1. The radiomimetic enediyne, 20'-deschloro-C-1027 induces inter-strand DNA crosslinks in hypoxic cells and overcomes cytotoxic radioresistance.

    DNA Repair 21:165 (2014) PMID 24986640 PMCID PMC4126566

    The ability of the radiomimetic anti-tumor enediyne C-1027 to induce DNA inter-strand crosslinks (ICLs), in addition to the expected DNA strand breaks, is unique among traditional DNA targeted cancer therapies. Importantly, radiation therapy and most radiomimetic drugs have diminished effect in ...
  2. DNA damage by C1027 involves hydrogen atom abstraction and addition to nucleobases.

    Bioorganic & Medicinal Chemistry 20(15):4744 (2012) PMID 22748380 PMCID PMC3406177

    C1027 is a potent antitumor agent that damages DNA. It has the unusual ability to produce double strand breaks and interstrand cross-links (ICLs) intracellularly, which enable it to initiate concurrent ataxia-telangiestasia mutated (ATM) and Rad-3 related (ATR) independent damage responses. The ...
  3. C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells.

    Cancer Research 69(2):593 (2009) PMID 19147573 PMCID PMC2758494

    The hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies such as ionizing radiation and conventional radiomimetics because their mechanisms require oxygen to induce lethal DNA breaks. For example, the conventional radiomimetic enediyne neocarzinostatin is 4-fol...
  4. Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses.

    PNAS 104(45):17632 (2007) PMID 17978180 PMCID PMC2077023

    The ability of the radiomimetic anticancer enediyne C-1027 to induce ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)-independent damage responses was discovered to reside in its unique ability to concurrently generate robust amounts of double-strand breaks (DSBs) and interstra...
  5. Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks.

    Cancer Research 67(2):773 (2007) PMID 17234789

    The radiomimetic enediyne C-1027 induces almost exclusively DNA double-strand breaks (DSB) and is extremely cytotoxic. Unique among radiomimetics, ataxia-telangiectasia mutated (ATM) is dispensable for cellular responses to C-1027-induced DNA damage. This study explores the biological activity o...
  6. Inhibition of RecBCD enzyme by antineoplastic DNA alkylating agents.

    Journal of Molecular Biology 361(5):898 (2006) PMID 16887143

    To understand how bulky adducts might perturb DNA helicase function, three distinct DNA-binding agents were used to determine the effects of DNA alkylation on a DNA helicase. Adozelesin, ecteinascidin 743 (Et743) and hedamycin each possess unique structures and sequence selectivity. They bind to...
  7. The radiomimetic enediyne C-1027 induces unusual DNA damage responses to double-strand breaks.

    Biochemistry (Washington) 45(11):3747 (2006) PMID 16533058 PMCID PMC2504721

    Cells lacking the protein kinase ataxia telangiectasia mutated (ATM) have defective responses to DNA double-strand breaks (DSBs), including an inability to activate damage response proteins such as p53. However, we previously showed that cells lacking ATM robustly activate p53 in response to DNA...
  8. Hedamycin, a DNA alkylator, induces (gamma)H2AX and chromosome aberrations: involvement of phosphatidylinositol 3-kinase-related kinases and DNA replication fork movement.

    Molecular Cancer Therapeutics 4(8):1175 (2005) PMID 16093433

    Genotoxic treatments, such as UV light, camptothecin, and adozelesin, stall DNA replication and subsequently generate DNA strand breaks. Typically, DNA breaks are reflected by an increase in ataxia and Rad-related kinase (ATR)-regulated phosphorylation of H2AX (gammaH2AX) and require replication...
  9. The antitumor enediyne C-1027 alters cell cycle progression and induces chromosomal aberrations and telomere dysfunction.

    Cancer Research 65(12):5344 (2005) PMID 15958582

    This study examined the extent of chromosome instability induced in cultured human colon carcinoma HCT116 cells by the antitumor radiomimetic enediyne antibiotic C-1027. Spectral karyotype analysis showed frequent intrachromosomal fusions and fragmentations 26 hours after addition of as little a...
  10. DNA damage effects of a polyamide-CBI conjugate in SV40 virions.

    Molecular Pharmacology 67(3):877 (2005) PMID 15576630

    Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepress...
  11. SV40 DNA replication inhibition by the monofunctional DNA alkylator Et743.

