C-1027 Taiho Pharmaceutical Co Ltd
Ivan Brukner
Address
The Sir Mortimer B David Jewish General Hospital
Lady Davis Institute for Medical Research
McGill University
Montreal
Quebec
Canada
Email:ibrukner@hotmail.com
Current Opinion in Oncologic, Endocrine & Metabolic Investigational
Drugs 2000 2(3):
 PharmaPress Ltd ISSN 1464-8466
Taiho Pharmaceuticals is investigating an enediyne antibiotic
analog, C-1027, a DNA intercalator for the potential treatment of
tumors [174872]. Its mechanism of action is thought to be
apoptosis induction [182687].
Production of the antibiotic from Streptomyces setonii C-1027 was
claimed in the Japanese patent JP-1104183 [368485], published 21
April 1989.
Synthesis and SAR
The macromolecular antibiotic, C-1027 (15 kDa), was
originally isolated from Streptomyces sertonii C-1027 [368285]
and has also been isolated from S globisporus C-1027
[242331]. C-1027 comprises a 9-membered enediyne
chromophore and an apoprotein (10.5 kDa), which form a
non-covalent 1:1 binding complex with a Kd of 68.8 µM.
Fourier-transform infrared (FT-IR) spectroscopy and the
circular dichroism (CD) spectrum revealed abundant β
structures. A prediction of the hydropathic index suggested
that the hydrophobic residues of the apoprotein are
predominantly located in these β-sheet structures, which
indicates hydrophobic interaction in the binding between
chromophore and apoprotein [175292], [242306], [242317].
In a clonogenic assay, the free chromophore displayed potent
cytotoxicity similar to that of intact C-1027 but this activity
decreased more rapidly than that of intact C-1027, indicating
that the apoprotein protects the chromophore from
inactivation. Following pronase digestion of C-1027, the
cytotoxicity of a 3 to 5 kDa fragment (comprising a peptide
fragment and the chromophore) approximated that of intact C-
1027, with an extremely low IC50 value of 0.07 fM [242306].
An acyclic derivative of the enediyne unit of the C-1027
chromophore, the structure of another active form of the C-
1027 enediyne chromophore and the efficient synthesis of the
C-1027 chromophore have been reported [242290], [356193],
[356196]. SAR information for C-1027 has been reviewed
[356190]. The antitumor C-1027 apoprotein gene has been
cloned and sequenced [24319]. The cloning of a gene cluster for
C-1027 from S globisporus has also been described [356185] and
genes involved in the biosynthesis of C-1027 have been cloned
into plasmid pIJ702 and expressed in S lividans TK54 [356198].
Pharmacology
C-1027 and other enediyne antitumor antibiotics, including
neocarzinostatin and calicheamicin γ 1 (Wyeth-Ayerst
Research), formed covalent drug-DNA interstrand crosslinks
Originator Taiho Pharmaceutical Co Ltd
Status Discovery
Indication Neoplasm
Action DNA intercalator
Registry No 120177-69-7
Synonyms Lidamycin
O O CH2
H3C
N O
CHH3 C H
3
CH3
N O O
H3C O C
C
O OH
HO C C
H O
OH O O
Cl
NH2
and monoadducts under anaerobic conditions. The diradical
species of the activated drug initiated anaerobic DNA damage
by abstracting hydrogen atoms from the C4', C1' and C5'
positions of the A1, A2, and A3 nucleotides, respectively, in the
most preferred 5'-GTTA1T/5'-ATA2A3C-binding sequence, a
mechanism similar to that of the aerobic reaction. The
anaerobic reaction process is a kinetically competitive one,
depending on the proximity of the drug unsaturated ring
system or dioxygen to the sugar radicals and their quenching
by other hydrogen sources, such as solvent or thiols.
Interstrand crosslinks were mainly generated by C-1027,
whereas most of the anaerobic lesions produced by
neocarzinostatin were drug monoadducts. Calicheamicin γ 1
was less efficient in producing either lesion [356201]. The
authors postulate that the anaerobic DNA lesions induced by
enediyne antitumor antibiotics may have implications for their
potent cytotoxicity in the central regions of large tumors,
where relatively anaerobic conditions prevail; however, the
biological relevance is not clear.
In contrast to other enediyne antibiotics, such as
neocarzinostatin, calicheamicin, esperamicin and kedarcidin
(Bristol-Myers Squibb Co), C-1027 damages duplex DNA
even in the absence of thiols. This damage includes double-
strand (ds) breaks, singles-trand (ss) breaks, and abasic sites.
Experiments with plasmid DNA and [32P]-end-labeled
restriction fragments demonstrated that the chromophore,
extracted from the holoantibiotic, interacts in the DNA
minor groove and cleaves double-helical DNA with high
sequence-selectivity, causing direct ds breaks. The ds
cleavage sites occur predominantly at CTTTT/AAAAG,
ATAAT/ATTAT, CTTTA/TAAAG, CTCTT/AAGAG and,
especially, GTTAT/ATAAC. Single-strand breaks, which are
mainly produced at adenylate and thymidylate residues,
appear to be separate events presumably resulting from
different binding modes of the drug to DNA [175292].
In the presence of 50 nM C-1027, the intracellular episomal,
mitochondrial and genomic DNAs of the episome-containing
cell line, 935.1, were cleaved 285-fold more efficiently than in a
cell-free environment. Cleavage of the 935.1 cell episome
occurred at specific sites, including the bovine papilloma virus
(BPV) origin of replication and E6/E7 open reading frame
regions, as well as the murine mammary tumor virus (MMTV)
LTR promoter region [175287]. C-1027 activity was also
examined by measuring both the extent and specificity of
damage to simian virus 40 (SV40) DNA in lytically infected
mammalian BSC-1 cells and in purified SV40 DNA
preparations. In the cellular environment, 50% of SV40
supercoiled DNA was cleaved (a combination of ds and ss
breaks) by C-1027, with greater cleavage of viral DNA versus
cell genomic DNA (ds breaks were 80- to 40-fold more frequent
in SV40 than in BSC-1 cell genomic DNA). Restriction enzyme
digestion analysis revealed ds damage at a number of specific
sites throughout the genome (both purified and intracellular
DNA), particularly within the early region of the SV40 genome
(eg, within the coding sequence for large T-antigen). No
significant damage was observed in either the origin (ORI) or
the termination (TER) regions of SV40 replication [175285].
Cleavage of tRNA(Phe) in the presence of Mg2+ ions [183265]
and limited aminopeptidase activity [242323] have also been
reported for C-1027 but the strongest biochemical effect
appears to be on the metabolism of DNA. In HL-60 human
promyelocytic leukemia cells, exposure to C-1027 (0.1 to 10
nM) for 2 h delayed progression through the S phase,
blocked the cells at G2/M phase and caused a strong
reduction in mitotic index within 1 h [242328]. However, at
the cellular level, concentrations of C-1027 as low as 5 nM
