C-1027
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| 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
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| Other names
Lidamycin chromophore
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| Identifiers | |
3D model (
JSmol ) |
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| ChEBI | |
| ChEMBL | |
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| DrugBank |
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PubChem CID
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| 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).
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C-1027 or lidamycin is an
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 shows promise as an anticancer drug and is currently undergoing
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]
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]
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]
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]
C-1027
The four building blocks are then combined into C-1027, although the exact mechanisms and order of this is relatively unknown.[12]
References
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