C-1027

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Contents

C-1027 chromophore [1]
C-1027 chromophore.svg
Names
IUPAC name
(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
Other names
Lidamycin chromophore
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
PubChem CID
  • 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
    Key: DGGZCXUXASNDAC-QQNGCVSVSA-N
  • 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
  • Aromatized chromophore::[H]N1C(=O)C(=C)OC2=CC(OC)=CC(C(=O)O[C@H]3COC(=O)C[C@@H](C4=CC(O)=C(O[C@]5([H])C6=C(C=C3C=C6)C3=CC=C[C@]53O[C@@H]3OC(C)(C)[C@H]([C@@H](O)[C@H]3O)N(C)C)C(Cl)=C4)[N+]([H])([H])[H])=C12
Properties
C43H42ClN3O13
Molar mass 844.267 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

C-1027 or lidamycin is an antitumor antibiotic consisting of a complex of an enediyne chromophore and an apoprotein. [2] [3] [4] [5] [6] [7] It shows antibiotic activity against most Gram-positive bacteria. [8] 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.

C-1027's chromophore contains a nine-membered enediyne that is responsible for most of the molecule's biological activity. [8] 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 hypoxic tumor cells. [9]

C-1027 Mechanism C-1027 mechanism.png
C-1027 Mechanism

C-1027 shows promise as an anticancer drug and is currently undergoing phase II clinical trials in China, [10] with a 30% success rate. [11] 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. [7]

Biosynthesis

Enediyne

The structure of C-1027 is composed of a nine-membered enediyne complex, a deoxygenated aminosugar, a β-amino acid, and a benzoxazolinate moiety. Enediynes contain a double bond between two triple bonds, and their biosynthesis is distinct from other known polyketide and fatty-acid synthesis paradigms. The enediyne PKS, PKSE, from S. globisporusresponsible for the biosynthesis of the C-1027 enediyne is an ACP dependent protein with ketoacylsynthase (KS), acyltransferase (AT), ketoreductase (KR), and dehydratase (DH) domains. [12] PKSE also contains a C-termianal PPTase domain, and the process is terminated by a thioesterase (TE). Starting with acetyl-CoA, PKSE iteratively combines 7 units of malonyl-CoA creating an intermediate heptaene, which is then catalyzed by accessory enzymes into a 9 membered enediyne. [13] There is also a remarkable similarity between the biosynthesis of 9-membered and 10-membered enediynes such as the anticancer drug Calicheamicin. [14]

Enediyne Biosynthesis The Enediyne.png
Enediyne Biosynthesis

Deoxy Aminosugar

The deoxy aminosugar found in C-1027 is derived from 5-glucose-1-phosphate. The C-1027 gene cluster contains a thymine diphosphate glucose synthetase (SgcA1), a TDP-glucose 4,6-dehydratase (SgcA2), a TDP-4-keto-6-deoxyglucose epimerase (SgcA2), a C-methyl transferase (SgcA3), an amino transferase (SgcA4), an N-methyl transferase (SgcA5), and a glycosyl transferase (SgcA6). These are all the necessary enzymes to synthesize the deoxy aminosugar and attach it to the enediyne core. [12]

Deoxy Aminosugar Biosynthesis The Deoxy Aminosugar.png
Deoxy Aminosugar Biosynthesis

β-Amino Acid

The β-amino acid moiety is a non-ribosomal peptide synthesized from tyrosine. The necessary enzymes for its biosynthesis include a phenol hydroxylase (SgcC), a nonribosomal peptide synthetase adenylation enzyme (SgcC1), an NRPS peptidyl–carrier protein (SgcC2), a halogenase (SgcC3), an aminomutase (SgcC4), and an NRPS-condensation enzyme (SgcC5). All of these enzymes are encoded for within the C-1027 biosynthetic gene cluster. [12]