produced morphological changes (eg, condensation of
nuclear chromatin and nuclear fragmentation) and induced
apoptosis in up to 79% of these cells. The effect of C-1027 on
DNA replication thus seems more biologically relevant.
Since C-1027 induced apoptosis in up to 79% of HL-60 cells,
it might exert its antitumor effect by triggering apoptosis
[182687]. A difference between C-1027 concentration-
dependent cleavage of DNA and C-1027 concentration-
dependent cellular effects was revealed, ie, 0.2 to 10 nM of
C-1027 inhibited the replicative activity and formation of
new replication intermediates in SV40-infected BSC-1 cells
within 15 min of drug addition. However, SV40 DNA
cleavage was barely detectable at C-1027 concentrations
capable of virtually inhibiting replicative activity, indicating
that C-1027 replication inhibition occurs in trans [242287].
C-1027 inhibited Epstein-Barr viral (EBV) DNA replication
initiation in latently infected human Raji cells within a few
minutes. The non-nuclear mitochondrial genome was
insensitive to replication inhibition but highly sensitive to
damage induced by C-1027. C-1027 induced trans-inhibition of
nuclear but not mitochondrial DNA replication, which is an
observation consistent with a cell cycle checkpoint response to
a DNA-damaging agent. EBV replication and Raji cell growth
were inhibited at equivalent C-1027 dosages [356187].
C-1027 was conjugated with monoclonal antibody (MAb) 3A5
and its Fab fragment against human hepatoma BEL-7402 cells.
Fab-C1027 was 49-fold more cytotoxic than MAb-C1027;
moreover, Fab-C1027 was 160-fold more potent against the
hepatoma cells than the control KB cells [184442]. Another
MAb (H16) against hepatoma cells was conjugated with the C-
1027 apoprotein (MAb-C1027) in order to measure antitumor
efficacy against these cells. Two approaches were taken: (i)
directly linking the apoprotein with the MAb, using N-
succinimidyl-3-(2-pyridyldithio)propionate (SPDP) as linker
agent and (ii) making an assembled conjugate by
reconstitution of the chromophore with MAb-C1027. In a
clonogenic assay, the IC50 values for hepatoma cells were 42
and 5.5 pM, respectively, for the direct and assembled
conjugates [242320].
125
A biodistribution study of [ I]-labeled MAb 3A5 and its Fab
fragment in hepatoma-bearing nude mice revealed that ID%/g
values of MAb 3A5 were higher than those of the Fab fragment
in tumor, liver, spleen and kidney; however, the T/NT ratios
of Fab were higher than those of MAb 3A5. The biodistribution
and imaging potential of the rat MAb 3A5 against human
hepatoma cells and its Fab fragment were also monitored
using BEL-7402 xenografts in nude mice. The tumor could be
131
visualized at 12 h after injection of [ I]-labeled Fab and at 40 h
131
after injection of [ I]-labeled MAb [242312]. The therapeutic
efficacy of the conjugate was evaluated using BEL-7402
xenografts in nude mice. At day 3 post-transplantation, the
Fab-C1027 conjugate and free C-1027 (0.15 mg/kg) inhibited
tumor growth by 85 and 59%, respectively [184442]. In general,
the Fab fragment displayed higher tumor specificity and
exerted a stronger inhibitory effect on the growth of
established tumor xenografts [184442], [242312].
In order to estimate potential clinical applications, the
antibiotic and antitumor activities of C-1027 were
determined. C-1027 displayed low antibacterial activity
against E coli, moderate antimycoplasmic activities and
extremely strong antitumor activity [356192]. These data are
compatible with data above, showing replication inhibition
of nuclear but not mitochondrial DNA.
C-1027 was compared with mitomycin for its efficacy against
Lewis lung carcinoma in mice. At an equitoxic dosage (25% of
the LD50), C-1027 was more effective at inhibiting pulmonary
metastases, displaying 98% inhibition versus 78% inhibition
for mitomycin. C-1027 was also highly effective at inhibiting
angiogenesis in a chick embryo chorioallantoic membrane
assay, in which it displayed a minimum effective dose of 0.021
µg/egg. Furthermore, C-1027 blocked bFGF binding to its
receptor with an IC50 value of 2.3 pg/ml. The mechanism of
angiogenesis suppression by C-1027 may be related to its
blocking of bFGF binding to its receptor [356214].
Metabolism
No published data are currently available.
Toxicity
No published data are currently available.
Clinical Development
No published data are currently available.
Current Opinion
C-1027 displayed anticancer activity at extremely low
concentrations (pM to fM range). When conjugated to a tumor-
specific MAb and/or its Fab fragment, IC50 values are also in
this range. The putative anticancer mechanism is that C-1027
triggers apoptosis. The inhibition of DNA replication in the
nM range is also of pharmacological interest. In fact, the fast
trans inhibition of nuclear/viral DNA replication initiation
(within min or h) is connected with the fast cascade of
apoptotic events. Questions remain as to the identity of the
first nuclear target and how the C-1027-mediated signal enters
the nucleus so rapidly. The isoelectric point of apoprotein is
extremely low (acidic; pI ~ 3). If the apoprotein enters the
nucleus, then interactions with basic nucleic-acid binding
proteins are highly likely. The potent inhibition of binding of
bFGF to its receptor by the C-1027 chromophore indicates that
the pharmacologically relevant effect of C-1027 might begin on
the membrane and push the cell into carrying out suicidal
replication. It would be interesting to follow the intracellular
movement and distribution of chemically synthesized and
labeled C-1027. Differential centrifugation of cell homogenates
at various intervals (at the min scale) after the addition of
labeled C-1027 might reveal mechanisms of C-1027 action. If
the apoptotic effect of C-1027 is retained following (i) fusion of
the C-1027 apoprotein with a fluorescent reporter, such as
green fluorescent protein (GFP), and (ii) reconstitution of this
GFP-apoprotein fusion with the chromophore, monitoring of
the cellular localization of C-1027 will be possible.
Overall, C-1027 is a very promising antiviral and anticancer
drug. Increasing the specificity of the MAb-C1027 conjugate
could make this drug an excellent choice for future
development in the domain of cancer chemotherapy. It
should be noted that genes involved in biosynthesis of C-
1027 were cloned relatively recently. Further optimization of
expression vectors and microbial hosts might thus enable
large-scale biotechnological production of C-1027 and
significantly reduce the production price of this drug. It will
also be important to obtain data on the half-life of drug
activity in biologically relevant systems.

