Multidimensional explorations into chemical reactivity: the reactivity space

This paper discusses the empirical methods we developed for quantifying electronic and thermochemical effects in organic molecules. The parameters thus calculated can be used as coordinates of a space; points in that space represent the breaking of bonds. The study of such spaces by computer graphics provides important insights into the driving forces of chemical reactions and can help in elucidating reaction mechanisms.     

Cooperative bimetallic reactivity

A number of bimetallic complexes of a macrocyclic binucleating ligand containing both six- and four-coordinate binding sites have been prepared in order to try to reproduce the behavior of certain metalloproteins. It was found that two-metal oxidation is severely impeded in bimetallic systems. It is postulated that the mutual deactivation of metal oxidation is principally the result of unfavorable ligand conformational adjustments which occur after the first metal is oxidized. It is shown that when these conformational restraints are removed, two-metal oxidations are possible.     

Immunological reactivity of tuberculosis patients

Summary The investigation made byWilkens andTasman (1959) into the immunization of tuberculosis patients with Tetanus Phosphate Toxoid has been extended to a further group of patients and control subjects. The work described here covered a total of 29 controls and 54 tuberculosis patients; the latter were from two different clinics (SAZU and “Zonnegloren”). On the whole, the results previously reported byWilkens andTasman were comfirmed in that tuberculosis patients were found to respond to primary immunization with Tetanus-P.T. (2 injections of 0.5 ml at a one-month interval) by a less marked and slower antitoxin production than the normal controls. The patients treated at SAZU showed a more deviant behaviour in this respect, than did the “Zonnegloren” patients. A number of specifically designed animal experiments showed that administration of PAS had an unfavourable effect on development of immunity after the first P.T. injection. This fact might possibly explain the behaviour seen in the tuberculosis patients. It might also explain the marked difference in immunological reactivity between the SAZU and the “Zonnegloren” patients, because the former chiefly received this agent by intravenous drip, while the latter were given oral medication. It is possible that intravenous administration of PAS produces higher blood concentrations than oral administration.     

Characterising covalent warhead reactivity

Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.     

Biomimetic modeling of copper oxidase reactivity

Bioinspired copper-model-complexes that react with O(2) provide an opportunity to probe biological reactivity at a small-molecule level of detail. Biological structural information combined with appropriate ligand design has proven sufficient to create Cu:O(2) complexes capable of external substrate oxidation. Most notable developments during the review period are the bioinspired catalysts capable of aerobic alcohol-oxidation. The extension of this oxidative reactivity to other important organic transformations beyond the scope of the inspiring system completes a modeling paradigm.     

Chemical reactivity of some isothiazolone biocides

C ollier , P.J., R amsey , A., W aigh , R.D., D ouglas , K.T., A ustin , P. & G ilbert , P. 1990. Chemical reactivity of some isothiazolone biocides. Journal of Applied Bacteriology 69 , 578–584.
Chemical reactions between the isothiazolone biocides, N-methylisothiazol-3-one (MIT), benzisothiazol-3-one (BIT) and 5-chloro-N-methylisothiazol-3-one (CMIT) with cysteine have been investigated by u.v. and NMR spectroscopy. At physiological pH all three agents interacted oxidatively with thiols to form disulphides. Further interaction with thiols caused the release of cystine and formation of a reduced, ring-opened form of the biocide (mercaptoacrylamide). In an analogous fashion to the initial reaction the mercaptoacrylamide reacted with another molecule of biocide to give biocide dimers. NMR spectral studies indicated that for CMIT the mercaptoacrylamide form is capable of tautomerization to a highly reactive thio-acyl chloride. Formation of mercaptoacrylamide was in all cases highly pH-dependent. Alcohol dehydrogenase was insensitive to all three agents but was highly sensitive to CMIT when co-administered with dithiothreitol. Capacity to form a thioacyl chloride from the mercaptoacrylamide is suggested to account for much of this enhanced activity. Stopped-flow spectroscopic studies showed rates of reaction with glutathione (GSH) to directly parallel antimicrobial activity. Additionally, CMIT was able to react directly with both ionization states of GSH (pH 7–10) whilst BIT and MIT appeared only to interact when the glutamyl-nitrogen of GSH was charged (pH 8.5).     

Chemical reactivity of some isothiazolone biocides

Chemical reactions between the isothiazolone biocides, N-methylisothiazol-3-one (MIT), benzisothiazol-3-one (BIT) and 5-chloro-N-methylisothiazol-3-one (CMIT) with cysteine have been investigated by u.v. and NMR spectroscopy. At physiological pH all three agents interacted oxidatively with thiols to form disulphides. Further interaction with thiols caused the release of cystine and formation of a reduced, ring-opened form of the biocide (mercaptoacrylamide). In an analogous fashion to the initial reaction the mercaptoacrylamide reacted with another molecule of biocide to give biocide dimers. NMR spectral studies indicated that for CMIT the mercaptoacrylamide form is capable of tautomerization to a highly reactive thio-acyl chloride. Formation of mercaptoacrylamide was in all cases highly pH-dependent. Alcohol dehydrogenase was insensitive to all three agents but was highly sensitive to CMIT when co-administered with dithiothreitol. Capacity to form a thioacyl chloride from the mercaptoacrylamide is suggested to account for much of this enhanced activity. Stopped-flow spectroscopic studies showed rates of reaction with glutathione (GSH) to directly parallel antimicrobial activity. Additionally, CMIT was able to react directly with both ionization states of GSH (pH 7-10) whilst BIT and MIT appeared only to interact when the glutamyl-nitrogen of GSH was charged (pH 8.5).