B-Amino Acid Biosynthesis The B-Amino Acid.png
B-Amino Acid Biosynthesis

Benzoxazolinate

The benzoxazolinate moiety is synthesized from chorismate, which itself is biosynthesized from the shipmate pathway. Chorismate is sequentially acted upon by a 2-amino-2-deoxyisochorismate synthase, and an iron–sulfur FMN-dependent ADIC dehydrogenase to synthesize 3-enolpyruvoylanthranilate (OPA). OPA is then further catalyzed into the benzoxazolinate precursor for C-1027. [15]

Benzoxazolinate Biosynthesis The Benzoxazolinate.png
Benzoxazolinate Biosynthesis

C-1027

The four building blocks are then combined into C-1027, although the exact mechanisms and order of this is relatively unknown. [12]

C-1027 Biosynthesis The C-1027.png
C-1027 Biosynthesis

Related Research Articles

Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms. While there exist a wide range of peptides that are not synthesized by ribosomes, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

<span class="mw-page-title-main">Mitomycin</span> Group of antibiotics

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

<span class="mw-page-title-main">Neocarzinostatin</span> Chemical compound

Neocarzinostatin (NCS) is a macromolecular chromoprotein enediyne antitumor antibiotic secreted by Streptomyces macromomyceticus.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

<span class="mw-page-title-main">Calicheamicin</span> Chemical compound

The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "caliche pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.

<span class="mw-page-title-main">Ascofuranone</span> Chemical compound

Ascofuranone is an antibiotic produced by various ascomycete fungi including Acremonium sclerotigenum that inhibits the Trypanosoma brucei alternative oxidase and is a lead compound in efforts to produce other drugs targeting this enzyme for the treatment of sleeping sickness. The compound is effective both in vitro cell culture and in infections in mice.

<span class="mw-page-title-main">Aminodeoxychorismate synthase</span>

In enzymology, an aminodeoxychorismate synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Enediyne</span> Any organic compound containing one double and two triple bonds

Enediynes are organic compounds containing two triple bonds and one double bond.

<span class="mw-page-title-main">Sparsomycin</span> Chemical compound

Sparsomycin is a compound, initially discovered as a metabolite of the bacterium Streptomyces sparsogenes, which binds to the 50S ribosomal subunit and inhibits protein synthesis through peptidyl transferase inhibition. As it binds to the 50S ribosomal subunit, it induces translocation on the 30S subunit. It is a nucleotide analogue. It was also formerly thought to be a possible anti-tumor agent, but interest in this drug was later discarded after it was discovered that it resulted in retinopathy and as a tool to study protein synthesis; it is not specific for bacterial ribosomes and so not usable as an antibiotic.

<span class="mw-page-title-main">Dynemicin A</span> Anti-cancer drug

Dynemicin A is an anti-cancer enediyne drug. It displays properties which illustrate promise for cancer treatments, but still requires further research.

2-Amino-4-deoxychorismate dehydrogenase is an enzyme with systematic name (2S)-2-amino-4-deoxychorismate:FMN oxidoreductase. This enzyme catalyses the following chemical reaction

2-amino-4-deoxychorismate synthase is an enzyme with systematic name (2S)-2-amino-4-deoxychorismate:2-oxoglutarate aminotransferase. This enzyme catalyses the following chemical reaction

Free radical damage to DNA can occur as a result of exposure to ionizing radiation or to radiomimetic compounds. Damage to DNA as a result of free radical attack is called indirect DNA damage because the radicals formed can diffuse throughout the body and affect other organs. Malignant melanoma can be caused by indirect DNA damage because it is found in parts of the body not exposed to sunlight. DNA is vulnerable to radical attack because of the very labile hydrogens that can be abstracted and the prevalence of double bonds in the DNA bases that free radicals can easily add to.

<span class="mw-page-title-main">Kedarcidin</span> Chemical compound

Kedarcidin is a chromoprotein antitumor antibiotic first isolated from an Actinomycete in 1992, comprising an ansa-bridged enediyne chromophore (shown) as well as an apoprotein that serves to stabilize the toxin in the Actinomycete. Like other members of the enediyne class of drugs—so named for the nine-or-ten-membered core structure bearing an alkene directly attached to two alkynyl appendages—kedarcidin was likely evolved to kill bacteria that compete with the producing organism. Because it achieves this by causing DNA damage, however, kedarcidin is capable of harming tumor cells, as well. Kedarcidin is thus the subject of scientific research, both for its structural complexity as well as its anticancer properties.