Development History
DEVELOPER COUNTRY STATUS INDICATION DATE REFERENCE
Taiho Pharmaceutical Co Ltd Japan DR Neoplasm 174872

Literature classifications
Key references relating to the drug are classified according to a set of standard headings to provide a quick guide to the
bibliography. These headings are as follows:
Chemistry: References which discuss synthesis and structure-activity relationships.
Biology: References which disclose aspects of the drug’s pharmacology in animal models.
Metabolism: References that discuss metabolism, pharmacokinetics and toxicity.
Clinical: Reports of clinical phase studies in volunteers providing, where available, data on the following: whether the
experiment is placebo-controlled or double- or single-blind; number of patients; dosage.

Chemistry
STUDY TYPE RESULT REFERENCE
Isolation/characterization C-1027 was isolated from Streptomyces globisporus. 242331

Synthesis C-1027 chromophore synthesis described. 242290

Cloning Cloning/sequencing of C-1027 apoprotein. 242319

Synthesis of C1027 conjugate Linking apoprotein with MAb and/or its Fab fragment and chromophore 242320
reconstitution described.

Cloning Cloning of gene cluster involved in C-1027 biosynthesis. 356185

Cloning/complementation assay Genes involved in C-1027 biosynthesis cloned into pIJ702 and expressed in S. 356198
lividans TK54. Secretion of apoprotein and C-1027 confirmed.

Structure characterization Chemical structure of another active form of C-1027 enediyne chromophore. 356193

Progress report Enediyne biosynthesis and self-resistance. 356194

Synthesis Total synthesis of C-1027 and its acyclic derivative of C-1027 chromophore. 356196

Biology
STUDY TYPE EFFECT STUDIED EXPERIMENTAL MODEL RESULT REFERENCE
In vitro Mechanism of antitumor Antitumor activity of 0.1 to 10 2-h treatment resulted in morphological 182687
action. nM C-1027 against HL-60 changes, condensation of nuclear
human promyelocytic chromatin and nuclear fragmentation; 5
leukemia cells. nM induced apoptosis in up to 77% of
cells; C-1027 exerts antitumor activity by
triggering apoptosis.
Biology (continued)
STUDY TYPE EFFECT STUDIED EXPERIMENTAL MODEL
In vitro Aminopeptidase activity. Cleavage of L-phenylalanyl 4-
methyl-coumaryl-7-amide as
the substrate.
In vitro DNA cleavage. DNA damaging of intracellular
SV40 and genomic DNA in
green monkey kidney BSC-1
cells.
In vitro DNA cleavage. Episome-containing cell line
9351.
In vitro DNA cleavage. Sequence-dependent
cleavage of plasmid DNA.
In vitro DNA replication. C-1027 effect on DNA
replication.
In vitro Antitumor action. Human hepatoma BEL-7402
cells.
In vitro Antitumor effect of MAb Cultured hepatoma cells.
C-1027 conjugate.
In vitro Antitumor effect. Cell culture.
In vitro /in vivo Antitumor effect and Immunoconjugate composed
therapeutic effect. of C-1027 and Fab fragment
from a monoclonal antibody
directed against human
hepatoma.
In vivo Biodistribution and Biodistribution and antitumor
antitumor effect of drug. effect of MAb-C1027 and its
Fab-C1027 conjugate on
hepatoma xenografts.
RESULT REFERENCE
C-1027 showed some aminopeptidase 242323
activity, 1/15 (on the basis of the
activity per mg protein) that of porcine
kidney enzyme (E.C. 3.4.11.2.).
Topological assay reveal 50% 175285
reduction of supercoiled SV40 form of
DNA after treatment with 50 nM C-
1027.
Topological form conversion assay 175287
revealed that DNA is cleaved by C-
1027 285-fold more efficiently in cells
than in a cell-free environment; with
the following rank order: episome >
mitochondrial DNA >> genomic DNA.
Cleavage occurred predominantly in 175292
CTTT/AAAAG, ATAAT/ATTAT,
CTTTA/TAAAG, CTCTT/AAGAG and
GTTAT/ATAAC motifs.
2-D agarose gel techniques revealed 242287
rapid decrease of DNA replication of
SV40, at 5 nM C-1027, 15 min after
drug addition; strand damage was
barely detectable at concentrations
where inhibition of replication activity
was complete.
Tritium-labeled precursor-incorporation 242328
assay showed inhibited DNA and
RNA synthesis; flow cytometry
showed delayed the progression of
hepatoma cells through the S-phase
and blocked the cells at G2/M. There
was drastic reduction in the mitotic
index within 1 h.
IC50 values for hepatoma cells for 242320
MAb-C-1027 conjugate were 5.5 pM.
IC50 values for irrelevant MAb M3-
C1027 conjugate was 1,400 M.
Cytotoxicity; expressed IC50 value was 242306
0.07 fmol/l.
Fab-C1027 was 160-fold more potent 184442
in cytotoxicity to hepatoma cells than
to KB cells; therapeutic effect was
evaluated with hepatoma BEL-7402
xenograft in nude mice. 3 Days after
transplantation of the tumor, treatment
with 0.1 mg/kg x 6 started and 85%
inhibition of the tumor growth was
obtained.
[131I]-labeled 3A5 MAb and its Fab 242312
showed clear images of the tumor 12 h
after injection of Fab and 40 h after
that of MAb 3A5. IC50 values for MAb-
C1027 and its Fab-C1027 were 4.2 x
10 (-14) and 8.6 x 10 (-16),
respectively. 3 Days after
transplantation of the tumor treatment
started with equivalent dose of MAb-
C1027 and Fab-C1027 (0.15 mg/kg iv
x3), tumor inhibition rates for MAb-
and Fab-C1027 were 24% and 54%
respectively.
Biology (continued)
STUDY TYPE EFFECT STUDIED EXPERIMENTAL MODEL RESULT REFERENCE
In vitro/in vivo Antitumor effect and Immunoconjugate composed Fab-C1027 was 160-fold more potent in 184442
therapeutic effect. of C-1027 and Fab fragment cytotoxicity to hepatoma cells than to KB
from a monoclonal antibody cells; therapeutic effect was evaluated
directed against human with hepatoma BEL-7402 xenograft in
hepatoma. nude mice. 3 Days after transplantation
of the tumor, treatment with 0.1mg/kg x
6 started and 85% inhibition of the tumor
growth was obtained.

