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| {{Chembox | | {{Short description|A potent antitumor antibiotic}} |
| | Reference = <ref>{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/9962646#section=Substances-by-Category|title=Lidamycin|first=|last=Pubchem|website=pubchem.ncbi.nlm.nih.gov|access-date=5 May 2018}}</ref>
| | {{DISPLAYTITLE:C-1027}} |
| <!-- Images -->
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| | ImageFile = C‐1027 chromophore.svg
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| | ImageSize = 200
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| <!-- Names -->
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| |Name = C-1027 chromophore
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| | IUPACName =(3R,4R,14R,19S)-22-chloro-4-{[(2S,3R,4R,5S)-5-(dimethylamino)-3,4-dihydroxy-6,6-dimethyloxan-2-yl]oxy}-23-hydroxy-14-(3-hydroxy-7-methoxy-2-methylidene-2H-1,4-benzoxazine-5-carbonyloxy)-17-oxo-2,16-dioxapentacyclo[18.2.2.1⁹,¹³.0³,¹⁰.0⁴,⁸]pentacosa-1(22),5,7,9,11,13(25),20,23-octaen-19-aminium
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| | OtherNames = Lidamycin chromophore
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| <!-- Sections -->
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| | Section1 = {{Chembox Identifiers
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| | PubChem = 9962646
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| | ChEBI = 68320
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| | InChI = 1S/C43H42ClN3O13/c1-21-39(52)46-34-26(17-25(54-6)18-30(34)56-21)40(53)57-31-20-55-33(49)19-28(45)23-15-27(44)37(29(48)16-23)58-32-11-7-9-22(31)12-13-24-10-8-14-43(24,32)60-41-36(51)35(50)38(47(4)5)42(2,3)59-41/h8-10,14-18,28,31-32,35-36,38,41,48,50-51H,1,19-20,45H2,2-6H3,(H,46,52)/b22-9+/t28-,31-,32+,35-,36+,38-,41-,43+/m0/s1
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| | InChIKey = DGGZCXUXASNDAC-QQNGCVSVSA-N
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| | SMILES = CC1(C(C(C(C(O1)OC23C=CC=C2C#CC4=CC#CC3OC5=C(C=C(C=C5Cl)C(CC(=O)OCC4OC(=O)C6=CC(=CC7=C6NC(=O)C(=C)O7)OC)N)O)O)O)N(C)C)C
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| | SMILES1 = CC1([C@H]([C@H]([C@H]([C@@H](O1)O[C@]23C=CC=C2C#C/C/4=C\C#C[C@H]3OC5=C(C=C(C=C5Cl)[C@H](CC(=O)OC[C@@H]4OC(=O)C6=CC(=CC7=C6NC(=O)C(=C)O7)OC)N)O)O)O)N(C)C)C
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| }}
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| | Section2 = {{Chembox Properties
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| | Formula = C<sub>43</sub>H<sub>42</sub>ClN<sub>3</sub>O<sub>13</sub>
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| | MolarMass = 844.267 g·mol−1
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| '''C-1027''' or '''Lidamycin''' is a [[antitumor]] [[antibiotic]] consisting of a complex of an [[enediyne]] [[chromophore]] and an [[apoenzyme|apoprotein]].<ref name="HuXue1988">{{cite journal|last1=Hu|first1=Jilan|last2=Xue|first2=Yu-Chuan|last3=Xie|first3=Mei-Yu|last4=Zhang|first4=Rui|last5=Otani|first5=Toshio|last6=Minami|first6=Yoshinori|last7=Yamada|first7=Yuji|last8=Marunaka|first8=Teruyoshi|title=A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity.|journal=The Journal of Antibiotics|volume=41|issue=11|year=1988|pages=1575–1579|pmid= 3198491 |doi=10.7164/antibiotics.41.1575}}</ref><ref name="OtaniMinami1988">{{cite journal|last1=Otani|first1=Toshio|last2=Minami|first2=Yoshinori|last3=Marunaka|first3=Teruyoshi|last4=ZHANG|first4=Rui|last5=Xie|first5=Mei-Yu|title=A new macromolecular antitumor antibiotic, C-1027. II. Isolation and physico-chemical properties.|journal=The Journal of Antibiotics|volume=41|issue=11|year=1988|pages=1580–1585|pmid= 3198492 |doi=10.7164/antibiotics.41.1580}}</ref><ref name="ZhenMing1989">{{cite journal|last1=Zhen|first1=Yong-Su|last2=Ming|first2=Xiu-Ying|last3=Yu|first3=Bin|last4=Otani|first4=Toshio|last5=Saito|first5=Hitoshi|last6=Yamada|first6=Yuji|title=A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity.|journal=The Journal of Antibiotics|volume=42|issue=8|year=1989|pages=1294–1298|pmid= 2759910 |doi=10.7164/antibiotics.42.1294}}</ref><ref name="Ken-ichiroMinami1993">{{cite journal|last1=Ken-ichiro|first1=Yoshida|last2=Minami|first2=Yoshinori|last3=Azuma|first3=Ryotaro|last4=Saeki|first4=Mayuko|last5=Otani|first5=Toshio|title=Structure and cycloaromatization of a novel enediyne, C-1027 chromophore|journal=Tetrahedron Lett.|volume=34|issue=16|year=1993|pages=2637–2640|doi=10.1016/S0040-4039(00)77644-1}}</ref> | | '''C-1027''' is a potent antitumor antibiotic complex produced by the bacterium ''[[Streptomyces]] globisporus''. It is known for its strong cytotoxic activity against a variety of cancer cell lines. C-1027 is a member of the enediyne class of antibiotics, which are characterized by their unique chemical structure and powerful biological activity. |