<span class="mw-page-title-main">Maduropeptin</span> Chemical complex

Maduropeptin consists of a 1:1 complex of a carrier protein (MdpA) and a chromophore isolated from Actinomadura madurae. The chromophore has an enediyne structure and is an antibiotic with anticancer activity.

<span class="mw-page-title-main">Leinamycin</span> Chemical compound

Leinamycin is an 18-membered macrolactam produced by several species of Streptomyces atroolivaceus. This macrolactam has also been shown to exhibit antitumor properties as well as antimicrobial properties against gram-positive and gram-negative bacteria. The presence of a spiro-fused 1,3-dioxo-1,2-dithiolane moiety was a unique structural property at the time of this compound's discovery and it plays an important role in leinamycin's antitumor and antibacterial properties due to its ability to inhibit DNA synthesis.

<span class="mw-page-title-main">Shishijimicin A</span> Chemical compound

Shishijimicin A is an enediyne antitumor antibiotic isolated from Didemnum proliferum. Isolated in 2003 it is part of the family of 10 member ringed enediyne antitumor antibiotic agents, which includes: namenamicin, esperamicin and, calicheamicin. Due to its high potency from cytotoxicity, Shishjimicin A is currently undergoing testing as a possible Antibody-antibiotic Conjugate (ADCs) cancer treatment. Laboratory tests indicate it to be “more than 1,000 times as toxic to cancer cells as the anticancer drug taxol”, also known as Paclitaxel, a prevalent chemotherapy medication. As such, theoretically, only an administration of a minuscule dose of the molecule would be necessary per each treatment. As shishjimicin A supply is scarce and the full extent of its side effects is not yet established, there is still a need for further biological and clinical studies.

Tautomycetin is a natural product first isolated from Streptomyces griseochromogenes, a bacterium found in the soil of the Zhejiang Province, China. It was also later found in Penicillium urticae. It is a linear polyketide very similar in structure to tautomycin, both of which contain a unique dialkylmaleic anhydride moiety, which is essential for their pharmacological activity. Tautomycetin is a selective inhibitor of protein phosphatase 1.

<span class="mw-page-title-main">Tetracenomycin C</span> Chemical compound

Tetracenomycin C is an antitumor anthracycline-like antibiotic produced by Streptomyces glaucescens GLA.0. The pale-yellow antibiotic is active against some gram-positive bacteria, especially against streptomycetes. Gram-negative bacteria and fungi are not inhibited. In considering the differences of biological activity and the functional groups of the molecule, tetracenomycin C is not a member of the tetracycline or anthracyclinone group of antibiotics. Tetracenomycin C is notable for its broad activity against actinomycetes. As in other anthracycline antibiotics, the framework is synthesized by a polyketide synthase and subsequently modified by other enzymes.

<span class="mw-page-title-main">Trehalosamine</span> Chemical compound

Trehalosamines are amino sugars in which a hydroxyl group of trehalose is replaced with an amino group. While 2-, 3-, and 4-trehalosamine derived from actinomycetes have been reported as natural compounds, 6-trehalosamine has been reported as a synthetic compound. They have weak antimicrobial activity and could be considered as a class of aminoglycoside antibiotics. The properties and functions of 4-trehalosamine have been well investigated as follows.