In vitro/in vivo Mechanism of inhibition Epstein-Barr viral (EBV) C-1027 induced trans inhibitions of 356187
of replication and cell replication on latently infected nuclear, but not mitochondrial DNA
growth by C-1027. cultured human Raji cells. replication in low nM range of C-1027,
on a time scale of minutes to hours.
Raji cell growth was 50% to 90%
reduced in 3 days using 10 pM and
100 pM range of C-1027.

In vitro Mechanism of covalent Structural study of mechanism C-1027 mainly generates interstrand 356192
C-1027-induced DNA of DNA interstrand cross-links cross-links under anaerobic
interstrand cross-links induced by C-1027, using conditions, biological relevance not
and monoadducts. denaturing gel electrophoresis. clear.

In vitro/in vivo C-1027 effect on Chick embryo chorioallantoic
angiogenesis and tumor membrane assay
metastasis. (angiogenesis), bFGF receptor
binding assay (mechanism of
angiogenesis). Spontaneous
pulmonary metastasis of Lewis
carcinoma in mice (tumor
metastasis).
Suppressing angiogenesis with 356214
minimum effective dose of 0.01 mg/egg.
Blocking of bFGF binding with an IC50
value of 2.3 x 10 (-6) µg/ml. Pulmonary
metastasis inhibition of Lewis carcinoma
was more effective than with mitomycin
(98% and 78%, respectively), using
equitoxic dosage level (quarter LD50).

In vitro Mechanism of antitumor Antitumor activity of 0.1 to 10
action. nM C-1027 against HL-60
human promyelocytic
leukemia cells.
2-h treatment resulted in morphological 182687
changes, condensation of nuclear
chromatin and nuclear fragmentation; 5
nM induced apoptosis in up to 77% of
cells; C-1027 exerts antitumor activity by
triggering apoptosis.

In vitro t-RNA activity. Cleavage of yeast t- In the presence of Mg2+ ions where the 183265
RNA(Phe). t-RNA attains a stable 3D structure,
the C-1027 chromophore exhibits high
cleavage selectivity to the anticodon
arm.

