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

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.

Fig. (1)

Dihydrofolate reductase (DHFR) inhibitors aminopterin and methotrexate (1) and trimethoprim (2) developed for anticancer and antibacterial therapy, respectively. Aminopterin and methotrexate also possess DHFR-based antibacterial activity, while trimethoprim is selective for bacterial DHFR.

Fig. (2)

Bacterial Type II topoisomerase inhibitors novobiocin (3) and cyclothialidine (5) compared to eukaryotic Hsp90 inhibitors geldanamycin (4) and radicicol (6). All four natural products bind to a common ATPase Bergerat fold motif. Based on X-ray co-crystal structures, both novobiocin and geldanamycin “anchor” to the key Asp-water motif in the ATPase Bergerat fold via a primary carbamate moiety while cyclothialidine and radicicol analogously bind via a phenol hydroxyl group. The Asp-water motif interaction of both enzymes with ATP substrate is deduced from the crystallographic binding of ADPNP (adenosine 5′-(β,γ-imido)triphosphate, a stable ATP mimetic, shown) in bacterial topoisomerase and from the binding of ADP (shown) in Hsp90. The Asp-water motif binding interactions for all six compounds are highlighted in red. Novobiocin and cyclothialidine largely occupy a binding pocket adjacent to the ATP binding site, while geldanamycin and radicicol largely overlap with the ATP binding site.

Fig. (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).

Fig. (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.

Fig. (5)

Schematic representation of antibacterial fluoroquinolone moxifloxacin 12 as part of the ternary complex (“cleavable complex”) with bacterial gyrase (GyrA/GyrB) or topo IV (ParC/ParE) and DNA. Moxifloxacin and other fluoroquinolones make interactions with both enzyme subunits, as well as p-stacking interactions with the DNA base pairs. A strand break between two base pairs, mediated by a topoisomerase catalytic tyrosine, is not shown.

Fig. (6)

Model for the eukaryotic Type II topoisomerase, topo II, in covalent (“cleavable”) complex with DNA. This representation is a composite of the two PDB entries 1ZXN (N terminal human topo IIα with ATP analog ADPNP in the ATP binding site) from Wei et al. [133] and 3QX3 (C-terminal catalytic domain of human topo IIβ with bound and cleaved DNA and bound etoposide) from Wu et al. [134]. The pink represents the ATP binding domains, analogous to bacterial GyrB (or ParE) and the green represents the DNA binding domains, analogous to bacterial GyrA (or ParC). The vertical line indicates the enzyme dimeric composition as two symmetrical monomers (right and left).

Fig. (7)

Schematic representation of anticancer agents doxorubicin 13 (left panel) and etoposide 14 (right panel) bound as the ternary complex (“cleavable complex”) with eukaryotic topo II and DNA. The binding modes of 13 and 14 are broadly similar to that of moxifloxacin 12 in the prokaryotic ternary complex (compare Fig. 5). Renderings adapted from crystal structure information by Wu et al. and Chan et al. [135, 136] employing topo IIβ. Topo II amino acids which form known interactions with the drugs based on crystallography are shown in each of the two panels, although the specific interactions are not depicted. A strand break between two base pairs, mediated by a topoisomerase catalytic tyrosine, is not shown.

Fig. (8)

Structures of Pfizer’s experimental quinolones CP-67015 (26) and CP-115,953 (27) compared to Sterling’s earlier launched drug rosoxacin 25. The cytotoxicity displayed by 27 is equivalent to the marketed anticancer drug etoposide 14.

Fig. (9)

Pfizer C-7 quinolone substituted 1,8-bridged analogs; racemates and enantiomers.

Fig. (10)

Evolution of early antibacterial 1,8-bridged quinolone scaffolds to ofloxacin (42) and the antibacterial N-1phenyl and eukaryotic/prokaryotic cell active quinobenoxazine variants of Abbott.

Fig. (11)

Similarity of position in space of the primary amino groups of S-116/PD117579 (24) and (-)-BO2376 (116). The common bonds for placement of the primary amino group at C-7 for the two compounds are shown in bold.

Fig. (12)

Representative quinolone structures from Bayer patent applications reporting antiproliferative/anticancer activities.

Fig. (13)

Comparison of the structures of N-thiazole quinolone analogs from Parke Davis and Dainippon.

Fig. (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.

Fig. (15)

Eukaryotic-active quinolone scaffolds discussed in this review, grouped by overall mechanism and associated SAR (Group A and B). SAR summaries for each group is shown at the bottom of the Figure.

Fig. (16)

Comparison of three experimental cytotoxic quinolones with corresponding marketed antibacterial quinolones (27 vs 39; 116 vs 47; 24 vs 102) showing structural elements (in bold) common between the pairs which are considered to potentiate cytotoxicity.

Fig. (17)

Evolution of Abbott quinobenoxazine 55 through 172 and 173 which partially display G-quaduplex activity in addition to DNA/topo II activity, to quarfloxin 174 having pure G-quadruplex activity (upper panel). An earlier example of a scaffold evolution of an anticancer agent resulting in a different mechanism of action is the transformation of podophyllotoxin (tubulin mechanism) to the epipodophyllotoxin class having a DNA/topo II-based mechanism (lower panel).