, Urs A. Meyer, Eds.; Academic Press: San Diego, CA, 1997, pp. 73-111 (ISBN: 0-12-013330-X).
answered May 11 at 20:25
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1$\begingroup$ thank you!may I aks if you have such a clear explanation about the agent N-acetyl gamma calicheamicin dimethyl hydrazide (NAc-gamma calicheamicin DMH) as well? $\endgroup$ – marilu May 12 at 9:35
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$\begingroup$ Sounds like it it is calicheamicin $\gamma_1$ with a linker. I didn't know biochemical manipulation of the natural product. Yet, it won't hurt if you ask the question. $\endgroup$ – Mathew Mahindaratne May 12 at 9:41
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1$\begingroup$ yes it has been used for the production of a drug, gemtuzumab ozogamicin. thank you! ema.europa.eu/en/documents/assessment-report/… $\endgroup$ – marilu May 12 at 9:44
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$\begingroup$ hello! could someone help me to decipher the structure of this molecule? I am trying to understand the structure of gemtuzumab ozogamicin: The anti-CD33 antibody is acylated with the bifunctional AcBut linker, which allows for hydrazone formation with the calicheamicin derivative. This derivative, N-acetyl-gcalicheamicin dimethylhydrazide (DMH), has a disulfide stabilized by both the two methyl groups and the calicheamicin bicyclic core, and an acetylated amino sugar. References: Joel C. Barrish, Percy H. Carter, Peter T. W. Cheng, Robert Zahler Accou... $\endgroup$ – marilu May 15 at 20:37
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$\begingroup$ @ marilu: You should post this as a new question for better results. $\endgroup$ – Mathew Mahindaratne May 16 at 2:01