Associated patent
Title C-1027 substance

Assignee Taiho Yakuhin Kogyo KK

Publication JP-1104183 21-APR-89

Bibliography 175285 Effects of the DNA-damaging enediyne C-1027 on

intracellular SV-40 and genomic DNA in green monkey
•• of outstanding interest kidney BSC-1 cells. McHugh MM, Woynarowski JM, Gawron
• of special interest LS, Otani T, Beerman TA BIOCHEMISTRY 1995 34 5 1805-
1814
166132 Some characteristics of DNA strand scission by • DNA cleavage activity measured by topological assay. Preference
macromolecular antitumor antibiotic C-1027 containing a novel for cleavage of episomal DNA reported.
enediyne chromophore. Sugiura Y, Matsumoto T
BIOCHEMISTRY 1993 32 21 5548-5553 175287 Effects of the enediyne C-1027 on intracellular DNA
targets. Cobuzzi RJ Jr, Kotsopoulos SK, Otani T, Beerman TA
174872 DNA intercalation by the chromophore of the antitumor BIOCHEMISTRY 1995 34 2 583-592
antibiotic C-1027. Yu L, Otani T, Dedon P PROC AM ASSOC • Preference for C-1027-induced cleavage of episomal versus
CANCER RES 1995 36 Abs 2103 genomic DNA reported. In cell, DNA is cleaved 285-fold more
than in cell-free environment. There is/are unknown extra
175000 Mechanistic studies of enediyne C-1027-mediated DNA intracellular component(s), increasing the frequency of
damage at a model 5`GTTAT-5`ATAAC site. Xu YJ, Zhen YS, cleavage of DNA. Sequence-dependent cleavage of tRNA(Phe)
Goldberg IH PROC AM ASSOC CANCER RES 1995 36 Abs 2090 reported.
175289 Efficient route to the nine-membered cyclic diyne
system: Tuning of the extremely facile cope rearrangment of
1,5-diyne Kyoichiro Iida, Masahiro H J AM CHEM SOC 1994 116
22 10310-10311
175291 Organic synthesis and cell biology: Partners in
controlling gene expression. Halcomb RL PROC NATL ACAD
SCI U S A 1994 91 20 9197-9199
175292 C-1027 chromophore, a potent new enediyne anti-
tumour antibiotic, induces sequence-specific double-strand
DNA cleavage. Xu YJ, Zhen YS, Goldberg IH BIOCHEMISTRY
1994 33 19 5947-5954
• Sequence-dependent cleavage preference for some DNA motifs
reported.
175358 DNA intercalation by the chromophore of the antitumor
antibiotic C-1027. Yu L, Otani T, Dedon P PROC AM ASSOC
CANCER RES 1995 36 Abs 2103
182687 Induction of apoptosis by enediyne antitumour
antibiotic C1027 in HL-60 human promyelocytic leukaemia
cells. Jiang B, Li DD, Zhen YS BIOCHEM BIOPHYS RES
COMMUN 1995 208 1 238-244
• Morphological changes at cellular level and induction of apoptosis
detected at nanomolar levels of C-1027.
183265 RNA cleavage by C-1027 chromophore, an enediyne
antitumour antibiotic: high selectivity to an anticodon arm.
Totsuka R, Aizawa Y, Uesugi M, Okuno Y, Matsumoto T, Sugiura Y
BIOCHEM BIOPHYS RES COMMUN 1995 208 1 168-173
184406 NMR studies of the post-activated neocarzinostatin
chromophore-DNA complex. Conformational changes induced
in drug and DNA. Gao X, Stassinopolous A, Gu J, Goldberg IH
BIOORG MED CHEM 1995 3 6 795-809
184410 DNA intercalation by chromophore of the antitumour
antibiotic C-1027 Yu L, Otani T, Dedon P PROC AM ASSOC
CANCER RES 1995 36 353
184414 Mechanistic studies of enediyne C-1027-mediated DNA
damage at a model 5' GTTAT - 5' ATAAC site. Xu YJ, Zhen YS,
Goldberg IH PROC AM ASSOC CANCER RES 1995 36 351
184423 DNA cleavage kinetics of the enediyne anticancer drug
C-1027. Kirk C, Goodisman J, Beerman T, Dabrowiak JC BIOPHYS
J 1995 68 2 Pt 2 A105
184429 Synthesis and absolute stereochemistry of the amino
sugar moiety of antibiotic C-1027 chromophore. Iida K, Ishii T,
Hirama M, Otani T, Minai Y, Yoshida K TETRAHEDRON LETT
1993 34 25 4079-4082
184432 Structure and cycloaromatization of a novel enediyne,
C-1027 chromophore. Yoshida K-I, Minami Y, Azuma R, Saeki M,
Otani T TETRAHEDRON LETT 1993 34 16 2637-2640
184435 Structure of an aromatization product of C-1027
chromophore. Minami Y, Yoshida K-I, Azuma R, Saeki M, Otani T
TETRAHEDRON LETT 1993 34 16 2633-2636
184438 The amino acid sequence of actinoxanthin apoprotein
deduced from the bas sequence of the gene. Sakata N, Mase T,
Ikeno S, Hori M, Otani T J ANTIBIOT 1993 46 9 1475-1477
184439 Conformation studies on and assessment by spectral
analysis of the protein-chromophore interaction of the
macromolecular antitumour antibiotic C-1027. Otani T J
ANTIBIOT 1993 46 5 791-802
184440 Specific interaction between a novel enediyne
chromophore and apoprotein in macromolecular antitumour
antibiotic C-1027. Matsumoto T, Okuno Y, Suguira Y BIOCHEM
BIOPHYS RES COMMUN 1993 195 2 659-666
184441 Crystallization and preliminary X-ray diffraction studies
of C-1027-AG, the apoprotein of the macromolecular
antitumour antibiotic C-1027 from Streptomyces globisporus.
Briozzo P, Inaka K, Minami Y, Otani T, Miki K ACTA
CRYSTALLOGR, SECT D: BIOL CRYSTALLOGR 1993 49 4 372-
374
184442 Antitumour effect of the immunoconjugate composed
of antibiotic C-1027 and FAB fragment from a monoclonal
antibody directed against human hepatoma. Li JZ, Jiang M, Xue
YC, Zhen YS YAO HSUEH HSUEH PAO 1993 28 4 260-265
• Cytotoxicity to hepatoma cells of anti-hepatoma MAb and its Fab
fragment conjugate with C-1027, in vitro.
184443 Cloning and nucleotide sequencing of the antitumour
antibiotic C-1027 apoprotein gene. Sakata N, Ikeno S, Hori M,
Hamada M, Otani T BIOSCI BIOTECH BIOCHEM 1992 56 10 1592-
1595
213300 Effects of the DNA-reactive antitumour enediyne C-1027
