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Acta Chimica Slovenica Dec 2016The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of... (Review)
Review
The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these minor groove binders (MGBs) were also investigated for their capability for the treatment of cancer and in particular lung cancer.
Topics: Animals; Anti-Bacterial Agents; Computer Simulation; DNA; DNA Footprinting; Distamycins; Humans; Magnetic Resonance Spectroscopy; Trypanocidal Agents
PubMed: 28004090
DOI: 10.17344/acsi.2016.2775 -
Pharmaceutical Biology Dec 2017Natural oligopeptide antibiotic distamycin A (Dst) biosynthesized by Streptomyces distallicus is traditionally used in medical practice as an anti-inflammatory and...
CONTEXT
Natural oligopeptide antibiotic distamycin A (Dst) biosynthesized by Streptomyces distallicus is traditionally used in medical practice as an anti-inflammatory and antitumour drug.
OBJECTIVE
Dst was investigated for its effect on the structural components of native chromatin directly within isolated rat liver nuclei in the presence of physiologically significant cations (magnesium or spermine and spermidine).
MATERIALS AND METHODS
Differential scanning calorimetry (DSC) was used to study the Dst action at molar ratio Dst/DNA = 0.1 and 0.15 mM Dst on the melting profile of nuclei suspension in different conditions.
RESULTS
Results showed that the thermodynamic parameters of control nuclei in the presence of polyamines or Mgwere different. The incubation of nuclei with Dst raised transition temperatures of relaxed (peak II) and topologically constrained DNA (peak III) by 6-8 °C and decreased by 2-4 °C that of core-histones (peak I). The total excess transition enthalpy (ΔH) in buffer with polyamines (24.7 kJ/mol DNA nucleotides) increased by1.5 times versus control but in buffer with Mg, the value of ΔH (35.8 kJ/mol DNA nucleotides) remained unchanged.
CONCLUSIONS
The association of Dst with chromatin in the nucleus weakens histone-DNA contacts and causes additional strengthening of interaction between two complementary DNA chains. Our results contribute towards validation of DSC to test drug ability to modulate chromatin structure in the physiological environment and to clarify the mechanism of these modulations.
Topics: Animals; Anti-Bacterial Agents; Calorimetry, Differential Scanning; Cell Nucleus; Chromatin; Chromatin Assembly and Disassembly; DNA; Distamycins; Female; Histones; Liver; Magnesium; Nucleic Acid Conformation; Protein Binding; Rats; Spermidine; Spermine; Temperature
PubMed: 27982735
DOI: 10.1080/13880209.2016.1258427 -
Bioorganic & Medicinal Chemistry Letters Aug 2016A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma...
A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cancer.
Topics: Antineoplastic Agents, Phytogenic; Biological Products; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Distamycins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship; Gemcitabine
PubMed: 27349332
DOI: 10.1016/j.bmcl.2016.06.040 -
European Journal of Medicinal Chemistry Jun 2016A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have...
A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activity.
Topics: Computer Simulation; HEK293 Cells; Humans; Inhibitory Concentration 50; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei
PubMed: 27060763
DOI: 10.1016/j.ejmech.2016.03.064