Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate

Background: Multi drug resistance (MDR) or cross-resistance to multiple classes of chemotherapeutic agents is a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are an important determinant of MDR. Therefore, there is an urgent need for development of novel compounds that are not substrates of P-glycoprotein and are effective against drug-resistant cancer. Methodology/Principal Findings: In this present study, we have synthesized a novel, redox active Fe (II) complex (chelate), iron N- (2-hydroxy acetophenone) glycinate (FeNG). The structure of the complex has been determined by spectroscopic means. To evaluate the cytotoxic effect of FeNG we used doxorubicin resistant and/or sensitive T lymphoblastic leukemia cells and show that FeNG kills both the cell types irrespective of their MDR phenotype. Moreover, FeNG induces apoptosis in doxorubicin resistance T lymphoblastic leukemia cell through mitochondrial pathway via generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR. Conclusion/Significance: Our study provides evidence that FeNG, a redox active metal chelate may be a promising ne

Silanes and germanes as free-radical reducing agents: an ab initio study of hydrogen atom transfer from some trialkylsilanes and germanes to alkyl radicals

Ab initio molecular orbital calculations using a (valence) double-ζ pseudopotential (DZP) basis set, with (MP2, QCISD) and without (SCF ) the inclusion of electron correlation predict that hydrogen atoms, methyl, ethyl, isopropyl and tert-butyl radicals abstract hydrogen atom from silane, methylsilane, dimethylsilane, trimethylsilane, trisilylsilane and the analogous germanes via transition states in which the attacking and leaving radicals adopt colinear (or nearly so) arrangements. Except for reactions involving trisilylsilane which are predicted at the MP2/DZP level to involve transition states with Si–C distances of about 3.19 Å, transition states which have (overall) Si–C and Ge–C separations of 3.12–3.15 and 3.24–3.26 Å respectively are calculated; these distances appear to be independent of the number of methyl substituents on the group(IV) element, but appear to be slightly sensitive to the nature of the attacking radical, with marginally earlier transition states calculated as the degree of alkyl substitution on the attacking radical is increased. At the highest level of theory (QCISD/DZP//MP2/DZP), energy barriers (ΔE1‡) of 27–57 (Si) or 26–44 (Ge) kJ mol–1 are predicted for the forward reactions, while the reverse reactions (ΔE2‡) are calculated to require 85–134 (Si) or 102–138 (Ge) kJ mol–1. These values are marginally affected by the inclusion of zero-point vibrational energy correction. Importantly, QCISD and MP2 calculations appear to predict correctly the relative ordering of activation energies for alkyl radical reduction by silanes: tertiary < secondary < primary; SCF/DZP, AM1 and AM1 (CI = 2) calculations perform somewhat more poorly in their prediction of relative radical reactivity

Steric trends and kinetic parameters for radical reductions involving alkyldiphenyltin hydrides

Absolute rate constants and Arrhenius parameters for hydrogen atom abstraction by primary alkyl radicals from methyldiphenyl-, ethyldiphenyl-, butyldiphenyl-, isopropyldiphenyl-, cyclohexyldiphenyl- and (trimethylsilyl)methyldiphenyltin hydride were determined in tert-butylbenzene through utilization of the ‘5-hexenyl radical clock’ reaction. At 80 °C, rate constants (kH) for all hydrides were found to lie in the range (8.2–11.5) × 106 lmol−1 s−1, with similar Arrhenius expressions for all reactions studied [viz. log kH = (8.92–8.97)−(3.03–3.24)/2.3RT]. The nature of the alkyl substituent appears to have a subtle effect on the function of the hydride such that the order or reactivity of stannanes (RPh2SnH) is Me > Et > Bu > i-Pr > c-Hex ≥ Me3SiCH2; this trend can be directly traced to steric effects operating in the transition states for hydrogen transfer from tin to carbon. The implications of these observations are discussed