■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks

Isolation and synthesis of biologically active carbazole alkaloids

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

New squaric acid/4-aminoquinoline hybrid compounds are synthesized by condensation of commercially available squarates with the heteroaromatic core of the antimalarial drugs chloroquine and primaquine.

Squaric Acid/4-Aminoquinoline Conjugates: Novel Potent Antiplasmodial Agents.

In this work, we studied the role played by the inactive sites present on the substrate of a growing surface. In our model, one particle sticks at the surface if the site where it falls is an active site. However, we allow the deposited particle to diffuse along the surface in accordance with some mechanism previously defined. Using Monte Carlo simulations, and some analytical results, we have investigated the model in ( 1 + 1 ) and ( 2 + 1 ) dimensions considering different relaxation mechanisms. We show that the consideration of non-active sites is a crucial point in the model. In fact, we have seen that the saturation regime is not observed for any value of the density of inactive sites. Besides, the growth exponent β turns to be one, at long times, whatever the mechanism of diffusion we consider in one and two dimensions.

Growth exponents in surface models with non-active sites

Enantioselective Formal Synthesis of ent-Rhynchophylline (I) and ent-Isorhynchophylline (II).

Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders.

Protein-protein interactions (PPIs) are essential in the regulation of many biological pathways including apoptosis and cell cycle arrest. When the balance of PPIs is altered pathologies can appear. In this chapter the authors give an overview of the importance of PPIs as therapeutic targets for anticancer drug discovery. Two case studies of the development of small molecule PPIs inhibitors are discussed in detail: the MDM2 inhibitor APG-115 and the BET bromodomain ligand I-BET762. Finally, a summary of the PPI inhibitors currently in clinical trials for cancer treatment is presented.

Maria M. M. Santos

Papers

Squaric Acid/4-Aminoquinoline Conjugates: Novel Potent Antiplasmodial Agents.

Growth exponents in surface models with non-active sites

Enantioselective Formal Synthesis of ent-Rhynchophylline (I) and ent-Isorhynchophylline (II).

Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders.

PPIs as therapeutic targets for anticancer drug discovery: the case study of MDM2 and BET bromodomain inhibitors