Preface

Abstract

The macrolactam natural product, FK506 (Tacrolimus), acts as apowerful and clinically useful immnosuppressant through disruption ofsignaling events mediated by the calciumdependent serine/threonineprotein phosphatase, calcineurin (CaN), in T lymphocytes. Its mechanism of action involves the formation of a molecular complex with the intracellula FK506binding protein-12 (FKBP12), thereby acquiring the ability to interactwith CaN and to interfere w i t h i t s a c c e s s t o a n d d e p h o s p h o r y l a t i o n o f v a r i o u s s u b s t r a t e s . A m o n g the CaN substrates whose activity is altered by FK506, the nuclear factors of activated T cells (NFAT), a family of transcription factors regulating lymphokine gene expression, have been shown to play a prominent role in FK506-induced immunosuppression. Over the past few years, additional members of the FKBP and NFAT families of proteins have been identified, providing further insights into the complexity of FK506 biological effects. Furthermore, it has become clear that, predominantly as a result of CaN inhibition, FK506 alters multiple biochemical processes in a variety of cells besides lymphocytes. This may account for the adverse side effects of the drug, including neurotoxicity and nephrotoxicity. Extensive medicinal chemistry efforts have been devoted to the generation of analogs of FK506 with the hope of identifying compounds with an improved therapeutic index, that could have broader therapeutic utility than the parent drug. These efforts yielded several compounds with unique biochemical attributes, showing evidence for a dissociation between immunosuppressive and toxic properties, which may pave the way towards designing safer FK506-related immunosuppressants.

Action mechanisms of boundary lubrication additives — A review, Part I

“…propagated by: rS,t + RCH=CH,4 rS,'CH(R)-CH,' \ TS,'CH(R)-CH, + RCH + CH' TS,' CH(R)-CH,' + RCH=CH, TS,tCH(R)=CH, + RCH,CH,' RCH + CH' RCH + CHS,' + s, -3 RCH,CH, RCH,CH,S,' Lubrication Science 16-4, August 2004. (16) 410 ISSN 0954-0075 $50.00 -A review, Part I The termination step may be given as: RCH + CH' RCH,CH, + rS; + RCH,CH,S,r RCH + CHSJ TS,'CH(R)-CH, rS:CH( R)-CH,S,T…”