on replicating DNA. McHugh MM, Burhans WC, Beerman TB
PROC AM ASSOC CANCER RES 1996 37 Abs 2454
217031 The Enediyne antibiotics. Smith AL, Nicolaou KC J MED
CHEM 1996 39 11 2103-2117
242287 DNA-damaging enediyne C-1027 inhibits initiation of
intracellular SV40 DNA replication in trans. McHugh MM,
Beerman TA, Burhans WC BIOCHEMISTRY 1997 36 5 1003-1009
• Inhibition of DNA replication in trans at nanomolar range of C-
1027.
242288 The chemistry of enediynes, enyne allenes and related
compounds. Grissom JW, Gunawardena GU, Klingberg D, Huang
D TETRAHEDRON 1996 52 19 6453-6518
242289 Studies on the synthesis of the core structures of the
antitumor agents neocarzinostatin, kedarcidin, C-1027 and
maduropeptin. Magnus P, Carter R, Davies M, Elliott J, Pitterna T
TETRAHEDRON 1996 52 18 6283-6306
242290 Efficient synthesis of a carbocyclic core moiety with the
stereochemistry of the C-1027 chromophore. Sato I, Akahori Y,
Iida KI, Hirama M TETRAHEDRON LETT 1996 37 29 5135-5138
• The chemistry of enediyane and studies on efficient synthesis of
the C-1027 chromophore.
242291 Absolute configuration of C-1027 chromophore. Iida KI,
Fukuda S, Tanaka T, Hirama M, Imajo S, Ishiguro M, Yoshida KI,
Otani T TETRAHEDRON LETT 1996 37 28 4997-5000
242292 Interaction of C-1027 chromophore with d(GTATAC)2: A
binding model based on NMR experiments. Okuno Y, Iwashita T,
Otani T, Sugiura Y J AM CHEM SOC 1996 118 19 4729-4730
242293 Synthesis of 10-membered masked oxaenediyne
analogue of Kedarcidin-chr. and C-1027-chr., and its DNA
cleaving activity. Takahashi T, Tanaka H, Matsuda A, Yamada H,
Matsumoto T, Sugiura Y TETRAHEDRON LETT 1996 37 14 2433-
2436
242294 Effect of dietary fat content on oral bioavailability of
menatetrenone in humans. Uematsu T, Nagashima S, Niwa M,
Kohno K, Sassa T, Ishii M, Tomono Y, Yamato C, Kanamaru M J
PHARM SCI 1996 85 9 1012-1016
242295 Mechanisms of target selection by DNA-damaging
chemicals: studies with enediyne anticancer drugs. Dedon PC
INT ARCH OCCUP ENVIRON HEALTH 1996 68 6 408-414
242296 Effects of the DNA-reactive antitumor enediyne C-1027
on replicating DNA. McHugh MM, Burhans WC, Beerman TB
PROC AM ASSOC CANCER RES 1996 37 360
242297 A single binding mode of activated enediyne C1027
generates two types of double-strand DNA lesions: deuterium
isotope-induced shuttling between adjacent nucleotide target
sites. Xu YJ, Xi Z, Zhen YS, Goldberg IH BIOCHEMISTRY 1995 34
38 12451-12460
242298 The benzoxazolinate of C-1027 confers intercalative
DNA binding. Yu L, Mah S, Otani T, Dedon P J AM CHEM SOC
1995 117 34 8877-8878
242299 Synthesis and characterization of nine-membered
cyclic enediynes, models of C-1027 and kedarcidin
chromophore: Equilibration with a p-benzyne biradical and
kinetic stabilization. Iida I, Hirama M J AM CHEM SOC 1995 117
34 8875-8876
242300 Preliminary X-ray diffraction study of a new crystal form
of C-1027-AG, the apoprotein of the macromolecular antitumor
antibiotic C-1027 from Streptomyces globisporus. Motojima F,
Inaka K, Minami Y, Otani T, Miki K ACTA CRYSTALLOGR, SECT
D: BIOL CRYSTALLOGR 1995 51 6 1084-1085
242301 Enediyne-mediated cleavage of RNA. Battigello JM, Cui
M, Roshong S, Carter BJ BIOORG MED CHEM 1995 3 6 839-849
242302 Free radical generating and scavenging compounds as
a new type of drug. Matsugo S, Mizuno M, Konishi T CURR MED
CHEM 1995 2 4 763-790
242303 Effect of dietary fat content on oral bioavailability of
menatetrenone in humans. Uematsu T, Nagashima S, Niwa M,
Kohno KI, Sassa T, Ishii M, Tomono Y, Yamato C, Kanamaru M J
PHARM SCI 1996 85 9 1012
242304 Effects of the DNA-reactive antitumor enediyne C-1027
on replicating DNA. McHugh MM, Burhans WC, Beerman TB
PROC AM ASSOC CANCER RES 1996 37 360
242305 DNA intercalation by the chromophore of the antitumor
antibiotic C1027. Yu L, Otani T, Dedon P PROC AM ASSOC
CANCER RES 1995 36 353
242306 Relationship between the molecular composition of
C1027, a new macromolecular antibiotic with enediyne
chromophore, and its antitumor activity. Shao RG, Zhen YS
YAO HSUEH HSUEH PAO 1995 30 5 336-342
• Composition and characteristics of C-1027 antibiotic are reported.
Anticancer activity at extremely low concentrations reported.
242307 DNA cleavage kinetics of the enediyne anticancer drug
C-1027. Kirk C, Goodisman J, Beerman T, Dabrowiak JC J BIOMOL
STRUCT DYN 1995 12 6 A110
242308 Remarkable kinetic solvent isotope effect on the
cycloaromatization of C- 1027 chromophore, a 9-membered
enediyne, and the thermochemistry. Yoshida KI, Minami Y,
Otani T, Tada Y, Hirama M TETRAHEDRON LETT 1994 35 29
5253-5256
242309 Computer modeling analysis for enediyne
chromophore-apoprotein complex of macromolecular
antitumor antibiotic C-1027. Okuno Y, Otsuka M, Sugiura Y J
MED CHEM 1994 37 15 2266-2273
242310 Alterations of binding mode and cutting site by G-->I
replacement in preferred cleavage sequences 5'-AGG of
chromoprotein C-1027. Matsumoto T, Sugiura Y BIOCHEM
BIOPHYS RES COMMUN 1994 205 3 1533-1538
242311 Monoclonal antibody raised against apoprotein of C-
1027: effect on biochemical and biological activities of the
holoantibiotic. S-Tsuchiya K, Arita M, Hori M, Otani T J ANTIBIOT
1994 47 7 787-791
242312 Biodistribution of monoclonal antibody and Fab
fragment and antitumor effect of their conjugates on hepatoma
xenografts. Li J, Zhen Y, Yang Z CHUNG KUO I HSUEH KO