References

  1. ↑ Pubchem. "Lidamycin". pubchem.ncbi.nlm.nih.gov. Retrieved 5 May 2018.
  2. ↑ Hu J, Xue Y, Xie M, Zhang R, Otani T, Minami Y, Yamada Y, Marunaka T (1988). "A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity". The Journal of Antibiotics. 41 (11): 1575–1579. doi: 10.7164/antibiotics.41.1575 . PMID   3198491.
  3. ↑ Otani T, Minami Y, Marunaka T, ZHANG R, Xie M (1988). "A new macromolecular antitumor antibiotic, C-1027. II. Isolation and physico-chemical properties". The Journal of Antibiotics. 41 (11): 1580–1585. doi: 10.7164/antibiotics.41.1580 . PMID   3198492.
  4. ↑ Zhen Y, Ming X, Yu B, Otani T, Saito H, Yamada Y (1989). "A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity". The Journal of Antibiotics. 42 (8): 1294–1298. doi: 10.7164/antibiotics.42.1294 . PMID   2759910.
  5. ↑ Ken-ichiro Y, Minami Y, Azuma R, Saeki M, Otani T (1993). "Structure and cycloaromatization of a novel enediyne, C-1027 chromophore". Tetrahedron Lett. 34 (16): 2637–2640. doi:10.1016/S0040-4039(00)77644-1.
  6. ↑ Liang ZX (April 2010). "Complexity and simplicity in the biosynthesis of enediyne natural products". Natural Product Reports. 27 (4): 499–528. doi:10.1039/b908165h. PMID   20336235.
  7. 1 2 Zhen YZ, Lin YJ, Li Y, Zhen YS (July 2009). "Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice". Acta Pharmacologica Sinica. 30 (7): 1025–32. doi:10.1038/aps.2009.75. PMC   4006655 . PMID   19575006.
  8. 1 2 Xu YJ, Zhen YS, Goldberg IH (May 1994). "C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage". Biochemistry. 33 (19): 5947–54. doi:10.1021/bi00185a036. PMID   8180224.
  9. ↑ Chen Y, Yin M, Horsman GP, Shen B (March 2011). "Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus". Journal of Natural Products. 74 (3): 420–4. doi:10.1021/np100825y. PMC   3064734 . PMID   21250756.
  10. ↑ Wang L, Wang S, He Q, Yu T, Li Q, Hong B (August 2012). "Draft genome sequence of Streptomyces globisporus C-1027, which produces an antitumor antibiotic consisting of a nine-membered enediyne with a chromoprotein". Journal of Bacteriology. 194 (15): 4144. doi:10.1128/JB.00797-12. PMC   3416545 . PMID   22815456.
  11. ↑ Shen B, Yan X, Huang T, Ge H, Yang D, Teng Q, Rudolf JD, Lohman JR (January 2015). "Enediynes: Exploration of microbial genomics to discover new anticancer drug leads". Bioorganic & Medicinal Chemistry Letters. 25 (1): 9–15. doi:10.1016/j.bmcl.2014.11.019. PMC   4480864 . PMID   25434000.
  12. 1 2 3 4 Liu W, Christenson S, Standage S, Shen B (2002). "Biosynthesis of the Enediyne Antitumor Antibiotic C-1027". Science. 297 (5584): 1170–1173. Bibcode:2002Sci...297.1170L. doi:10.1126/science.1072110. PMID   12183628. S2CID   52817812.
  13. ↑ Shen B, Zhiang J, Van Lanen SG, Ju J, Liu W, Dorrestein PC, Li W, Kelleher NL (2008). "A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis". Proceedings from the National Academy of Sciences. 105 (5): 1460–1465. Bibcode:2008PNAS..105.1460Z. doi: 10.1073/pnas.0711625105 . PMC   2234166 . PMID   18223152.
  14. ↑ Alhert J, Shepard E, Lomovskaya N, Zazopoulos E, Staffa A, Bachmann BO, Huang K, Fonstein L, Czisny A, Whitwam RE, Farnet CM, Thorson JS (2002). "The Calicheamicin Gene Cluster and Its Iterative Type I Enediyne PKS". Science. 297 (5584): 1173–1176. doi:10.1126/science.1072105. PMID   12183629. S2CID   8227050.
  15. ↑ Shen B, Van Lanen SG, Lin S (2008). "Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism". Proceedings from the National Academy of Sciences. 105 (2): 494–499. Bibcode:2008PNAS..105..494V. doi: 10.1073/pnas.0708750105 . PMC   2206564 . PMID   18182490.
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