Correlation between energetics of collisionally activated decompositions, interaction energy and biological potency of carbamate FAAH inhibitors

Abstract

Correlation between energetics of collisionally activated decompositions, interaction energy and biological potency of carbamate FAAH inhibitorsMass spectrometry (MS) might usefully be employed to study the mechanism of action, the structure-activity relationships (SARs) or the side effects of pharmacologically active compounds that undergo bioactivation to electrophilic intermediates or nucleophilic attack prior to the development of their effects, although the literature mainly report examples in which MS was employed to characterize reactive metabolites. 1 Quite early we used MS techniques to establish quantitative SARs for some potential anticancer agents (aryl and heteroaryl triazenes), 2 -4 and more recently for novel inhibitors of the fatty acid amide hydrolase (FAAH) enzyme. 5 The latter compounds are characterized by an N-alkylcarbamic acid O-aryl ester structure, and they can be exemplified by the irreversible and systemically active inhibitor cyclohexylcarbamic acid 3 0 -carbamoylbiphenyl-3-yl ester (URB597). 6 The chemical rationalization of the mode of action of these FAAH inhibitors and their SARs were approached by modeling studies 7 -9 and also by MS techniques. 5 Irreversible enzyme inactivation is envisaged to occur through two distinct and consecutive processes (Scheme 1), i.e. formation of a noncovalent complex (recognition step), and nucleophile attack to the carbamate by Ser241 10,11 leading to its carbamoylation and to irreversible inactivation of the enzyme (inactivation step). The recognition step is related to stereoelectronic complementarity between the inhibitor and the active site of the enzyme and it was rationalized by molecular modeling studies, 8,9 whereas the inactivation reaction may be related to the propensity of the C(O)-O bond to be cleaved and it may be described by suitable indicators of bond reactivity. In this particular case, the second step was studied by breakdown curves, 12 relative to ESI-generated protonated molecules, which, taking place under collisional conditions during resonance excitation in an ion trap, exclusively gave fragments related to the C(O)-O bond cleavage. 5 The crossing points (CPs) (corresponding to the collision energy necessary to fragment 50% of the precursor ion population) between the decreasing [MH] C ion abundance and the increasing ion fragment abundance w (Scheme 2) were related to the energetics Ł Correspondence to: P. Traldi, CNR-ISTM, Corso Stati Uniti 4,

The relationship between electrospray ionization behavior and cytotoxic activity of [MI(P)4]+‐type complexes (M = Cu, Ag and Au; P = tertiary phosphine)

“…[14,15] A linear relationship between the energetics of C(O)-O bond cleavage of some carbamic acid O-aryl esters and their fatty acid amide hydrolase (FAAH) inhibition activity has been proved by electrospray ionization (ESI) ion-trap mass spectrometry. [16][17][18] In the frame of our ongoing interest in the use of phosphino metal complexes in medicinal chemistry, we extended the syntheses of [Cu(P) 4 ] + -type species to heavier group 11 metals by preparing [Ag(P) 4 ] + and [Au(P) 4 ] + compounds (P = PTA, thp and tris-(hydroxypropyl)phosphine (thpp)). These compounds were tested for their cytotoxic activity on a panel of human tumor cell lines in comparison with homologous [Cu(P) 4 ] + complexes.…”

“…For example, electron ionization and metastable ion studies provide evidence of the correlation between the mutagenic properties of a series of aryl and heteroaryl triazenes and mass spectrometric data . A linear relationship between the energetics of C(O)–O bond cleavage of some carbamic acid O ‐aryl esters and their fatty acid amide hydrolase (FAAH) inhibition activity has been proved by electrospray ionization (ESI) ion‐trap mass spectrometry …”

The relationship between the electrospray ionization behaviour and biological activity of some phosphino Cu(I) complexes

“…Thus, for example, the electron ionization induced fragmentation of some aryl‐ and heteroaryl‐triazenes has been correlated to their mutagenic and antimetastatic properties 1, 2. More recently, a class of systematically active inhibitors of the intracellular activity of fatty acid amide hydrolase (FAAH) has been studied by mass spectrometry 3–5. These compounds, characterized by an N ‐alkylcarbamic acid O ‐aryl ester structure, show an easy collisionally induced cleavage of the C(O)–O bond and the energetic of this decomposition process was found to be linearly correlated with their FAAH‐inhibitory activity.…”

The power of energy‐resolved tandem mass spectrometry experiments for resolution of isomers: the case of drug plasma stability investigation of multidrug resistance inhibitors

“…It is interesting to observe that the plasma stability results described above can be related to the energetics of decomposition determined by ERMS [22][23][24] and represented by CP values (Table 1). Apparently, the energetic data seem to be just the opposite of that obtained in plasma, i.e.…”