Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

Privileged Scaffolds for Library Design and Drug Discovery

Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.

Lymphocyte-Mediated Cytotoxicity

The development of new palladium catalysts for the arylation of amines and alcohols with aryl halides and sulfonates is reviewed. Initial systems as well as mechanistic issues are discussed briefly, while subsequent generations of catalysts are described in greater detail. For these later generations of catalysts, substrate scope and limitations are also discussed. The review is organized by substrate class. Modifications and improvements in technical aspects of reaction development are described where appropriate. In addition, applications of this technology toward natural product synthesis, new synthetic methodology, and medicinal chemistry are chronicled. This review is organized in a manner that is designed to be useful to the synthetic organic chemist.

Practical Palladium Catalysts for C-N and C-O Bond Formation

Cytotoxic T lymphocytes (CTLs) provide potent defences against virus infection and intracellular pathogens. However, CTLs have a dark side--their lytic machinery can be directed against self-tissues in autoimmune disorders, transplanted cells during graft rejection and host tissues to cause graft-versus-host disease, which is one of the most serious diseases related to CTL function. Although this duplicitous behaviour might seem contradictory, both beneficial and detrimental effects are the result of the same effector proteins. So, an understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies.

/pdf/cytotoxic-t-lymphocytes-all-roads-lead-to-death-27xkawbqy3.pdf

Cytotoxic T lymphocytes: all roads lead to death

The present invention is directed to pyrrolidine compounds of formula (I) wherein R?1, R2, R3, R4, R5, R6? and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.

Pyrrolidine modulators of chemokine receptor activity

The present invention is directed to pyrrolidine and piperidine compounds of formula (I), (wherein R?1, R2, R3, R4a, R4b, R4c, R4d, R4e, R4f, R4g, R4h?, m, n, x and y are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.

Pyrrolidine and piperidine modulators of chemokine receptor activity

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(01)00018-7.pdf

The three-dimensional structure of human granzyme B compared to caspase-3, key mediators of cell death with cleavage specificity for aspartic acid in P1.

Christopher A. Willoughby

Papers

Pyrrolidine modulators of chemokine receptor activity

Pyrrolidine and piperidine modulators of chemokine receptor activity

The three-dimensional structure of human granzyme B compared to caspase-3, key mediators of cell death with cleavage specificity for aspartic acid in P1.

Discovery of potent, selective human granzyme B inhibitors that inhibit CTL mediated apoptosis.

Solid phase synthesis of aryl amines