Current Medicinal Chemistry - Volume 9, Issue 21, 2002

Lung cancer is the leading cause of death from cancer in most developed nations. The most common type of lung cancer is of non-small cell histology, representing approximately 80% of the total. Despite aggressive treatments in early stages and improvement of polychemotherapy outcomes in advanced disease, the five years survival rate for lung cancer remains under 15%. Fortunately, our improved knowledge of tumor biology and mechanisms of oncogenesis suggests several new potential targets for clinical research in cancer therapy. A substantial body of evidence indicates that cyclooxigenase (COX)-2 and prostaglandins (PGs) play an important role in tumorigenesis. Mechanisms involved in COX-2 participation in tumorigenesis and tumor growth include xenobiotic metabolism, angiogenesis stimulation, inhibition of immune surveillance and inhibition of apoptosis. COX-2 is frequently overexpressed in bronchial premalignancy, lung adenocarcinoma and squamous cell carcinoma and COX-2 overexpression is a marker of poor prognosis in surgically resected stage I non-small cell lung cancer. Treatment with COX-2 inhibitors reduces the growth of NSCLC cells in vitro and in xenograft studies. Recent studies have defined some of the mechanisms involved in COX-2 participation in NSCLC development and diffusion. These evidences support the hypothesis that selective COX-2 inhibitors (coxibs) may prove beneficial in the prevention and treatment of NSCLC.

During our investigation in pyrrole antibacterial area we have identified a subclass with a good potent in vitro activity against mycobacteria and fungi. We have individuated the salient structural feature and BM 212 as lead for the class. SAR studies allowed us to synthesize several analogue derivatives. Some of them revealed more active than BM 212 against mycobacteria, but they lost antifungal activity. In particular the Protection Index (PI) was very interesting for some derivatives, comparable to that of reference compounds, Isoniazid (INH), Streptomycin (SM) and Rifampin (RF). Many of the synthesized compounds revealed active against intracellular mycobacteria and they showed to be inhibitory to drug-resistant mycobacteria of clinical origin. On the base of microbiological results we have hypothesized a pharmacophore model that was also optimized. The rational design, and the evaluation of the in vitro activity against mycobacteria are described.

The core or the building block is an important component in drug development. In this article, we propose and review p-aminobenzoic acid (PABA) as a building block used in the design of drugs or drug candidates. PABA is frequently found as a structure moiety in drugs. For example, in a database of 12111 commercial drugs, 1.5% (184 drugs) were found to contain the PABA moiety. These drugs have a wide range of therapeutic uses, such as: sun-screening, antibacterial, antineoplastic, local anesthetic, anticonvulsant, antiarrhythmic, anti-emetic, gastrokinetic, antipsychotic, neuroleptic, and migraine prophylactic. This article reviews the molecular targets and the mechanisms of these activities. Drugs containing PABA also show a wide range of structural diversity. Of the 184 PABA containing drugs identified, 95 different substitutions were found at the carboxylic group and 61 were found at the amino group of the building block. Substitution on the aromatic ring was also diverse. 13, 3, and 13 different side chains were found to modify positions 2, 3 and 5 of the aromatic ring respectively. In some drugs, the amino group is further substituted to form tertiary amine (4 different side chains). Substitutions at the carboxyl and amino groups of PABA are particularly suitable for the generation of combinatorial libraries. Just by reshuffling the identified side chains of the 184 PABA containing drugs, 4.5 million compounds can be generated. Consequently, PABA fits well as a building block for a general chemical library of “drug-like” molecules with a wide range of functional and structural diversity.

Cells of the macrophage lineage play an important role in initial infection with HIV-1 and contribute to the pathogenesis of the disease throughout the course of infection. Both blood monocytes and tissue macrophages can be infected with HIV-1 in vivo and in vitro, although the latter are more susceptible to infection. They express the CD4 receptor and chemokine coreceptors for HIV-1 entry, and hence are targets for HIV-1 infection. Cells of the macrophage lineage can be infected predominantly with macrophage (M)-tropic strains, although infection with some T cell line (T)-tropic strains or dual-tropic isolates of HIV-1 (exhibiting features of both M-tropic and T-tropic isolates) has also been reported. Following infection with HIV-1, monocyte / macrophages are resistant to cytopathic effects and persist throughout the course of infection as long-term stable reservoirs for HIV-1 capable of disseminating the virus to tissues. Infectious virus can be recovered from blood monocytes obtained from patients receiving highly active antiretroviral therapy with no detectable HIV-1 in blood. Cells of the macrophage lineage play an important role in the neuropathogenesis of HIV-1 infection and contribute to HIV-induced dementia via production of proinflammatory cytokines and neurotoxins. Following HIV-1 infection, effector functions carried out by monocyte / macrophages are also impaired, including phagocytosis, intracellular killing, chemotaxis and cytokine production. Such defects contribute to the pathogenesis of AIDS by allowing reactivation and development of opportunistic infections. This review focuses on the overall role of monocytes and macrophages in the pathogenesis of HIV-1 infection and considers the mechanisms underlying defective monocyte / macrophage function.

A literature review on the human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). This review includes its life cycle, HIV protease structure, function, and substrates, as well as the mechanism and the design of inhibitors including the clinically approved drugs. Moreover the review mentioned the problems that hindered the development of peptidomimetic drug candidates as HIV protease inhibitors and the different approaches used by medicinal chemists to overcome these problems. A special attention was made to the design rationale as well as the lead optimization processes that provided inhibitors that possess high potency, reduced molecular weight and lower lipophilicity of the allophenylnorstatine (Apns) containing HIV protease inhibitors.

Adenosine modulates several physiological functions in the CNS and in peripheral tissues via membrane receptors which have been classified into four adenosine subtypes. A1 activation produces neuronal depression: this inhibition allows A1 agonists to produce ischemic tolerance and protection in neuronal tissue.In order to selectively reproduce these effects, several A1 selective ligands have been synthesised and evaluated to understand how they interact with the adenosine A1 receptor. The investigation methods include SAR studies using native and chemically modified A1 receptors, molecular cloning of native and mutant adenosin A1 receptors, molecular modeling and thermodynamic analysis of drug-receptor interaction. Despite the great quantity of information available on the adenosine A1 receptor, no A1 agonist has so far entered in clinical use against brain diseases in view of the side effects, moreover selective A1 agonists appear to be poorly adsorbed into the brain and can be quickly degraded in vivo or in the whole blood.In an attempt to overcome these problems studies have been undertaken dealing with the use of partial agonists to inhibit side-effects and the employment of prodrugs to increase stability and diffusion through lipid barriers of A1 ligands. Other attempts involve either the use of A1 receptor enhancers as modulators able to locally enhance the action of endogenously produced adenosine, or the encapsulation of A1 agonists in drug delivery systems targeted to the brain.In this review, these approaches will be described together with the effects of adenosine A1 receptor ligands and their binding mechanisms on the central nervous system.