In vitro antiproliferative activity of 4-substituted 2-(2-hydroxyphenyl)thiazolines on murine leukemia cells.
Two previously synthesized and two structurally novel thiazoline iron chelators are described. N4-Benzyl-N1,N8-bis[[2-(2-hydroxyphenyl)thiazolin-4-yl]carbonyl] homospermidine (5) proved to be the most potent antiproliferative and cytocidal compound in the series with in vitro IC50 values of 3 and 1 microM on L1210 and P388 murine cell lines. The N4-acetyl analogue 7 was considerably less active than 5 with IC50 and cell viability values that were similar to those of the structurally simple thiazolines 2 and 3. The antiproliferative activity of 3 and 7 could be substantially reduced or ablated by delivery to cell suspensions as a 1:1 molar mixture with FeCl3, while the activity of 5 was unaffected by Fe(III) chelation. As expected, 3 induced a G1/S cell cycle block at the 100 microM block consistent with interference with DNA synthesis while 10 microM 5 did not affect L1210 cell cycle distribution. Tritiated thymidine incorporation studies confirmed that 5 was incapable of interfering with DNA synthesis at concentrations below 40 microM. Alkaline elution studies indicate that 5 does not cause DNA strand breaks in vitro at concentrations of 10 microM. The N4-benzyl group of 5 appears to impart in vitro potency as the N4-acetyl analogue 7 lacks comparable in vitro antiproliferative and cytocidal activity.
Elliott
G T
GT
Ribi ImmunoChem Research, Inc., Hamilton, Montana 59840.
Nagle
W A
WA
Kelly
K F
KF
McCollough
D
D
Bona
R L
RL
Burns
E R
ER
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D013844:Thiazoles