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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.


Antibacterial delafloxacin (10) and anticancer vosaroxin (11), inhibitors of bacterial and human Type II topoisomerases, respectively, were evaluated in Phase III studies during 2014. Inhibitors of bacterial Type II topoisomerase (DNA gyrase and topoisomerase IV) have been a significant class of antiinfectives since the launch of nalidixic acid (7) in 1964. The antibacterials norfloxacin (8) and tosufloxacin (9) can be viewed as intermediate agents on the evolutionary path toward both 10 and 11. The ring numbering for both quinolones and naphthyridones is represented by nalidixic acid (a naphthyridone).
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Figure 3: Antibacterial delafloxacin (10) and anticancer vosaroxin (11), inhibitors of bacterial and human Type II topoisomerases, respectively, were evaluated in Phase III studies during 2014. Inhibitors of bacterial Type II topoisomerase (DNA gyrase and topoisomerase IV) have been a significant class of antiinfectives since the launch of nalidixic acid (7) in 1964. The antibacterials norfloxacin (8) and tosufloxacin (9) can be viewed as intermediate agents on the evolutionary path toward both 10 and 11. The ring numbering for both quinolones and naphthyridones is represented by nalidixic acid (a naphthyridone).

Mentions: antibacterial programs were found to potently inhibit topo II and, in contrast to the clinically used quinolones, demonstrated eukaryotic cytotoxicity. As a consequence, several pharmaceutical companies (e.g. Abbott, Dainippon, Sterling) opportunistically investigated these compounds for application as “cytotoxic” anticancer drugs, while other companies (e.g. Pfizer and Parke Davis) studied the eukaryotic SAR only in order inform and “de-risk” their ongoing antibacterial programs. As of late 2014, the quinolone class is still under active investigation for both new antibacterial and anticancer therapies as evidenced by Phase III trials of the antibacterial delafloxacin 10 and the anticancer vosaroxin 11. The lines of research leading to both of these compounds can be traced through earlier analogs such as norfloxacin 8 and tosufloxacin 9 (Fig. 3). Technically, nalidixic acid 7, tosufloxacin 9, and vosaroxin 11 are 8-azaquinolones, also called 1,8-naphthyridones, while norfloxacin 8 and delafloxacin 10 are “pure” quinolones. However, the term quinolone (or fluoroquinolone) is often used informally to encompass both these core variations. The ring numbering for both quinolones and naphthyridones is depicted in Fig. (3) (nalidixic acid used an example).


A “ Double-Edged ” Scaffold: Antitumor Power within the 
 Antibacterial Quinolone
Antibacterial delafloxacin (10) and anticancer vosaroxin (11), inhibitors of bacterial and human Type II topoisomerases, respectively, were evaluated in Phase III studies during 2014. Inhibitors of bacterial Type II topoisomerase (DNA gyrase and topoisomerase IV) have been a significant class of antiinfectives since the launch of nalidixic acid (7) in 1964. The antibacterials norfloxacin (8) and tosufloxacin (9) can be viewed as intermediate agents on the evolutionary path toward both 10 and 11. The ring numbering for both quinolones and naphthyridones is represented by nalidixic acid (a naphthyridone).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Antibacterial delafloxacin (10) and anticancer vosaroxin (11), inhibitors of bacterial and human Type II topoisomerases, respectively, were evaluated in Phase III studies during 2014. Inhibitors of bacterial Type II topoisomerase (DNA gyrase and topoisomerase IV) have been a significant class of antiinfectives since the launch of nalidixic acid (7) in 1964. The antibacterials norfloxacin (8) and tosufloxacin (9) can be viewed as intermediate agents on the evolutionary path toward both 10 and 11. The ring numbering for both quinolones and naphthyridones is represented by nalidixic acid (a naphthyridone).
Mentions: antibacterial programs were found to potently inhibit topo II and, in contrast to the clinically used quinolones, demonstrated eukaryotic cytotoxicity. As a consequence, several pharmaceutical companies (e.g. Abbott, Dainippon, Sterling) opportunistically investigated these compounds for application as “cytotoxic” anticancer drugs, while other companies (e.g. Pfizer and Parke Davis) studied the eukaryotic SAR only in order inform and “de-risk” their ongoing antibacterial programs. As of late 2014, the quinolone class is still under active investigation for both new antibacterial and anticancer therapies as evidenced by Phase III trials of the antibacterial delafloxacin 10 and the anticancer vosaroxin 11. The lines of research leading to both of these compounds can be traced through earlier analogs such as norfloxacin 8 and tosufloxacin 9 (Fig. 3). Technically, nalidixic acid 7, tosufloxacin 9, and vosaroxin 11 are 8-azaquinolones, also called 1,8-naphthyridones, while norfloxacin 8 and delafloxacin 10 are “pure” quinolones. However, the term quinolone (or fluoroquinolone) is often used informally to encompass both these core variations. The ring numbering for both quinolones and naphthyridones is depicted in Fig. (3) (nalidixic acid used an example).

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.