RESUMEN
As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a range of homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding beta-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral alpha,beta-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral alpha,beta-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the beta-amino ester products of conjugate addition gives access to polyoxygenated beta-amino acid derivatives.
Asunto(s)
Amidas/química , Dioxolanos/química , Ésteres/química , Aminoácidos/síntesis química , Litio/química , EstereoisomerismoRESUMEN
ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K(d) = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.
Asunto(s)
Adenina/análogos & derivados , Diseño de Fármacos , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinas/farmacología , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Adenosina/análogos & derivados , Dominio Catalítico , Humanos , Conformación Molecular , Docilidad , Unión Proteica , Pirrolidinas/síntesis química , Relación Estructura-ActividadRESUMEN
The characterization of the transition state structure of a number of N-ribosyltransferases has enabled the design and synthesis of some extremely powerful inhibitors of these enzymes. We have three generations of inhibitors for some nucleoside processing enzymes which are therapeutic targets, and the potency of these compounds confers special advantages in their development as new drugs against cancer, autoimmune diseases, microbial infections and malaria.
Asunto(s)
Inhibidores Enzimáticos/química , N-Glicosil Hidrolasas/antagonistas & inhibidores , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Animales , Bovinos , Humanos , N-Glicosil Hidrolasas/química , Purina-Nucleósido Fosforilasa/químicaRESUMEN
Transition state analogues of PNP, the Immucillins and DADMe-Immucillins, were designed to match transition state features of bovine and human PNPs, respectively. A third generation of inhibitors has been designed that contain an acyclic iminoalcohol to replace the cyclic mimic of the ribooxacarbenium ion at the transition states of PNPs. The best third generation inhibitor is equivalent to the best inhibitors found in the previous transition state analogues.
Asunto(s)
Plasmodium falciparum/enzimología , Purina-Nucleósido Fosforilasa/química , Purina-Nucleósido Fosforilasa/metabolismo , Pirimidinonas/química , Pirrolidinas/química , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Humanos , Iminas/química , Iminas/metabolismo , Iminas/farmacología , Cinética , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Pirrolidinas/metabolismo , Pirrolidinas/farmacologíaRESUMEN
Defined contribution or consumer-driven health approaches will shift to employees not just the risks and rewards of the managed care system, but also decisions that will determine whether that system can survive. This article reviews the current state of the employer-sponsored health care system, describes defined contribution and consumer-driven health plan concepts, and outlines the approaches and steps employers can take to implement them. The author argues that, if fully implemented, such approaches could salvage the embattled managed care system by giving employees a financial stake in controlling medical costs while educating them to wisely take control of health plan spending decisions.