C-1027

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 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)	Interactive image Interactive image
ChEBI	CHEBI:68320
PubChem CID	9962646
InChI 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
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 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
Properties
Chemical formula	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).
Infobox references

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]

References

1. Pubchem. "Lidamycin". pubchem.ncbi.nlm.nih.gov. Retrieved 5 May 2018.
2. Hu, Jilan; Xue, Yu-Chuan; Xie, Mei-Yu; Zhang, Rui; Otani, Toshio; Minami, Yoshinori; Yamada, Yuji; Marunaka, Teruyoshi (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, Toshio; Minami, Yoshinori; Marunaka, Teruyoshi; ZHANG, Rui; Xie, Mei-Yu (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, Yong-Su; Ming, Xiu-Ying; Yu, Bin; Otani, Toshio; Saito, Hitoshi; Yamada, Yuji (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, Yoshida; Minami, Yoshinori; Azuma, Ryotaro; Saeki, Mayuko; Otani, Toshio (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. 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. 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.