Current Medicinal Chemistry - Volume 16, Issue 11, 2009

Since the introduction into clinical practice of vinca alkaloids, tubulin has become a key and well-established target of modern antineoplastic chemotherapy. When taxanes became available their broad spectrum of activity was striking and opened up new horizons for cancer patients' treatment. However, taxanes' susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein, is not infrequent and their use may be limited by poor solubility, synthetic problems and toxicity. The epothilones are a new class of chemotherapeutic agents with a mechanism of action similar to that of taxanes, but different enough to escape, for example, the multidrug resistance caused by P-glycoprotein. Moreover, the epothilones (that are strong promoters of tubulin polymerization) have significant antitumor activity against human cancer cells that are taxane-resistant, express the multidrug resistance gene MDR-1, and have acquired tubulin mutations. Finally, starting from the natural molecules, several synthetic analogues have been developed. Besides their antineoplastic efficacy, all the antitubulin drugs share a common toxicity on the peripheral nervous system and peripheral neurotoxicity is a major, potentially dose-limiting side effect also of the epothilones. The current knowledge regarding the features of epothilones' peripheral neurotoxicity and their comparison with taxanes will be reviewed.

The chemical properties of copper allow it to take part in many biological functions such as electron transfer, catalysis, and structural shaping. The ability to cycle between +1 and +2 oxidation state is one of the features that has been exploited by organisms throughout the evolutionary process. Since copper is potentially toxic to cells also a finely controlled mechanism for copper handling has evolved. On the other side, many copper complexes were synthesized and tested for their anticancer activity in vitro and in vivo. Their ability to kill cancer cells is mainly related to the induction of an oxidative stress, but recently it emerged their ability to inhibit the proteasome, a protein complex whose proteolitic activity is needed by several cellular process. It has generally been described that the toxic effects of copper complexes leads to cell death either by necrosis or through the activation of the apoptotic process. Evidences are rising about the ability of some copper compounds to induce alternative non-apoptotic form of programmed cell death. Since copper is indispensable for the formation of new blood vessels, angiogenesis, a different antitumor approach based on the administration of copper sequestering agents has been attempted and its effectiveness is currently under evaluation by clinical trials. The proven essentiality of copper for angiogenesis, together with the marked sensitivity shown by several cancer cell lines to the copper toxicity, open a new perspective in the anticancer strategy: exploiting the tumor need of copper to accumulate toxic amount of the metal inside its cells.

Matrix metalloproteinase-9 (MMP-9) plays an important role in the onset and prognosis of myocardial infarction. Targets of angiotensin converting enzyme (ACE) inhibitors might include not only ACE but also MMP-9, and ACE seems to be closely associated with complications of hypertension such as cardiovascular remodeling whereas MMP-9 is closely related to coronary diseases. We postulate that ACE inhibitors prevent coronary diseases via direct MMP-9 inhibition and could interact with the MMP-9 active sites using specific modes similar to those used for the ACE active sites. Research of the molecular interaction between MMP-9 active sites and ACE inhibitors appears to be an important key in the development of effective MMP-9 inhibitors for cardiovascular protection.

Signaling through the Rho family of small GTPases has been increasingly investigated for their involvement in a wide variety of diseases such as cardiovascular, pulmonary, and neurological disorders as well as cancer. Rho GTPases are a subfamily of the Ras superfamily proteins which play essential roles in a number of biological processes, especially in the regulation of cell shape change, cytokinesis, cell adhesion, and cell migration. Many of these processes demonstrate a common theme: the rapid and dynamic reorganization of actin cytoskeleton of which Rho signaling has now emerged as a major switch control. The involvement of dynamic changes of Rho GTPases in disease states underscores the need to produce effective inhibitors for their therapeutic applications. Fasudil and Y-27632, with many newer additions, are two classes of widely used chemical compounds that inhibit Rho kinase (ROCK), an important downstream effector of RhoA subfamily GTPases. These inhibitors have been successful in many preclinical studies, indicating the potential benefit of clinical Rho pathway inhibition. On the other hand, except for Rac1 inhibitor NSC23766, there are few effective inhibitors directly targeting Rho GTPases, likely due to the lack of optimal structural information on individual Rho-RhoGEF, Rho- RhoGAP, or Rho-RhoGDI interaction to achieve specificity. Recently, LM11A-31 and other derivatives of peptide mimetic ligands for p75 neurotrophin receptor (p75NTR) show promising effects upstream of Rho GTPase signaling in neuronal regeneration. CCG-1423, a chemical compound showing profiles of inhibiting downstream of RhoA, is a further attempt for the development of novel pharmacological tools to disrupt Rho signaling pathway in cancer. Because of a rapidly growing number of studies deciphering the role of the Rho proteins in many diseases, specific and potent pharmaceutical modulators of various steps of Rho GTPase signaling pathway are critically needed to target for therapeutic intervention in cardiovascular disease, neurological disorders, and cancer progression.

Spinal cord injury (SCI) is a devastating condition generally leading to a permanent and irreversible loss of sensory and motor functions. We have identified recently a number of serotonergic, adrenergic and dopaminergic receptor agonists or precursors that can acutely elicit some motor and locomotor-like movements in completely spinal cordtransected (thoracic level) animals. However, only partial central network-activating effects were found with single molecules since none administered separately could elicit weight-bearing and functional stepping movements in Tx animals. In turn, a recent breakthrough revealed that full spinal locomotor network-activating effects may be induced with synergistic drug combinations. Indeed, specific cocktails comprising some of these agonists and precursors were found, indeed, to powerfully generate weight-bearing stepping with plantar foot placement in untrained, non-assisted and non-sensorystimulated Tx mice. This significant finding provides clear evidence suggesting that combinatorial approaches based on drug-drug synergistic interactions may constitute innovative solutions for the design and development of novel pharmacological therapies in the field of SCI and related neurological disorders.