HSUEH YUAN HSUEH PAO 1994 16 5 328-333
• In vivo studies: therapeutic effect of the MAb-C1027 and Fab-
C1027 conjugates was evaluated with hepatoma BEL-7402
xenograft in nude mice.
242313 Antitumor activity of the new enediyne antibiotic C1027.
Zhen Y, Xue Y, Shao R CHIN J ANTIBIOT 1994 19 2 164-169
242314 Synthesis and absolute stereochemistry of the
aminosugar moiety of antibiotic C-1027 chromophore. Iida K,
Ishii T, Hirama M, Otani T, Minami Y, Yoshida K TETRAHEDRON
LETT 1993 34 25 4079-4082
242315 Structure and cycloaromatization of a novel enediyne,
C-1027 chromophore. Yoshida KI, Minami Y, Azuma R, Saeki M,
Otani T TETRAHEDRON LETT 1993 34 16 2637-2640
242316 Structure of an aromatization product of C-1027
chromophore. Minami Y, Yoshida KI, Azuma R, Saeki M, Otani T
TETRAHEDRON LETT 1993 34 16 2633-2636
242317 Conformation studies on and assessment by spectral
analysis of the protein-chromophore interaction of the
macromolecular antitumor antibiotic C-1027. Otani T J
ANTIBIOT 1993 46 5 791-802
• Kd between C-1027 chromophore and apoprotein measured.
242318 Crystallization and preliminary X-ray diffraction studies
of C-1027-AG, the apoprotein of the macromolecular antitumor
antibiotic C-1027 from Streptomyces globisporus. Briozzo P,
Inaka K, Minami Y, Otani T, Miki K ACTA CRYSTALLOGR, SECT
D: BIOL CRYSTALLOGR 1993 49 4 372-374
242319 Cloning and nucleotide sequencing of the antitumor
antibiotic C-1027 apoprotein gene. Sakata N, Ikeno S, Hori M,
Hamada M, Otani T BIOSCIENCE 1992 56 10 1592-1595
• Cloning and nucleotide sequencing of the antitumor antibiotic C-
1027 apoprotein gene was done.
242320 Antitumor activity of new antitumor antibiotic C1027
and its monoclonal antibody assembled conjugate. Shao RG,
Zhen YS YAO HSUEH HSUEH PAO 1992 27 7 486-491
• A monoclonal antibody against hepatoma cells (MAb) and its Fab
fragment were conjugated to C-1027. Pharmacologically relevant
results.
242321 Isolation and construction of restriction endonuclease
map of plasmid pSGL1 from antitumor antibiotic C-1027
production strain Streptomyces globisporus. Li X, Li Y CHIN J
ANTIBIOT 1992 17 5 326-332
242322 An antitumor activity of C-1027, a new experimental
macromolecular antitumor antibiotic. Ohie S, Otani T, Sakawa K,
Matsumoto H, Nomura N, Takeda S ICAAC 1992 32nd Anaheim
194
242323 Aminopeptidase activity of an antitumor antibiotic, C-
1027. Sakata N, Tsuchiya KS, Moriya Y, Hayashi H, Hori M, Otani
T, Nagai M, Aoyagi T J ANTIBIOT 1992 45 1 113-117
• Weak aminopeptidase activity reported.
242324 Isolation and characterization of non-protein
chromophore and its degradation product from antibiotic C-
1027 [letter]. Otani T, Minami Y, Sakawa K, Yoshida K J ANTIBIOT
1991 44 5 564-568
242325 Antitumor activity of the monoclonal antibody
conjugate prepared from a highly-potent antitumor antibiotic C-
1027. Zhen YS, Peng Z, Xu YJ, Shao YG PROC AM ASSOC
CANCER RES 1991 32 Abs 432
242326 Purification and primary structure of C-1027-AG, a
selective antagonist of antitumor antibiotic C-1027, from
Streptomyces globisporus. Otani T, Yasuhara T, Minami Y, Shimazu
T, Zhang R, Xie MY AGRIC BIOL CHEM 1991 55 2 407-417
242327 Mechanism of action of a new macromolecular
antitumor antibiotic, C-1027. Sugimoto Y, Otani T, Oie S, Wierzba
K, Yamada Y J ANTIBIOT 1990 43 4 417-421
242328 Mode of action of C-1027, a new macromolecular
antitumor antibiotic with highly potent cytotoxicity, on human
hepatoma BEL-7402 cells. Xu YJ, Li DD, Zhen YS CANCER
CHEMOTHER PHARMACOL 1990 27 1 41-46
• Analysis of C-1027 effect on cell cycle and mitosis.
242329 A new macromolecular antitumor antibiotic, C-1027. III.
Antitumor activity. Zhen YS, Ming XY, Yu B, Otani T, Saito H,
Yamada Y J ANTIBIOT 1989 42 8 1294-1298
242330 C-1027-AG, a selective antagonist of the
macromolecular antitumor antibiotic C-1027. Otani T, Minami Y,
Marunaka T, Zhang R, Xie MY J ANTIBIOT 1988 41 11 1696-1698
242331 A new macromolecular antitumor antibiotic, C-1027. II.
Isolation and physico-chemical properties. Otani T, Minami Y,
Marunaka T, Zhang R, Xie MY J ANTIBIOT 1988 41 11 1580-1585
• A macromolecular antibiotic C-1027 was isolated from
Streptomyces globisporus C-1027, described and characterized.
242332 A new macromolecular antitumor antibiotic, C-1027. I.
Discovery, taxonomy of producing organism, fermentation and
biological activity. Hu JL, Xue YC, Xie MY, Zhang R, Otani T, Minami
Y, Yamada Y, Marunaka T J ANTIBIOT 1988 41 11 1575-1579
262929 36th IUPAC Congress: Frontiers in Chemistry, New
perspectives for the 2000s Geneva, Switzerland. Black D IDDB
MEETING REPORT 1997 August 17-22
318524 Biosynthetic gene cluster for the enediyne antitumor
antibiotic C-1027 from Streptomyces globisporus C-1027. Shen
B, Liu W, Christenson SD ACS 1999 217 Anaheim ORGN 154
321669 C-1027 induced alterations in Epstein-Barr viral and
mitochondrial DNA replication in latently infected cultured
human Raji cells: Relationship to DNA damage. McHugh MM,
Beerman TA PROC AM ASSOC CANCER RES 1999 40 Abs 30
322439 Current Drugs' Summary of the American Chemical
Society 217th National Meeting Anaheim, CA, USA. Garratt J,
Agathangelou P IDDB MEETING REPORT 1999 March 21-25
356185 Genes for production of the enediyne antitumor
antibiotic C-1027 in Streptomyces globisporus are clustered
