C-1027

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C-1027 chromophore[1]
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
  • 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 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

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

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

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

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

References

  1. ^ Pubchem. "Lidamycin". pubchem.ncbi.nlm.nih.gov. Retrieved 5 May 2018.
  2. ^ Hu J, Xue YC, Xie MY, 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 MY (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 YS, Ming XY, 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. ^ a b 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. ^ a b 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. ^ a b c d 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. Bibcode:2002Sci...297.1173A. 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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