Dipyridyl Thiosemicarbazone Chelators with Potent and Selective Antitumor Activity Form Iron Complexes with Redox Activity

Abstract

Table S1. Crystal data and structure refinement for HDp4mT. Identification code ds2369 Empirical formula C 13 H 13 N 5 S Formula weight 271.34 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 19.740(2) Å α= 90°. b = 11.694(1) Å β= 91.391(9)°. c = 11.514(2) Å γ = 90°. Volume 2657.1(6) Å 3 Z 8 Density (calculated) 1.357 Mg/m 3 Absorption coefficient 0.237 mm -1 F(000) 1136 Crystal size 0.5 x 0.5 x 0.3 mm 3 Theta range for data collection 2.02 to 24.96°. Index ranges 0<=h<=23, 0<=k<=13, -13<=l<=13 Reflections collected 2399 Independent reflections 2329 [R(int) = 0.0491] Completeness to theta = 24.96° 99.7 % Absorption correction Psi-scan Max. and min. transmission 0.9317 and 0.8896 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2329 / 0 / 172 Goodness-of-fit on F 2 1.039 Final R indices [I>2sigma(I)] R1 = 0.0382, wR2 = 0.0926 R indices (all data) R1 = 0.0623, wR2 = 0.1029 Largest diff. peak and hole 0.202 and -0.209 e.Å -3

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

“…Considering this finding, we suggest that it is the effect of the chelator entering the cancer cell, binding Fe, and forming the cytotoxic Fe complex (10,26) that leads to its antitumor activity. In fact, we have shown that the antitumor efficacy of the DpT chelators is proportional to their effective redox activity (26).…”

“…Furthermore, upon PKIH and DpT ligands forming Fe complexes, these ligands generate cytotoxic ROS (10,(26)(27)(28). The resulting oxidative damage potentiates the antiproliferative activity of PKIH and DpT chelators compared with 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone or DFO, which bind Fe but do not redox cycle (29).…”

“…The resulting oxidative damage potentiates the antiproliferative activity of PKIH and DpT chelators compared with 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone or DFO, which bind Fe but do not redox cycle (29). The higher activity of DpT series relative to the PKIH class can be ascribed, at least in part, to the electrochemical potentials of their Fe complexes (26,28). In fact, the Fe III/II redox potentials of the Fe(DpT) 2 complexes (ϩ153-225 mV) are much lower than the PKIH analogs (approximately ϩ500 mV) and lie in a range accessible to cellular oxidants and reductants (26,28).…”

“…Previous studies showed that increased ROS can activate HIF-1␣ (24,25). Because the Dp44mT-Fe complex is highly redox-active (10,26), it can be speculated that ROS generation by this compound leads to increased transcription of these genes via HIF-1.…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…The current understanding of the structure activity relationship of MDR selective isatin-β-TSCs suggests a beneficial effect of an aromatic moiety at N4 [21,39]. Similarly, introduction of a phenyl substituent to the N4 position has been shown to increase the toxicity of dipyridylketone TSCs to a comparable extent as terminal dimethylation [23,47]. In contrast to Dp44mT and NSC73306, the toxicity of the terminally unsubstituted NNS thiosemicarbazone Triapine is attenuated by P-gp [20,21,48].…”