Table 2. Pfizer eukaryotic SAR at quinolone N-1, C-7, and C-8. CP-115,953 (27) is the most potent analog and displays a similar level of cytotoxicity compared to etoposide (14). Cytotoxicity correlated better with stimulation of DNA cleavage (generation of cell-toxic fragments) than with inhibition of DNA relaxation (measure of topo II catalytic activity).
| Compound | R7 | R8 | R1 |
Topo II DNA relaxation
IC50 (μg/ml)a,b |
Topo II DNA cleavage
EC2 (μg/ml)a,b, c |
CHO cellsd
CC50 (μg/ml)a |
|---|---|---|---|---|---|---|
|
14 etoposide |
- | - | - | * | 10 | 5 |
|
27 CP-115,953 |
F | 1.2 | 0.1 | 3 | ||
| 28 | F | 73 | 7 | 30 | ||
| 29 | F | >185 | >185 | 36 | ||
| 30 | F | 50 | 19 | 37 | ||
| 31 | F | 67 | 36 | >170 | ||
|
16 8-F- ciprofloxacin |
F | 46 | 22 | 82 | ||
| 32 | H | 11 | 1 | * | ||
| 33 | H | 120 | >175 | * | ||
|
15 ciprofloxacin |
H | 35 | 56 | >165 | ||
| 34 | F | 39 | 4 | * | ||
| 35 | F | >165 | >165 | * | ||
|
8 norfloxacin |
H | >165 | 162 | * |
aValues originally reported as μM were converted to μg/ml for this table; bDNA topoisomerase II purified from calf thymus; cEC2 is defined as the effective concentration of drug required to enhance double-stranded DNA cleavage twofold; dChinese hamster ovary cells; *no data reported.