Table 1.
Chemical structure, antiproliferative activity against human tumor cell lines, and Tubulin Polymerization Inhibition (TPI) of novel Microtubule Destabilizing Sulfonamides (MDS). Compounds have been divided into three different series according to the substituents on the aromatic B ring (ArB). TM: 3,4,5-trimethoxyphenyl.
Series 1:
|
Antiproliferative Activity
IC50 (nM) |
TPI | ||||
| TPI % | ||||||
| Z | RN | Compound | HeLa | MCF7 | 10 µM | IC50 (µM) |
| H | H | 1a | 240 | 375 | 0 | >20 |
| H | SO2–4-OMePh | 1b | >1000 | >1000 | 0 | >20 |
| H | Me | 2a | 71 | 127 | 35 | >20 |
| H | CH2-Dim | 2b | >1000 | >1000 | 0 | >20 |
| H | Et | 3 | 99 | 87 | 25 | >20 |
| H | EtBr | 4 | 94 | 340 | 30 | >20 |
| H | Ac | 5 | 287 | 270 | 0 | >20 |
| H | CH2CN | 6 | 143 | 275 | 0 | >20 |
| H | CH2COOEt | 7 | 217 | 335 | 21 | >20 |
| H | CH2COOH | 8 | >1000 | >1000 | 0 | >20 |
| H | Benzyl | 9 | 750 | 830 | 21 | >20 |
| H | COOBenzyl | 10 | >1000 | >1000 | 11 | >20 |
| NO2 | H | 11 | >1000 | >1000 | 10 | >20 |
| NH2 | H | 12 | >1000 | >1000 | 0 | >20 |
| NH2 | Me | 13 | >1000 | >1000 | 0 | >20 |
| NH2 | CH2-Dim | 14 | >1000 | >1000 | 0 | >20 |
| NHAc | H | 15 | >1000 | >1000 | 0 | >20 |
| NHAc | Me | 16 | >1000 | >1000 | 0 | >20 |
| NHCHO | H | 17 | >1000 | >1000 | 4 | >20 |
| N(CH3)2 | H | 18 | >1000 | >1000 | 0 | >20 |
| N(CH3)2 | Me | 19 | >1000 | >1000 | 0 | >20 |
| Br | H | 20 | >1000 | >1000 | 0 | >20 |
| Gly-tBOC | H | 21 | >1000 | >1000 | 0 | >20 |
| Succinic | H | 22 | >1000 | >1000 | 0 | >20 |
| -N=N- | 23 | >1000 | >1000 | 0 | >20 | |
| -N=CH- | 24 | >1000 | >1000 | 0 | >20 | |
Series 2:
|
Antiproliferative Activity
IC50 (nM) |
TPI | ||||
| TPI % | ||||||
| R | RN | Compound | HeLa | MCF7 | 10 µM | IC50 (µM) |
| NO2 | H | 25 | >1000 | >1000 | 0 | >20 |
| NH2 | H | 26 | >1000 | >1000 | 0 | >20 |
| NH2 | Me | 27 | >1000 | >1000 | 0 | >20 |
| N(CH3)2 | H | 28 | 230 | 173 | 0 | >20 |
| N(CH3)2 | Me | 29a | 63 | 30 | 40 | >20 |
| N(CH3)2 | CH2-Dim | 29b | >1000 | >1000 | 0 | >20 |
| N(CH3)2 | Et | 30 | 66 | 81 | 45 | >20 |
| N(CH3)2 | Ac | 31 | 183 | 135 | 38 | 14 |
| N(CH3)2 | CH2CN | 32 | 55 | 120 | 17 | >20 |
| N(CH3)2 | CH2COOEt | 33 | 99 | 91 | 14 | >20 |
| N(CH3)2 | CH2COOH | 34 | >1000 | >1000 | 6 | >20 |
| N(CH3)2 | Benzyl | 35a | 330 | 100 | 72 | 5.3 |
| N(CH3)2 | COOBenzyl | 35b | >1000 | >1000 | 0 | >20 |
| NHCHO | H | 36 | >1000 | >1000 | 0 | >20 |
| NHCH3 | H | 37 | 607 | >1000 | 7 | >20 |
| NHCH3 | Me | 38 | 44 | 61 | 47 | 10 |
Series 3:
|
Antiproliferative Activity
IC50 (nM) |
TPI | ||||
| TPI % | ||||||
| Y | RN | Compound | HeLa | MCF7 | 10 µM | IC50 (µM) |
| NO2 | H | 40 | >1000 | >1000 | 0 | >20 |
| NH2 | H | 41 | 260 | 96 | 15 | >20 |
| NH2 | Me | 42 | 23 | 26 | 41 | 12 |
| NH2 | Et | 43 | 38 | 14 | 37 | >20 |
| NH2 | CH2CN | 44 | 60 | 8 | 5 | >20 |
| NH2 | Benzyl | 45 | 25 | 48 | 75 | 3.7 |
| NHCH2COOEt | Me | 46 | 210 | 48 | 13 | >20 |
| NHCH2COOEt | CH2COOEt | 47 | >1000 | >1000 | 0 | >20 |
| NHCH3 | Me | 48a | 440 | 1190 | 2 | >20 |
| N(CH3)2 | Me | 48b | >1000 | >1000 | 0 | >20 |
| Paclitaxel [52] | 2.6 | 2.5 | n.d. 1 | n.d. | ||
| Combretastatin A-4 | 2 | 1 | 100 | 3 | ||
| ABT-751 | 388 | 180 | 69 | 4.4 | ||
1 n.d.: not determined.