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A “ Double-Edged ” Scaffold: Antitumor Power within the 
 Antibacterial Quinolone

View Article: PubMed Central - PubMed

ABSTRACT

In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.

No MeSH data available.


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Models for bacterial Type II topoisomerase tetramers: DNA gyrase (left) and topoisomerase IV (right). The arrows show the relative locations of the ATP binding sites in GyrB and ParE and the DNA cleavage/ligation catalytic sites in GyrA and ParC which are shown binding the so-called “gateway” segment of DNA. Each monomer within the two tetramers is defined by a different color or shade of color. The models were constructed with S. pneumoniae ParC (PDB code 4I3H)[91]. E. coli ParE (1S16)[100], C. psychrerythraea 34H GyrA (3LPX), and E. coli GyrB (1EI1)[101] using the X-ray crystal structure of the complete tetramer from S. cerevisiae (4GFH)[102] as a template.
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Figure 4: Models for bacterial Type II topoisomerase tetramers: DNA gyrase (left) and topoisomerase IV (right). The arrows show the relative locations of the ATP binding sites in GyrB and ParE and the DNA cleavage/ligation catalytic sites in GyrA and ParC which are shown binding the so-called “gateway” segment of DNA. Each monomer within the two tetramers is defined by a different color or shade of color. The models were constructed with S. pneumoniae ParC (PDB code 4I3H)[91]. E. coli ParE (1S16)[100], C. psychrerythraea 34H GyrA (3LPX), and E. coli GyrB (1EI1)[101] using the X-ray crystal structure of the complete tetramer from S. cerevisiae (4GFH)[102] as a template.


A “ Double-Edged ” Scaffold: Antitumor Power within the 
 Antibacterial Quinolone
Models for bacterial Type II topoisomerase tetramers: DNA gyrase (left) and topoisomerase IV (right). The arrows show the relative locations of the ATP binding sites in GyrB and ParE and the DNA cleavage/ligation catalytic sites in GyrA and ParC which are shown binding the so-called “gateway” segment of DNA. Each monomer within the two tetramers is defined by a different color or shade of color. The models were constructed with S. pneumoniae ParC (PDB code 4I3H)[91]. E. coli ParE (1S16)[100], C. psychrerythraea 34H GyrA (3LPX), and E. coli GyrB (1EI1)[101] using the X-ray crystal structure of the complete tetramer from S. cerevisiae (4GFH)[102] as a template.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997924&req=5

Figure 4: Models for bacterial Type II topoisomerase tetramers: DNA gyrase (left) and topoisomerase IV (right). The arrows show the relative locations of the ATP binding sites in GyrB and ParE and the DNA cleavage/ligation catalytic sites in GyrA and ParC which are shown binding the so-called “gateway” segment of DNA. Each monomer within the two tetramers is defined by a different color or shade of color. The models were constructed with S. pneumoniae ParC (PDB code 4I3H)[91]. E. coli ParE (1S16)[100], C. psychrerythraea 34H GyrA (3LPX), and E. coli GyrB (1EI1)[101] using the X-ray crystal structure of the complete tetramer from S. cerevisiae (4GFH)[102] as a template.

View Article: PubMed Central - PubMed

ABSTRACT

In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.

No MeSH data available.


Related in: MedlinePlus