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The Journal of Physical Chemistry. B Nov 2020NMR studies have indicated that the anti-tumor therapeutic agent actinomycin D (ACTD) can induce seemingly single-stranded DNA (ssDNA) oligomer 5'-CCGTTGTGG-3' to form a...
NMR studies have indicated that the anti-tumor therapeutic agent actinomycin D (ACTD) can induce seemingly single-stranded DNA (ssDNA) oligomer 5'-CCGTTGTGG-3' to form a hairpin structure with tandem GT mismatches at the stem region next to a loop of three stacked thymine bases. In an effort to uncover the preference of binding sequence and to elucidate the thermodynamics properties of the binding, a combination of spectroscopic techniques and computational simulation studies was performed with d(CCGTTGTGG) and d(CCGAAGAGG) (denoted as GTT and GAA, respectively; = 3, 5, and 7) sequences. In the presence of 7-amino actinomycin D (7AACTD), all the six oligomers formed stable hairpin structures. The GTT-7AACTD/GAA-7AACTD hairpin structure was more stable than the corresponding GTT-7AACTD and GAA-7AACTD ( = 3, 7). No significant Δ difference was observed between GTT-7AACTD and GAA-7AACTD complexes with the same loop length. In agreement with the 7AACTD-induced hairpin stability results, the binding affinity of GTT and GAA with 7AACTD increased from = 3 to = 5 and then decreased when is 7. Moreover, GTT and GAA with the same loop length showed comparable binding affinities to 7AACTD. Furthermore, molecular dynamics simulations found that van der Waals interactions between GTT/GAA and 7AACTD were the primary attractive forces for 7AACTD binding, and the electrostatic interactions between the carbonyl groups of 7AACTD and bases in the hairpin were the major unfavorable forces. These findings furthered our understanding that 7AACTD is sensitive to the loop size and sequence as well as tandem GT/GA mismatches of their deoxyribonucleic acid (DNA) targets. A deep understanding of the thermodynamics and the molecular recognition mechanism of 7AACTD with ssDNAs would further the development of ACTD-like antitumor agents.
Topics: Base Sequence; DNA, Single-Stranded; Dactinomycin; Nucleic Acid Conformation; Thermodynamics
PubMed: 33136398
DOI: 10.1021/acs.jpcb.0c05593 -
Journal of Bacteriology Nov 1969Actinomycin synthesis by washed mycelia of Streptomyces antibioticus has been conducted in the presence of 3-hydroxy-4-methylanthranilate-(carboxyl-(14)C). Incorporation...
Actinomycin synthesis by washed mycelia of Streptomyces antibioticus has been conducted in the presence of 3-hydroxy-4-methylanthranilate-(carboxyl-(14)C). Incorporation of this compound into actinomycins has been observed, which constitutes further evidence that 3-hydroxy-4-methylanthranilate is an intermediate in actinomycin biosynthesis. The position of the incorporated label has been determined to be within the actinomycin chromophore, and the label appears to be equally distributed between both halves of the chromophore. Incidental to these findings was the observation that the (14)C-labeled actinomycins were subject to rapid reabsorption by the organism with actinomycin V taken up preferentially to actinomycin IV.
Topics: Carbon Isotopes; Chromatography, Thin Layer; Dactinomycin; Electrophoresis; Hydrogen Peroxide; Hydrogen-Ion Concentration; Paper; Streptomyces; Tryptophan; Valine; ortho-Aminobenzoates
PubMed: 4187701
DOI: 10.1128/jb.100.2.977-984.1969 -
Journal of Veterinary Internal Medicine 1994Fifty dogs with advanced malignancies were treated with actinomycin D at doses ranging from 0.5 to 1.1 mg/m2 every 3 weeks. The greatest number of responses was noted in...
Fifty dogs with advanced malignancies were treated with actinomycin D at doses ranging from 0.5 to 1.1 mg/m2 every 3 weeks. The greatest number of responses was noted in dogs with lymphoma, including dogs that had received prior chemotherapy. Other responding tumor types included anal sac adenocarcinoma, perianal adenocarcinoma, squamous cell carcinoma, thyroid carcinoma, and transitional cell carcinoma. The median time to maximum response for dogs with lymphoma was 7 days, with a median duration of 42 days. Gastrointestinal toxicity was the most frequently observed side effect. A dose of 0.6 to 0.7 mg/m2 appears to be appropriate for treating various malignancies in dogs.