| <ref name="Liang_2010">{{cite journal | vauthors = Liang ZX | title = Complexity and simplicity in the biosynthesis of enediyne natural products | journal = Natural Product Reports | volume = 27 | issue = 4 | pages = 499–528 | date = April 2010 | pmid = 20336235 | doi = 10.1039/b908165h }}</ref><ref name="Zhen_2009">{{cite journal | vauthors = Zhen YZ, Lin YJ, Li Y, Zhen YS | title = Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice | journal = Acta Pharmacologica Sinica | volume = 30 | issue = 7 | pages = 1025–32 | date = July 2009 | pmid = 19575006 | pmc = 4006655 | doi = 10.1038/aps.2009.75 }}</ref> It shows antibiotic activity against most [[Gram-positive bacteria]].<ref name="Xu_1994" /> It is one of the most potent [[cytotoxic]] molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.
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| C-1027’s chromophore contains a nine-membered enediyne that is responsible for most of the molecule’s [[biological activity]].<ref name="Xu_1994">{{cite journal | vauthors = Xu YJ, Zhen YS, Goldberg IH | title = C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage | journal = Biochemistry | volume = 33 | issue = 19 | pages = 5947–54 | date = May 1994 | pmid = 8180224 }}</ref> Unlike other enediynes, this molecule contains no triggering mechanism. It is already primed to undergo the cycloaromatization reaction without external activation to produce the toxic 1,4-benzenoid [[diradical]] species. C-1027 can induce oxygen-independent interstrand DNA crosslinks in addition to the oxygen-dependent single- and double-stranded DNA breaks typically generated by other enediynes. This unique oxygen-independent mechanism suggests that C-1027 may be effective against [[Tumor hypoxia|hypoxic tumor cells]].<ref>{{cite journal | vauthors = Chen Y, Yin M, Horsman GP, Shen B | title = Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus | journal = Journal of Natural Products | volume = 74 | issue = 3 | pages = 420–4 | date = March 2011 | pmid = 21250756 | pmc = 3064734 | doi = 10.1021/np100825y }}</ref>
| | ==Structure and Mechanism of Action== |
| [[File:C-1027 mechanism.png|thumb|363x363px|C-1027 Mechanism|center]]
| | C-1027 is composed of four distinct components: an enediyne core, a deoxyamino sugar, a benzoxazolinate moiety, and a β-amino acid. The enediyne core is responsible for the compound's potent cytotoxicity. Upon activation, the enediyne undergoes a Bergman cyclization to form a highly reactive diradical species. This diradical can abstract hydrogen atoms from the deoxyribose backbone of [[DNA]], leading to double-strand breaks and ultimately cell death. |
| C-1027 shows promise as an anticancer drug and is currently undergoing [[phase II clinical trial]]s in China,<ref>{{cite journal | vauthors = Wang L, Wang S, He Q, Yu T, Li Q, Hong B | title = Draft genome sequence of Streptomyces globisporus C-1027, which produces an antitumor antibiotic consisting of a nine-membered enediyne with a chromoprotein | journal = Journal of Bacteriology | volume = 194 | issue = 15 | pages = 4144 | date = August 2012 | pmid = 22815456 | pmc = 3416545 | doi = 10.1128/JB.00797-12 }}</ref> with a 30% success rate.<ref>{{cite journal | vauthors = Shen B, Yan X, Huang T, Ge H, Yang D, Teng Q, Rudolf JD, Lohman JR | title = Enediynes: Exploration of microbial genomics to discover new anticancer drug leads | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 1 | pages = 9–15 | date = January 2015 | pmid = 25434000 | pmc = 4480864 | doi = 10.1016/j.bmcl.2014.11.019 }}</ref> It can induce [[apoptosis]] in many cancer cells and recent studies have indicated that it induces unusual DNA damage responses to double-strand breaks, including altering cell cycle progression and inducing chromosomal aberrations.<ref name="Zhen_2009" />
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| == References ==
| | The benzoxazolinate moiety and the deoxyamino sugar are believed to play roles in the recognition and binding of the antibiotic to DNA, enhancing its specificity and potency. The β-amino acid component is thought to contribute to the stability and solubility of the molecule. |
