Mechanistic studies of organotellurium chemistry

The oxidation of bis(p-ethoxyphenyl) ditelluride by hydrogen peroxide has been studied kinetically. The reaction monitored was an oxidation from tellurium(I) to tellurium(II). The reaction stoichiometry ratio was found to depend upon the initial reagent concentrations. The presence of dioxygen was found to retard the rate and attributed to a dioxygen-ditelluride adduct. The rate varies in the following order of different atmospheres N2> Air> > O2. The final product obtained from the oxidation has been characterised by IR, NMR and ESR spectroscopy. A mechanism for the oxidation has been suggested. The reduction of p-EtOPhTeCl3 by the hydrazinium ion has been studied kinetically. The stoichiometric measurements show that four moles p-EtOPhTeCl3 are equivalent to three moles hydrazinium ion. The kinetics were studied under pseudo first order conditions. No ammonia was detected as a nitrogen containing product. The reduction proceeds via a two-electron process which indicates that it is inner-sphere in nature. A mechanism for the reduction is suggested. The solvolysis of p-EtOPhTeCl3 by methanol in benzene/methanol media has been studied. The study shows that the solvolysis is a reversible, acid catalysed reaction. Replacement of the chlorides on tellurium by methanol is agreed to be associative and replacement of the first chloride is rate determining. The rate of solvolysis varies in the order trichloride > tribromide > triiodide. A mechanism for the solvolysis is suggested. The synthesis of some tellurium heterocyclics is reported. The synthesis and characterisation of telluranthrene is reported. The attempted synthesis of telluraxanthene was unsuccessful.

Mechanistic differences between GSH transport by multidrug resistance protein 1 (MRP1/ABCC1) and GSH modulation of MRP1-mediated transport

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent polytopic membrane protein that transports many anticancer drugs and organic anions. Its transport mechanism is multifaceted, especially with respect to the participation of GSH. For example, vincristine is cotransported with GSH, estrone sulfate transport is stimulated by GSH, or MRP1 can transport GSH alone, and this can be stimulated by compounds such as verapamil or apigenin. Thus, the interactions between GSH and MRP1 are mechanistically complex. To examine the similarities and differences among the various GSH-associated mechanisms of MRP1 transport, we have measured first the effect of GSH and several GSH-associated substrates/modulators on the binding and hydrolysis of ATP by MRP1 using 8-azidoadenosine-5'-[(32)P]-triphosphate ([(32)P]azidoATP) analogs, and second the initial binding of GSH and GSH-associated substrates/modulators to MRP1. We observed that GSH or its nonreducing derivative S-methylGSH (S-mGSH), but none of the GSH-associated substrate/modulators, caused a significant increase in [gamma-(32)P]azidoATP labeling of MRP1. Moreover, GSH and S-mGSH decreased levels of orthovanadate-induced trapping of [alpha-(32)P]azidoADP. [alpha-(32)P]azidoADP.Vi trapping was also decreased by estone sulfate, whereas vincristine, verapamil, and apigenin had no apparent effects on nucleotide interactions with MRP1. Furthermore, estrone sulfate and S-mGSH enhanced the effect of each other 15- and 10-fold, respectively. Second, although GSH binding increased the apparent affinity of MRP1 for all GSH-associated substrates/modulators tested, only estrone sulfate had a reciprocal effect on the apparent affinity of MRP1 for GSH. Overall, these results indicate significant mechanistic differences between MRP1-mediated transport of GSH and the ability of GSH to modulate MRP1 transport.

A systematic and mechanistic evaluation of aspartic acid as filler for directly compressed tablets containing trimethoprim and trimethoprim aspartate

The generally accepted paradigm of 'inert' and 'mono functional' excipient in dosage form has been recently challenged with the development of individual excipients capable of exhibiting multiple functions (e.g. binder-disintegrants, surfactant which affect P-gp function). The proposed study has been designed within the realm of multifunctionality and is the first and novel investigation towards evaluation of aspartic acid as a filler and disintegration enhancing agent for the delivery of biopharmaceutical class IV model drug trimethoprim. The study investigated powder characteristics using angle of repose, laser diffractometry and scanning electron microscopy (SEM). The prepared tablets were characterised using Heckel analysis, disintegration time and tensile strength measurements. Although Heckel analysis revealed that both TMP and TMP aspartate salt have high elasticity, the salt form produced a stronger compact which was attributed to the formation of agglomerates. Aspartic acid was found to have high plasticity, but its incorporation into the formulations was found to have a negative impact on the compaction properties of TMP and its salt. Surface morphology investigations showed that mechanical interlocking plays a vital role in binding TMP crystals together during compaction, while the small particle size of TMP aspartate agglomerates was found to have significant impact on the tensile strength of the tablets. The study concluded that aspartic acid can be employed as filler and disintegrant and that compactability within tablets was independent of the surface charge of the excipients.