    Biochemistry (Washington) 43(44):14228 (2004) PMID 15518573

    Ecteinascidin 743 (Et743) is a highly cytotoxic anticancer agent isolated from the squirt Ecteinascidia turbinate, which alkylates DNA in the minor groove at GC-rich sequences resulting in an unusual bending toward the major groove. The ability of Et743 to block DNA replication was studied using...
  12. DNA damage responses triggered by a highly cytotoxic monofunctional DNA alkylator, hedamycin, a pluramycin antitumor antibiotic.

    Molecular Cancer Therapeutics 3(5):577 (2004) PMID 15141015

    Long-term exposure (72 h) to hedamycin, a monofunctional DNA alkylator of the pluramycin class of antitumor antibiotics, decreased growth of mammalian cells by 50% at subnanomolar concentrations. Short-term treatment (4 h) rapidly reduced DNA synthesis by 50% also at subnanomolar concentrations,...
  13. DNA crosslinking and biological activity of a hairpin polyamide-chlorambucil conjugate.

    Nucleic Acids Research 31(4):1208 (2003) PMID 12582240 PMCID PMC150233

    A prototype of a novel class of DNA alkylating agents, which combines the DNA crosslinking moiety chlorambucil (Chl) with a sequence-selective hairpin pyrrole-imidazole polyamide ImPy-beta-ImPy-gamma-ImPy-beta-Dp (polyamide 1), was evaluated for its ability to damage DNA and induce biological re...
  14. Induction of DNA damage responses by adozelesin is S phase-specific and dependent on active replication forks.

    Molecular Cancer Therapeutics 2(1):41 (2003) PMID 12533671

    Adozelesin is an alkylating minor groove DNA binder that is capable of rapidly inhibiting DNA replication in treated cells through a trans-acting mechanism and preferentially arrests cells in S phase. It has been shown previously that in cells treated with adozelesin, replication protein A (RPA)...
  15. Cell-free and cellular activities of a DNA sequence selective hairpin polyamide-CBI conjugate.

    Journal of Biological Chemistry 277(45):42431 (2002) PMID 12196541

    Alkylating agents are generally highly reactive with DNA but demonstrate limited DNA sequence selectivity. In contrast, synthetic pyrrole-imidazole polyamides recognize specific DNA sequences with high affinity but are unable to permanently damage DNA. An eight-ring hairpin polyamide conjugated ...
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  16. Cellular uptake of N-methylpyrrole/N-methylimidazole polyamide-dye conjugates.

    Bioorganic & Medicinal Chemistry 10(10):3313 (2002) PMID 12150878

    The cellular uptake and localization properties of DNA binding N-methylpyrrole/N-methylimidazole polyamide-dye conjugates in a variety of living cells have been examined by confocal laser scanning microscopy. With the exception of certain T-cell lines, polyamide-dye conjugates localize mainly in...
  17. Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM, ATR, and DNA-PK kinases.

    Journal of Biological Chemistry 277(23):20549 (2002) PMID 11927575

    The current paradigm based upon ionizing radiation (IR) studies states that cells deficient in either ataxia-telangiectasia-mutated kinase (ATM) or related phosphatidylinositol 3 (PI 3) -kinases (ATR and DNA-PK) are hypersensitive to DNA strand breaks because they are unable to rapidly activate ...
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  18. Inhibiting transcription factor/DNA complexes using fluorescent microgonotropens (FMGTs).

    Biochimica et Biophysica Acta 1574(1):100 (2002) PMID 11955618

    Fluorescent microgonotropens (FMGTs) are A/T selective, minor groove-binding bisbenzimidazole ligands. Basic side chains extending from these agents electrostatically contact the major groove side of the phosphodiester backbone of DNA, endowing them with high binding affinity. Here, we evaluate ...
  19. Cellular uptake ofN-methylpyrrole/N-methylimidazole polyamide-dye conjugates

    Bioorganic & Medicinal Chemistry 10(10):3313 (2002)

    The cellular uptake and localization properties of DNA binding N-methylpyrrole/ N-methylimidazole polyamide–dye conjugates in a variety of living cells have been examined by confocal laser scanning microscopy. With the exception of certain T-cell lines, polyamide–dye conjugates...
  20. Inhibiting transcription factor/DNA complexes using fluorescent microgonotropens (FMGTs)

    Biochimica et Biophysica Acta (BBA) - Gene Stru... 1574(1):100 (2002)

    Fluorescent microgonotropens (FMGTs) are A/T selective, minor groove-binding bisbenzimidazole ligands. Basic side chains extending from these agents electrostatically contact the major groove side of the phosphodiester backbone of DNA, endowing them with high binding affinity. Here, we eval...