Rebeccamycin analogs
Percentage of Chk1 inhibition at a drug concentration of 10 μM, IC50 values toward Chk1, topoisomerase I-mediated DNA cleavage, DNA binding, and in vitro antiproliferative activities against three tumor cell lines: murine leukemia L1210, and human A549 non-small cell lung carcinoma and HT29 colon carcinoma (IC50 μM).
Compound | Inhibition Chk1 at 10 mM | IC50 Chk1 | Topo I | DNA | L1210 | A549 | HT29 |
|---|---|---|---|---|---|---|---|
| % | μM | ||||||
| UCN-01 | 7.7 | − | N.E. | 0.271 | N.E. | 0.253 | |
| 1 | 61.8 | >10 | − | − | 0.14 | 0.3 | 0.3 |
| 2 | 5.29 | N.D. | +/− | − | 3.3 | <10 | <10 |
| 3 | 89.2 | 0.160 | +++ | ++ | 0.11 | 2.0 | 2.5 |
| 4 | 96 | 0.897 | +/− | ++ | 1.1 | <10 | <10 |
| 5 | 92.3 | N.D. | + | − | 1.5 | <10 | <10 |
| 6 | 89.1 | 0.091 | +/− | − | 0.68 | <10 | <10 |
| 7 | 97.57 | 0.116 | − | +++ | 0.023 | <1 | 0.1 |
| 8 | 92.4 | 0.083 | − | +++ | 0.025 | <0.1 | <0.1 |
| 9 | 96.97 | 0.273 | − | +++ | 0.035 | <0.1 | <0.1 |
| 10 | 100 | 0.158 | +/− | +++ | 0.35 | 1 | 1 |
| 11 | 6.86 | N.D. | +++ | − | 0.29 | 1 | <1 |
| 12 | 38.53 | N.D. | ++ (104%) | + | 1.1 | >10 | >10 |
| 13 | 100 | 0.010 | +++ | + | 0.11 | <10 | 10 |
| 14 | 49 | N.D. | ++ | − | 1.1 | >10 | >10 |
| 15 | 11.47 | N.D. | +/− | − | 4.9 | >10 | >10 |
| 16 | 55.8 | N.D. | +++ | − | 0.11 | 0.37 | 0.14 |
| 17 | 87 | 1.0 | ++ | + | 11.3 | >10 | >10 |
| 18 | 93.1 | 0.127 | + | + | 0.31 | <1 | 1 |
| 19 | 88.6 | 0.327 | ++a | + | 0.066 | 5.3 | 4.8 |
| 20 | 94 | 0.0028 | − | +++ | 0.22 | 0.36 | 0.16 |
| 21 | Inactive | − | +++ | 0.38 | 1.2 | 0.9 | |
| 22 | 39 | N.D. | + | − | 0.17 | >10 | >10 |
| 23 | 26.55 | N.D. | + | − | 18.1 | >10 | >10 |
| 24 | 88.9 | 0.017 | + | − | 19.3 | >10 | >10 |
| 25 | 91.25 | 0.165 | + | − | 0.16 | 0.40 | 0.21 |
| 26 | 8.76 | N.D. | + | − | 0.13 | >10 | >10 |
| 27 | 39.73 | N.D. | ++ | − | 0.081 | 0.3 | 0.3 |
| 28 | 90.9 | 0.013 | +++ | − | 0.68 | 10 | >10 |
| 29 | 3.83 | N.D. | +/− | − | 70.3 | >10 | 10 |
| 30 | 81 | 1.0 | +/− | − | 2.9 | >10 | >10 |
|
31
| 12.44 | N.D. | +/− | − | 0.26 | 0.1 | <0.1 |
N.D., not determined; N.E., not evaluated.
<10, IC50 = 1-10; <1, IC50 = 0.1-1.
Topoisomerase I inhibition quantified as the percentage of DNA cleavage with the drug/percentage of DNA cleavage with camptothecin: −, <20%/CPT; +/−, 20-34%/CPT; +, 35-49%/CPT; ++, 50-74%/CPT; +++, >75%/CPT
Binding to DNA evaluated by thermal denaturation profile of the synthetic polynucleotide poly(dA-dT) (dA-dT) with and without the drugs. Variations in melting temperature ΔTm (Tmdrug-DNA complex − TmDNA alone) in °C: −, − ΔTm ≤ 5°C; +, 5°C < ΔTm < 20°C; ++, 20°C ≤ ΔTm ≤ 30°C; +++, ΔTm > 30°C
↵ a DNA cleavage by topoisomerase I in the presence of the drug determined using sequencing gels and compared with DNA cleavage in the presence of camptothecin (Marminon, 2003).