C-1027 or lidamycin is an
antitumor
Cancer treatments are a wide range of treatments available for the many different types of cancer, with each cancer type needing its own specific treatment. Treatments can include surgery, chemotherapy, radiation therapy, hormonal therapy, targe ...
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
consisting of a complex of an
enediyne
Enediynes are organic compounds containing two triple bonds and one double bond.
Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne anticancer antibiotics). They are efficient at inducing apoptosis in c ...
chromophore
A chromophore is the part of a molecule responsible for its color. The word is derived .
The color that is seen by our eyes is that of the light not Absorption (electromagnetic radiation), absorbed by the reflecting object within a certain wavele ...
and an
apoprotein.
It shows antibiotic activity against most
Gram-positive bacteria
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
The Gram stain ...
.
It is one of the most potent
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...
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
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
.
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
In chemistry, a diradical is a chemical species, molecular species with two electrons occupying molecular orbitals (MOs) which are degenerate energy level, degenerate. The term "diradical" is mainly used to describe organic compounds, where most ...
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.

C-1027 shows promise as an anticancer drug and is currently undergoing
phase II clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
s in China, with a 30% success rate.
It can induce
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
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.
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.
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.
There is also a remarkable similarity between the biosynthesis of 9-membered and 10-membered enediynes such as the anticancer drug Calicheamicin.
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.
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.
Benzoxazolinate
The benzoxazolinate moiety is synthesized from chorismate, which itself is biosynthesized from the shikimate 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.
C-1027
The four building blocks are then combined into C-1027, although the exact mechanisms and order of this is relatively unknown.
References
{{Enediynes
Antibiotics
Experimental cancer drugs
Enediynes
Nine-membered rings
Vinylidene compounds