Topics: Animals; Carcinoma; Dactinomycin; Dog Diseases; Dogs; Female; Lymphoma; Male; Neoplasms; Treatment Outcome
PubMed: 8064663
DOI: 10.1111/j.1939-1676.1994.tb03224.x -
Nature Sep 1960
Topics: DNA; Dactinomycin
PubMed: 13751973
DOI: 10.1038/1871112a0 -
Natural Product Research May 2024Hemiactinomycin (), an intermediate derivative of actinomycin biosynthesis, together with three known actinomycins (-) , were isolated from the ethanolic extract of...
Hemiactinomycin (), an intermediate derivative of actinomycin biosynthesis, together with three known actinomycins (-) , were isolated from the ethanolic extract of H41-55 fermentation mycelium by using various column chromatography. The structure of the derivative was established by extensive spectroscopic analysis, including HRESIMS, 1D, and 2D NMR spectroscopy. In addition, the anti-inflammatory activities of all the isolates were tested. The derivative () showed inhibiting NO release activities in LPS-induced RAW 264.7 macrophages with the IC values of 15.41 ± 0.66 μM.
Topics: Streptomyces antibioticus; Dactinomycin; Streptomyces; Actinobacteria; Actinomyces
PubMed: 36564053
DOI: 10.1080/14786419.2022.2161541 -
Annals of the New York Academy of... Oct 1960
Topics: Animals; Dactinomycin; Neoplasms, Experimental
PubMed: 13723045
DOI: 10.1111/j.1749-6632.1960.tb20164.x -
Journal of Molecular Biology Sep 1996We have studied the sequence specificity in the binding of the potent antitumor drug actinomycin D (AMD) to single-stranded DNA (ssDNA) by fluorescence and NMR...
We have studied the sequence specificity in the binding of the potent antitumor drug actinomycin D (AMD) to single-stranded DNA (ssDNA) by fluorescence and NMR spectroscopy and by molecular modeling. The significant absorption and emission changes accompanying the interaction of the fluorescent derivative 7-amino-AMD with DNAs varying in length and base composition were used to calculate affinity constants for the drug-DNA complexes. The guanine-containing trinucleotide sequences AGT, AGA, and TGT embedded within 25-base oligonucleotides, constituted favorable binding sites. In contrast, the sequence TGA did not bind the drug appreciably. Among the DNAs studied, the highest affinity was for the tetranucleotide sequence TAGT. The binding was length dependent, an oligonucleotide of at least 14 bases being required for effective complex formation (Ka > 10(4) M1=). AMD also bound to poly(d(AGT)). Gel electrophoresis confirmed that the complex was formed between the drug and individual unstructured DNA strands. The 1H NMR spectra of oligonucleotides containing the TAGT site and their complexes with AMD provided further insight into the mode(s) of interaction. A comparison of the measured chemical shifts with those estimated from ring-current calculations provided strong evidence for a hemi-intercalation of AMD between the A and G purine bases with a preference for one of two possible relative orientations. The latter were modeled as complexes with the sequence T3AGT3 and refined by force field calculations with the AMBER program. The biological implications for this novel form of interaction of AMD with single-stranded DNA are discussed.
Topics: Base Sequence; Binding Sites; DNA, Single-Stranded; Dactinomycin; Intercalating Agents; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Protons; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet
PubMed: 8809179
DOI: 10.1006/jmbi.1996.0498 -
Food and Chemical Toxicology : An... Sep 2018Actinomycetes are main producers of antibiotics and targeted screening could improve the efficiency of discovering new drugs. This study describes, for the first time,...
Purification and identification of an actinomycin D analogue from actinomycetes associated with Ganoderma applanatum via magnetic molecularly imprinted polymers and tandem mass spectrometry.
