Current Chemical Biology - Volume 3, Issue 1, 2009

Human longevity is influenced by both inherited and environmental factors. Alterations in gene function that are related to inherited genetic mutations and polymorphisms can explain some features of aging and age-related diseases. However, in addition to inherited genetic factors, aging is influenced by the gradual accumulation of molecular alterations after birth. Epigenetic changes can influence gene function during aging without inherited and acquired DNA sequence alterations. In particular, promoter DNA methylation changes and associated gene silencing are epigenetic changes that are prominent in some cells and age-related diseases. Here, we review genetic approaches to understand aging, and discuss the potential role of epigenetic mechanisms in human aging and age-related diseases.

Protein misfolding causes a phenotype of disorders that is modulated by the action of multi-complexes formed by molecular chaperones and the proteasome machine. Hsp90 is a molecular chaperone involved in maintaining folding, stability and function of many proteins involved in apoptosis, signal-transduction pathways and cell-cycle regulation. Many of these proteins are usually deregulated in cancers and by keeping them active Hsp90 helps the stabilization of tumorogenic cells. Therefore, inhibition of Hsp90 will result in degradation of its client proteins via the proteasome followed by a down regulation of several properties of the malignant phenotype. As a consequence, Hsp90 has been considered to be an appealing target for cancer therapeutics because its inhibition can affect multiple oncogenic pathways simultaneously. Major efforts have generated Hsp90 inhibitors that passed Phase I clinical trials and have entered Phase II trials. Furthermore, other compounds are in development to improve efficacy as antitumor agents. In conclusion, the development of Hsp90 inhibitors is considered to be a good example of medicinal chemistry. Specific important aspects of Hsp90 structure and function, the role of the chaperone in cancer and the development of Hsp90 inhibitors that causes growth arrest and apoptosis in cancer cells are discussed.

Mammalian cells produce reactive oxygen species (ROS) which are carcinogens, key actors of the non-specific immune defense against pathogens and, in a more subtle way, of signal transduction, cellular metabolism and functions. Oxidative stress can induce severe damage to the host which in turn adapted to face oxidative injury. Disruption of redox balance leads to various pathological conditions, such as cancer. In this review we explore the network linking ROS, cancer cells, anti-tumor immunity and therapy. We emphasize recent findings regarding the oxidative tumor microenvironment and the correlation between ROS, proliferation and death of cancer cells. Further-on we highlight that granulocytes, as key inflammatory cells and ROS producers, are nowadays exploited for eradication of cancer cells. Finally, we focus on ROS-inducing anti-neoplastic therapies (radiotherapy and photodynamic therapy) and on controversial issues regarding the interference between chemotherapy, ROS and antioxidants. This review is directed mainly to researchers involved in anti-cancer drug development by pointing out that redox balance is a suitable therapeutic target, either alone or in combination with other pathways of cancer cells killing. We emphasize critical redoxcontrolled checkpoints that have to be taken into account in drug design for achieving good therapeutic efficiency and convenient side-effects.

Microtubules are important biological targets of antitumor chemotherapy. Tubulin polymerization inhibitors (TPIs) hinder polymerization whereas microtubule stabilizing agents (MSAs) promote tubulin polymerization and stabilize microtubules. The goal of enhancing binding affinity through favorable (positive) entropic contributions, a significant part of medicinal chemistry dogma, hinges on a rather simplistic assumption that ligand-protein binding interactions are primarily entropically driven. In turn, individual contributions of enthalpy and entropy to the overall potency of small molecules rarely are determined. Herein, we describe various antimitotic agents whose interactions with tubulin were explored and in which the individual enthalpic and entropic contributions were evaluated. These examples clearly demonstrate that the binding affinities of small molecules with their target proteins are more complex than often articulated; one should exercise caution when rationalizing the relative activity of these molecules and their analogues.

Several inflammatory mediators regulate the evolution of atherosclerosis. C-reactive protein (CRP) is an acutephase reactant, with a direct effect in inflammatory processes characterizing atherosclerosis. For this reason, CRP is actually considered as a factor, rather than simply a cardiovascular risk marker. The recent demonstration of CRP production not only by the liver, but also within atherosclerotic plaques by activated vascular cells, suggests a possible dual role, as both systemic and tissue molecule. Although more studies are needed, some therapeutic approaches to reduce CRP levels have been performed with encouraging results. Behavioral or pharmacologic interventions have been shown to reduce both CRP levels and the associated risk of cardiovascular acute events. Therefore, although most of national Cardiovascular Associations do not suggest high sensitivity CRP screening of the entire adult population as a public-health measure to stratify the cardiovascular risk, serum hs-CRP levels could be a promising target for therapies focused on reducing cardiovascular risk.

This review article deals with different aspects of imidazole derivatives with one nitrogen atom bearing a substituted or unsubstituted phenyl moiety, such as their presence in bioactive compounds, their activity, as well as the main strategies for their preparation.

To develop drugs to kill cancer cells, we chemically synthesized a number of anti-cancer agents by adding different side chains to the core backbone of saponin. With the use of bioassay-guided methods, we found one agent that possessed a high cytotoxicity to a number of cancer cell lines. Interestingly, this compound was later found to be an active component of a tradition Chinese herb Paris polyphylla known as Polyphyllin D (PD) (diosgenyl α-L-rhamnopyranosyl- (1→2)-(β-L-ara-binofuranosyl-(1→4)-β-D-glucopyranoside). In China, the rhizome of Paris polyphylla (Chong Lou) has been used as a traditional Chinese medicine to treat a number of cancers including pancreas and liver cancers for a long time. Results from our laboratory demonstrate that PD is a potent anti-cancer agent that bypasses multi-drug resistance (MDR) and induces programmed cell death in R-HepG2 cells over-expressing P-glycoprotein (P-gp). In this paper, we reviewed the mechanisms how PD overcomes the MDR and exhibits a stronger cytotoxicity in the R-HepG2 than its parent line without P-gp through mitochondrial injury.

Cystic Fibrosis, one of the most common inherited lethal disease among Caucasians, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The CFTR protein acts as a gated Cl- channel at the apical membrane of epithelial cells, thereby facilitating proper hydration of mucosal linings. Disease causing mutations in the CFTR protein can affect a variety of steps in the biogenesis of a functional protein including the folding and trafficking of CFTR as well as the channel activity of plasma membrane-localized protein. Therefore, current research is focused on the use of small molecules to not only correct folding defects but also to enhance channel activity of mutant CFTR proteins. This review discusses the current knowledge of the folding, trafficking, and gating defects caused by CFTR mutations, the manner by which these defects are monitored by the cell, as well as the strategies which are currently being utilized to develop and screen for small molecule therapeutics.

2-arylidene-1,3-indanediones undergo a regioselective 1,3-dipolar cycloaddition reaction with the azomethine ylide derived from isatin and proline to give a rare class of novel complex dispirooxindolopyrrolizidines in better yield under microwave irradiation than classical heating. X-ray crystal structure analysis of one of the product confirms the structure and regiochemical outcome of the cycloaddition reaction. Anti-microbial activity studies were carried out with all the newly synthesized dispiro-oxindolopyrrolizidines.