with the cagA gene that encodes the C- 1027 apoprotein. Liu W,
Shen B ANTIMICROB AGENTS CHEMOTHER 2000 44 2 382-392
• Genes for production of the enediyne antitumor antibiotic C-1027
in Streptomyces globisporus are cloned.
356187 C-1027-induced alterations in Epstein-Barr viral DNA
replication in latently infected cultured human Raji cells:
relationship to DNA damage. McHugh MM, Beerman TA
BIOCHEMISTRY 1999 38 21 6962-6970
• Inhibition of initiation of DNA replication documented, using
Epstein-Barr virus as a model system in latently infected cultured
human Raji cells. Mechanism of C-1027 action on initiation of
replication was suggested.
356188 Chinese medicine research: Introduction. Wang X. W
DRUGS FUTURE 1999 24 8 875-876
356190 C-1027. Antineoplastic antibiotic. Wang XW, Xie H
DRUGS FUTURE 1999 24 8 847-852
• Review-like information related to structure of C-1027.
356192 Studies of antibiotic and antitumor activity by enediyne
antitumor antitiotic C1027. Sun Y, Yu Q, Li D CHIN J ANTIBIOT
1999 24 6 457-459
• Studies of antibiotic, antimycoplasma and antitumor activity by
enediyne antitumor antibiotic C-1027. Clinical application discussed.
356193 C-1027 enediyne chromophore: presence of another
active form and its chemical structure. Otani T, Yoshida K,
Sasaki T, Minami Y J ANTIBIOT 1999 52 4 415-421
• Chemical structure of another active form of C-1027 enediyne
chromophore described.
356194 Enediyne biosynthesis and self-resistance: A progress
report. Thorson JS, Shen B, Whitwam RE, Liu W, Li Y, Ahlert J
BIOORG CHEM 1999 27 2 172-188
• General biotechnological/pharmacological value of C-1027 and
new developments in cloning of relevant genes discussed.
356196 Studies on total synthesis of enediyne antitumor
antibiotic C-1027 II. Synthesis of acyclic derivative of enediyne
unit of C-1027 chromophore. Jintao Z, Huiyuan G, Zhuorong L,
Zhiping Z CHIN J ANTIBIOT 1998 23 6 425-430
• Studies on total synthesis of C-1027 and acyclic derivative of C-
1027 chromophore.
356198 Study of biosynthesis gene cloning of novel antitumor
antibiotic C1027. Wen L, Yuan L CHIN J ANTIBIOT 1998 23 3 166-
169
• Important information for cloning relevant DNA fragments for C-
1027 biosynthesis. Very relevant data for potential large-scale
production of C-1027.
356201 Mechanism of formation of novel covalent drug. DNA
interstrand cross-links and monoadducts by enediyne
antitumor antibiotics. Xu YJ, Xi Z, Zhen YS, Goldberg IH
BIOCHEMISTRY 1997 36 48 14975-14984
• Formation of covalent drug-DNA interstrand cross-links and
monoadducts by C-1027 is enhanced under anaerobic conditions.
Biological relevance is not clear.
356202 Selective cleavages of tRNAPhe with secondary and
tertiary structures by enediyne antitumor antibiotics. Sugiura Y,
Totsuka R, Araki M, Okuno Y BIOORG MED CHEM 1997 5 6 1229-
1234
356212 Enediyne C1027 induces the formation of novel
covalent DNA interstrand cross-links and monoadducts. Xu Y,
Zhen Y, Goldberg IH J AM CHEM SOC 1997 119 5 1133-1134
356214 Inhibition of angiogenesis by antitumor antibiotic
C1027 and its effect on tumor metastasis. Zhen H, Xue Y, Zhen
Y CHUNG HUA I HSUEH TSA CHIH 1997 77 9 657-660
• Inhibition of angiogenesis by C-1027 and effect on tumor metastasis
documented. Blocking of bFGF binding to its receptor by C-1027,
suggested as relevant mechanism for inhibition of angiogenesis.
356216 Biochemical mechanisms of NCS-chromophore-
induced DNA cleavage and inhibition of protein kinase activity.
Ohtsuki K, Tanoue S, Karino A JPN J CANCER CHEMOTHER
1997 24 4 443-453
356217 Kinetics of cleavage of intra- and extracellular simian
virus 40 DNA with the enediyne anticancer drug C-1027. Kirk
CA, Goodisman J, Beerman TA, Gawron LS, Dabrowiak JC
BIOPHYS CHEM 1997 63 2-3 201-209
356220 Studies on total synthesis of endiyne antitumor antibiotic
C-1027. I. Synthesis of the 5-membered ring intermediates in
endiyne chromophore of antibiotic C-1027a. Jintao Z, Huiyuan G,
Zhuorong L, Zhiping Z CHIN J ANTIBIOT 1997 22 2 146-148
356385 C-1027 induced alterations in Epstein-Barr viral and
mitochondrial DNA replication in latently infected cultured
human Raji cells: Relationship to DNA damage. McHugh MM,
Beerman TA PROC AM ASSOC CANCER RES 1999 40 5
356387 Biosynthetic gene cluster for the enediyne antitumor
antibiotic C-1027 from streptomyces globisporus C-1027. Shen
B, Liu W, Christenson SD ACS 1999 217 1-2 ORGN154
357593 Formation of novel covalent DNA interstrand cross-
links and mono-adducts by enediyne antitumor antibiotics. Xu
YJ, Zhen YS, Goldberg IH PROC AM ASSOC CANCER RES 1997
38 307
357662 Characterization of the Streptomyces plasmid pSGL1.
Hong B, Li Y WEISHENGWU XUEBAO 1998 38 4 256-260
357663 Nucleotide sequence analysis of an antibiotic
biosynthesis gene of Streptomyces globisporus. Mao X, Li Y
WEISHENGWU XUEBAO 1998 38 1 32-36
362766 Lidamycin and its RGD-containing peptide conjugate
inhibit angiogenesis and metastasis. Zhen Y-S, Lin M, Zhen HY,
Wang XH PROC AM ASSOC CANCER RES 2000 41 April 1-5 Abs
4098
364437 Summary of the American Association for Cancer
Research 91st Annual Meeting San Francisco, CA, USA. Worker
C, Brown H IDDB MEETING REPORT 2000 April 1-5
368485 JP-11004183: C-1027 substance. Otani T, Matsumoto H,
Cho T, Minami Y, Kai B, Marunaka T, Saito H, Yamada Y
JAPANESE PATENT 1989 Taiho Yakuhin Kogyo KK