Actinomycetes are main producers of antibiotics and targeted screening could improve the efficiency of discovering new drugs. This study describes, for the first time, the isolation of endophytic actinomycetes from the macrofungus Ganoderma applanatum. To increase the efficiency of screening, novel actinomycin D (Act D) molecularly-imprinted polymers were adsorbed to the surface of FeO@SiO magnetic microspheres (MMIPs) and using in the isolation. A monolithic column prepared with magnetic molecularly imprinted polymers was employed to adsorb actinomycin D and its analogues for selective analysis and identification via MS/MS spectroscopy. The MMIP-monolithic column was selective for the structural features of Act D and its analogue, and the maximum loading of the MMIPs for Act D was ∼23.5 μg/g. The recognition time of the Act D was 20-30 min and had good discriminative ability. A new analogue was identified from endophytic actinomycetes KLBMP 2541, and it was purified using MMIPs comparison with MMIPs-solid phase extraction. Structural identification analysis confirmed that the new analogue was 2-methyl-actinomycin D, which has better anti-tumor activity than Act D. The presented method combines the advantages of MMIPs and MS with popular solutions to enable high affinity and selectivity screening of specific antibiotics from endophytic actinomycetes.
Topics: Cell Line, Tumor; Dactinomycin; Ferrous Compounds; Ganoderma; Humans; Magnetite Nanoparticles; Microscopy, Electron, Scanning; Molecular Imprinting; Molecular Structure; Polymers; Tandem Mass Spectrometry
PubMed: 29777719
DOI: 10.1016/j.fct.2018.05.015 -
Journal of Medicinal Chemistry Oct 19827-(2,3-Epoxypropoxy)actinomycin D has been synthesized along with its major companion product, 7-(2,3-dihydroxypropoxy)actinomycin D. They were characterized by...
7-(2,3-Epoxypropoxy)actinomycin D has been synthesized along with its major companion product, 7-(2,3-dihydroxypropoxy)actinomycin D. They were characterized by UV-visible and CD spectra and by NMR studies. According to UV-visible absorptiometry, circular dichroism, and thermal denaturation studies, they bind to DNA in a manner that is comparable to actinomycin D. The analogues are, like actinomycin D, extremely cytotoxic to human lymphoblastic leukemic cells (CCRF-CEM) in vitro but are significantly less toxic than actinomycin D to normal CDF1 mice is vivo. Unlike actinomycin, these analogues are metabolized in rats, and the metabolites are excreted in rat urine at a rapid rate. Compared to actinomycin D, the antitumor activity of the 7-(2,3-epoxypropoxy)actinomycin analogue against P-388 leukemia in mice is decidedly superior, and the therapeutic index is improved several fold.
Topics: Animals; Antibiotics, Antineoplastic; Cells, Cultured; Chemical Phenomena; Chemistry; Circular Dichroism; DNA; Dactinomycin; Hot Temperature; Leukemia, Experimental; Magnetic Resonance Spectroscopy; Male; Mice; Nucleic Acid Denaturation
PubMed: 7143358
DOI: 10.1021/jm00352a023 -
Bioorganic & Medicinal Chemistry Letters Jul 2000Natural analogues (D, C2, and VII) of actinomycin inhibit Grb2 SH2 domain binding with phosphopeptide-derived from Shc in vitro and in intracellular system. To study...
Natural analogues (D, C2, and VII) of actinomycin inhibit Grb2 SH2 domain binding with phosphopeptide-derived from Shc in vitro and in intracellular system. To study structure-activity relationships, 13 actinomycin analogues were synthesized and we found that the inhibition activity depended on the substituents of cyclic peptide groups in actinomycin and two analogues with Tyr residue are the most potent inhibitors with IC50 value of 0.5 and 0.8 microM, respectively.
Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Amino Acid Substitution; Animals; Antibiotics, Antineoplastic; Biological Assay; Cell Line, Transformed; Dactinomycin; GRB2 Adaptor Protein; Growth Inhibitors; Humans; Immunoblotting; Molecular Structure; Precipitin Tests; Protein Binding; Proteins; Recombinant Fusion Proteins; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; Structure-Activity Relationship; src Homology Domains
PubMed: 10888331
DOI: 10.1016/s0960-894x(00)00258-4