NAD(P) biosynthetic pathways can be considered a generous source of enzymatic targets for drug development. Key reactions for NAD(P) biosynthesis in all organisms, common to both de novo and salvage routes, are catalyzed by NMN/NaMN adenylyltransferase (NMNAT), NAD synthetase (NADS), and NAD kinase (NADK). These reactions represent a three-step pathway, present in the vast majority of living organisms, which is responsible for the generation of both NAD and NADP cellular pools. The validation of these enzymes as drug targets is based on their essentiality and conservation among a large variety of pathogenic microorganisms, as well as on their differential structural features or their differential metabolic contribution to NAD(P) homeostasis between microbial and human cell types. This review describes the structural and functional properties of eubacterial and human enzymes endowed with NMNAT, NADS, and NADK activities, as well as with nicotinamide phosphoribosyltransferase (NamPRT) and nicotinamide riboside kinase (NRK) activities, highlighting the species-related differences, with emphasis on their relevance for drug design. In addition, since the overall NMNAT activity in humans is accounted by multiple isozymes differentially involved in the metabolic activation of antineoplastic compounds, their individual diagnostic value for early therapy optimization is outlined. The involvement of human NMNAT in neurodegenerative disorders and its role in neuroprotection is also discussed.

Nucleoside analogs are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome), cytomegalovirus infections, cancer etc. However, most of these compounds suffer from poor bioavailability via oral route. In order to get around this drawback, researchers have imagined many strategies including drug metabolism inhibitors, bio adhesive nanoparticles, amino ester prodrugs, as well as enhancing absorption by increasing drug lipophilicity. This paper illustrated these approaches by developing their application to some nucleoside analogs. Moreover, some of these strategies were very successful and some resulting compounds are now approved by FDA (Food and Drug Administration).

Idiopathic Pulmonary Fibrosis (IPF) is characterized by injury and loss of lung epithelial cells, accumulation of fibroblasts/myofibroblasts and abnormal remodeling of the lung parenchyma. The prognosis for IPF patients is poor and current therapies are largely ineffective in preventing respiratory failure. Current therapeutic approaches target epithelial cell replacement, manipulation of fibroblasts/myofibroblasts, modulation of procoagulant/fibrinolytic activities, cytokine and growth factor production, angiogenesis, and reduction of oxidative stress. Myofibroblasts are the primary effector cells in fibrosis. These cells may be derived by the activation and proliferation of resident lung fibroblasts, from epithelialmesenchymal transition (EMT), or through recruitment of circulating fibrocytes. Transforming growth factor β (TGFβ) is a profibrotic factor that increases fibroblast proliferation, stimulates the synthesis and deposition of connective tissue, and inhibits connective tissue breakdown. TGFβ acts through the promoter of the type 1 collagen gene causing increased collagen synthesis. In addition, TGFβ induces EMT in alveolar epithelial cells (AECs) in vitro and in vivo. AECs exhibit substantial plasticity and may serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. Therapeutic interventions interfering with the pathways that lead to myofibroblast expansion and AEC apoptosis should be of considerable benefit in the treatment of IPF. This review will focus on the critical role of TGFβ on AECs EMT and myofibroblasts in the development of fibrosis.

The role of progesterone (PROG) in the regulation of reproductive behavior is well understood, but a large and growing body of evidence indicates that this hormone also exerts neuroprotective effects on the central nervous system (CNS), i.e. in spinal cord injuries, traumatic brain injuries and in the age-related pathological process. Its neuroprotective actions, now well documented by experimental studies, make it a particularly promising therapeutic agent for neuroinjury and neurodegenerative diseases. The purpose of this article is to review recent preclinical and epidemiological evidences that exogenous administration of PROG or its metabolites plays an important role in the CNS. The diverse signaling mechanisms and the dose- dependent neuroprotective actions of PROG are also summarized. Awareness of the pleiotropic effects of PROG may open a novel perspective for the treatment of injuries and diseases in the nervous system. PROG could be produced in the brain by neurons and glial cells in the CNS of both male and female. Laboratories around the world have reported that administering relatively large doses of PROG during the first few hours or even days after injury significantly limits CNS damage, reduces loss of neuronal tissue and improves functional recovery. PROG appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing the development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All these are plausible mechanisms of neuroprotection.

Diaryl-substituted bicyclic amines are a scarcely investigated class of compounds. Only few of them are described and their biological activities are reported poorly. During our work in the field of heterocyclic chemistry, we found that 4-dialkylaminobicyclo[2.2.2]octan-2-ones and -ols show antiprotozoal properties against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense, the causative organisms of Malaria tropica and of Human African Trypanosomiasis. Therefore, we synthesized over 200 derivatives in order to investigate their antitrypanosomal and antiplasmodial activities as well as their cyctotoxicity using in vitro microplate assays. Even if the target and the mechanism of action of these compounds are still unknown, we can at least provide several structure-activity relationships for this interesting class of compounds. Moreover, we achieved a distinct improvement of their antiplasmodial and antitrypanosomal properties.