Unexpected small molecules as novel SIRT2 suicide inhibitors

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.     

Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase

Lysyl oxidase initiates the covalent cross-linking of elastin and collagen, converting lysyl residues in these proteins to peptidyl aldehyde residues. The present study explored structural and electron withdrawing features required to generate mechanism-based inhibitors of this enzyme with antifibrotic potential. It was found that the electron withdrawing nitrile moiety of beta-aminopropionitrile (BAPN), a naturally occurring syncatalytic inhibitor of lysyl oxidase, can be replaced by chlorine, bromine, or the nitro function to yield 2-haloamines or nitroethylamine compounds which also act as mechanism-based irreversible inhibitors of this enzyme. BAPN and 2-bromo- and 2-chloroethylamine exhibit similar KI values of 6-10 microM. However, the enzyme becomes irreversibly inactivated significantly faster by either of the 2-haloamines than by BAPN. 2-Nitroethylamine has by far the poorest affinity for the enzyme and inactivates much more slowly than the other amines of this series, consistent with interference with optimal enzyme-inhibitor interactions by the anionic nitro group. Unlike BAPN, 2-bromoethylamine is processed to a detectable aldehyde product upon incubation with enzyme, showing a partition ratio of 1.2 mol of acetaldehyde formed per mol of 2-bromo-ethylamine which becomes covalently incorporated in the enzyme. The results are consistent with the processing of 2-bromo-ethylamine to an enzyme-ethyleneamine Schiff base subject to hydrolysis to acetaldehyde or to covalent attack at carbon 2 by an enzyme nucleophile. Thus, beta-haloamines represent a new series of suicide inhibitors of lysyl oxidase which can inactivate the enzyme faster than BAPN and hence may have antifibrotic potential.     

Ars moriendi: Proteases as sculptors of cellular suicide

The Ars moriendi, which translates to “The Art of Dying,” encompasses two Latin texts that gave advice on how to die well and without fear according to the Christian precepts of the late Middle Ages. Given that ten to hundred billion cells die in our bodies every day, it is obvious that the concept of a well and orderly (“regulated”) death is also paramount at the cellular level. In apoptosis, as the most well-studied form of regulated cell death, proteases of the caspase family are the central mediators. However, caspases are not the only proteases that act as sculptors of cellular suicide, and therefore, we here provide an overview of the impact of proteases in apoptosis and other forms of regulated cell death.     

Kinetic characterization of dopamine as a suicide substrate of tyrosinase

A kinetic study of the inactivation of frog epidermis tyrosinase by a suicide substrate dopamine hydrochloride is described. The kinetic parameters and constants which characterize this reaction have been determined and the effects of pH and the stoichiometric inhibition by chloride have been considered.     

Inactivation of potato lipoxygenase by hydroperoxy acids as suicide substrates

The preincubation of potato lipoxygenase with 9(S)-hydroperoxyoctadecatrienoic acid, 15(S)-hydroperoxyeicosatetraenoic acid or 5(S)-hydroperoxyeicosatetraenoic acid which can be subjected to further lipoxygenation led to the gradual inactivation of the lipoxygenase activity, whereas 13(S)-hydroperoxy-9,13,15-octadecatrienoic acid or 15(S)-hydroperoxy-11,13,17-eicosatrienoic acid had no significant effect. The inhibitory effect of the peroxy acids was abolished by hemoglobin. Based on these observations, it is proposed that the unstable epoxide intermediates from the respective peroxy acids may be responsible for the inactivation of potato lipoxygenase. In the comparative study, it was found that 15(S)-hydroperoxyeicosatetraenoic acid possessed more effective inhibitory role than the other acids with Ki value of 250 microM.     

Evolutionary suicide

The great majority of species that lived on this earth have gone extinct. These extinctions are often explained by invoking changes in the environment, to which the species has been unable to adapt. Evolutionary suicide is an alternative explanation to such extinctions. It is an evolutionary process in which a viable population adapts in such a way that it can no longer persist. In this paper different models, where evolutionary suicide occurs are discussed, and the theory behind the phenomenon is reviewed.     

Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide.

OBJECTIVE--To evaluate a policy to reduce the incidence of suicide by means of changing the prescribing of antidepressants from the older tricyclic antidepressants to the routine first line use of selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants. DESIGN--Cost effectiveness analysis with sensitivity analyses using observational data on costs, volume of prescribing, deaths, and toxicity. SETTING--United Kingdom primary care. INTERVENTIONS--Selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants compared with the use of older tricyclics. MAIN OUTCOME MEASURES--Cost per life saved and cost per life year saved. RESULTS--The potential number of lives which may be saved from a switch to the routine first line use of selective serotonin reuptake inhibitors is between 300 and 450 each year. The cost per life year gained ranges from 19,000 pounds to 173,000 pounds, depending on the assumptions used. The cost per life year gained through the use of the newer tricyclic and related antidepressants is considerably lower. CONCLUSIONS--The cost per life year gained through avoiding suicides by the routine first line use of serotonin reuptake inhibitors is likely to be high. The new tricyclics and related drugs are of similar toxicity to the serotonin reuptake inhibitors but are considerably cheaper and so are most cost effective for this purpose. Further research is required on such prescribing. Because of the great uncertainties the shift to considerably more expensive options must be further investigated.     

Kinetic characterisation of o-aminophenols and aromatic o-diamines as suicide substrates of tyrosinase

We study the suicide inactivation of tyrosinase acting on o-aminophenols and aromatic o-diamines and compare the results with those obtained for the corresponding o-diphenols. The catalytic constants follow the order aromatic o-diamineso-aminophenols>aromatic o-diamines.     

Neuroeconomics of suicide

Suicidal behavior is a leading cause of injury and death worldwide. Suicide has been associated with psychiatric illnesses such as depression and schizophrenia, as well as economic uncertainty, and social/cultural factors. This study proposes a neuroeconomic framework of suicide. Neuroeconomic parameters (e.g., risk-attitude, probability weighting, time discounting in intertemporal choice, and loss aversion) are predicted to be related to suicidal behavior. Neurobiological and neuroendocrinological substrates such as serotonin, dopamine, cortisol (HPA axis), nitric oxide, serum cholesterol, epinephrine, norepinephrine, gonadal hormones (e.g., estradiol and progesterone), dehydroepiandrosterone (DHEA) in brain regiouns such as the orbitofrontal/dorsolateral prefrontal cortex and limbic regions (e.g., the amygdala) may supposedly be related to the neuroeconomic parameters modulating the risk of suicide. The present framework puts foundations for "molecular neuroeconomics" of decision-making processes underlying suicidal behavior.     

Supporting irrational suicide

In this essay, we present three case studies which suggest that sometimes we are better off supporting a so–called irrational suicide, and that emotional or psychological distress – even if medically controllable – might justify a suicide. We underscore how complicated these decisions are and how murky a physician's moral role can be. We advocate a more individualized route to end–of–life care, eschewing well–meaning, principled, generalizations in favor of a highly contextualized, patient–centered, approach. We conclude that our Western traditions of promoting reasoned behavior and life themselves may at times be counter–productive.     

Is suicide preventable

Among 500 cases of suicide analyzed in Stockholm, fewer than a third were associated with depression. Most forms of psychiatric disease were represented. Nevertheless, most persons give some warning before attempting suicide, and these warnings should be the signal for preventive action. Centers with trained personnel could prevent many suicides, if the potential victims were recognized and referred early enough. Laymen too should be educated to recognize potential suicide and help avert it.