Limits...
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.


Related in: MedlinePlus

Effect of degree of planarity of the N-aryl substituent on cytotoxic potency. The N-thiazole napthyridone vosaroxin (11) likely achieves a planar bias due to constraint imposed by the C-8 nitrogen lone-pair donation to the thiazole sulfur. CC50 values represent the inhibition of proliferation of A549 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4997924&req=5

Figure 14: Effect of degree of planarity of the N-aryl substituent on cytotoxic potency. The N-thiazole napthyridone vosaroxin (11) likely achieves a planar bias due to constraint imposed by the C-8 nitrogen lone-pair donation to the thiazole sulfur. CC50 values represent the inhibition of proliferation of A549 cells.

Mentions: The co-planar preference of vosaroxin might be explained by a nitrogen-to-sulfur non-covalent interaction between the N-1 2-thiazole sulphur and the naphthyridone 8-nitrogen which could enforce the planar conformation depicted in Fig. (14) (partial structure 168). According to this argument, the N-1 2-thiazole C-S σ* orbital interacts with the lone pair of electrons from the 8-position naphthyridone ring nitrogen resulting in co-planarity between the scaffold aromatic rings [216]. Alternative non-sulfur containing heterocycles would not allow for this type of conformation constraint. The relatively high levels of potencies displayed by all of the thiazole analogs in the top row of Table 18 is consistent with this view. The thiadiazole and thiophene analogs (135, 136) are significantly less potent how-


A “ Double-Edged ” Scaffold: Antitumor Power within the 
 Antibacterial Quinolone
Effect of degree of planarity of the N-aryl substituent on cytotoxic potency. The N-thiazole napthyridone vosaroxin (11) likely achieves a planar bias due to constraint imposed by the C-8 nitrogen lone-pair donation to the thiazole sulfur. CC50 values represent the inhibition of proliferation of A549 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 14: Effect of degree of planarity of the N-aryl substituent on cytotoxic potency. The N-thiazole napthyridone vosaroxin (11) likely achieves a planar bias due to constraint imposed by the C-8 nitrogen lone-pair donation to the thiazole sulfur. CC50 values represent the inhibition of proliferation of A549 cells.
Mentions: The co-planar preference of vosaroxin might be explained by a nitrogen-to-sulfur non-covalent interaction between the N-1 2-thiazole sulphur and the naphthyridone 8-nitrogen which could enforce the planar conformation depicted in Fig. (14) (partial structure 168). According to this argument, the N-1 2-thiazole C-S σ* orbital interacts with the lone pair of electrons from the 8-position naphthyridone ring nitrogen resulting in co-planarity between the scaffold aromatic rings [216]. Alternative non-sulfur containing heterocycles would not allow for this type of conformation constraint. The relatively high levels of potencies displayed by all of the thiazole analogs in the top row of Table 18 is consistent with this view. The thiadiazole and thiophene analogs (135, 136) are significantly less potent how-

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