| {{Reflist}}
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| {{Enediynes}}
| | ==Biosynthesis== |
| | The biosynthesis of C-1027 is a complex process involving multiple gene clusters and enzymatic steps. The enediyne core is synthesized through a polyketide pathway, while the other components are assembled through various biosynthetic routes. The genes responsible for the biosynthesis of C-1027 have been identified and studied, providing insights into the enzymatic machinery required for the production of this potent antibiotic. |
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| {{antibiotic-stub}}
| | ==Clinical Applications== |
| {{oncology-stub}}
| | Due to its potent cytotoxicity, C-1027 has been investigated as a potential anticancer agent. However, its clinical application is limited by its high toxicity and instability. Researchers are exploring ways to modify the structure of C-1027 to improve its therapeutic index and reduce side effects. Strategies include the development of prodrugs, conjugation with targeting moieties, and the use of delivery systems to enhance its selectivity for cancer cells. |
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| | ==Research and Development== |
| | Ongoing research on C-1027 focuses on understanding its mechanism of action, improving its stability, and developing derivatives with enhanced therapeutic properties. Studies are also being conducted to explore its potential use in combination therapies with other anticancer agents. |
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| | ==Related Pages== |
| | * [[Enediyne]] |
| | * [[Antitumor antibiotic]] |
| | * [[Streptomyces]] |
| | * [[DNA damage]] |
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| [[Category:Antibiotics]] | | [[Category:Antibiotics]] |
| [[Category:Cancer treatments]] | | [[Category:Antitumor drugs]] |
| [[Category:Enediynes]] | | [[Category:Streptomyces]] |
| {{dictionary-stub1}}
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A potent antitumor antibiotic
C-1027 is a potent antitumor antibiotic complex produced by the bacterium Streptomyces globisporus. It is known for its strong cytotoxic activity against a variety of cancer cell lines. C-1027 is a member of the enediyne class of antibiotics, which are characterized by their unique chemical structure and powerful biological activity.
Structure and Mechanism of Action[edit]
C-1027 is composed of four distinct components: an enediyne core, a deoxyamino sugar, a benzoxazolinate moiety, and a β-amino acid. The enediyne core is responsible for the compound's potent cytotoxicity. Upon activation, the enediyne undergoes a Bergman cyclization to form a highly reactive diradical species. This diradical can abstract hydrogen atoms from the deoxyribose backbone of DNA, leading to double-strand breaks and ultimately cell death.
The benzoxazolinate moiety and the deoxyamino sugar are believed to play roles in the recognition and binding of the antibiotic to DNA, enhancing its specificity and potency. The β-amino acid component is thought to contribute to the stability and solubility of the molecule.
Biosynthesis[edit]
The biosynthesis of C-1027 is a complex process involving multiple gene clusters and enzymatic steps. The enediyne core is synthesized through a polyketide pathway, while the other components are assembled through various biosynthetic routes. The genes responsible for the biosynthesis of C-1027 have been identified and studied, providing insights into the enzymatic machinery required for the production of this potent antibiotic.
Clinical Applications[edit]
Due to its potent cytotoxicity, C-1027 has been investigated as a potential anticancer agent. However, its clinical application is limited by its high toxicity and instability. Researchers are exploring ways to modify the structure of C-1027 to improve its therapeutic index and reduce side effects. Strategies include the development of prodrugs, conjugation with targeting moieties, and the use of delivery systems to enhance its selectivity for cancer cells.
Research and Development[edit]
Ongoing research on C-1027 focuses on understanding its mechanism of action, improving its stability, and developing derivatives with enhanced therapeutic properties. Studies are also being conducted to explore its potential use in combination therapies with other anticancer agents.
Related Pages[edit]
