Mini Reviews in Medicinal Chemistry - Volume 7, Issue 2, 2007

myo-Inositol monophosphatase has long been a target for drug discovery. Recent work has given detailed insight into its mechanism and dynamics plus new activities and some novel series of inhibitors. The goal of a bio-available inhibitor for this enzyme, however, remains a major challenge for medicinal chemistry.

Exhaled breath analysis for clinical diagnosis and therapeutic monitoring is described with special reference to the techniques used and the underlying chemistry and physics involved. Brief outlines are given of the research carried out to date, and prospects for the future of this potentially valuable non-invasive technique are indicated.

Various classes of cytotoxic compounds which alkylate cellular thiols are described namely α, β-unsaturated ketones, α-methylene-γ -lactones, azines of Mannich bases, imexon, isothiocyanates, a benzoacronycine as well as activation by thiols prior to alkylation. The mechanisms of action of some of the molecules, such as the formation of reactive oxygen species, are presented. The cytotoxicity of a number of drugs can be influenced by modulation of the concentration of thiols including the observation that potencies can be increased by thiol activation. The ability of certain thiol reagents to reverse multidrug resistance as well as some miscellaneous actions of thiol alkylators are described.

Amyotrophic lateral sclerosis (ALS) is a clinically severe and fatal neurodegenerative disease characterized by a loss of both upper and lower motor neurons, resulting in progressive muscle loss and paralysis. While the exact cause of neuronal death in ALS remains unknown, it is proposed that multiple molecular defects trigger motor neuron cell death. These pathophysiological mechanisms include oxidative stress, mitochondrial impairment, protein aggregation, glutamate cytotoxicity, transcription dysfunction, inflammation, and apoptotic cell death. An understanding of how these potential therapeutic targets interrelate will provide direction both in the development of a pharmacotherapy and in the design of clinical trials in ALS. Important issues related to therapeutic development are the principals that should be followed in designing and conducting experiments using genetic animal models and what body of evidence is desirable to fully inform clinical decision making. In the context of ALS, we review some of the salient issues related to the use of genetic models in providing a guide to assessing studies in translating therapeutic strategies to patients with ALS and discuss therapeutic targets and pharmacological approaches to slowing disease progression. As in other neurodegenerative diseases, the most effective neuroprotection may result from combined treatment strategies.

Association of proteins into homo- and hetero-oligomers plays an important role in a plethora of biological phenomena. Inhibition of these interactions is increasingly recognized as a valuable new direction in drug design. In this mini-review we consider inhibition of protein misfolding and aggregation, molecules that disrupt enzyme quaternary structure, and signaling inhibitors, as emerging drugs.

Cholera Toxin (CT) recognizes the cell membrane through specific interactions with ganglioside GM1. Recent structural elucidation of the CT/GM1 complex has allowed the rational design of artificial receptors for the toxin, which could function as anti-cholera drugs. The efforts towards the rational design of Cholera Toxin inhibitors will be presented.

There is considerable evidence showing that oxidative damage is one of the earliest neuronal and pathological changes of Alzheimer disease and many, if not all, of the etiological and pathological causes of the disease are related, directly or indirectly, to free radical production and oxidative damage. Here we summarize the current body of knowledge suggestive that oxidative damage is, if not the key factor, certainly a major factor in Alzheimer disease. As such, therapeutic modalities encompassing antioxidants may be an effective approach to the treatment of neurodegenerative diseases and delay the aging process.

The existing chemical data such as those created by high throughput screening (HTS), structure-activity relationship (SAR) studies are converted into information as a result of storage and registration. Accessibility, manipulation, and data mining of such information make up the knowledge for drug development. Cheminformatics, exploiting the combination of chemical structural knowledge, biological screening, and data mining approaches is used to guide drug discovery and development and would assist by integrating complex series of rational selection of designed compounds with drug-like properties, building smarter focused libraries. This paper presents cheminformatics approaches and tools for designing and data mining of chemical databases and information. Many examples of success in lead identification and optimization in the area of anti-infective therapy have been discussed.

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the presence of the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase Bcr-Abl; this enzyme causes hyperproliferation of the stem cells and the consequent pathology of the disease. Targeted inhibitors of Bcr-Abl have antiproliferative effects on the leukemic cells and induce apoptosis, favouring a regression of the CML chronic phase, but in the successive blast crisis phase cancer cells frequently develop resistance to Bcr-Abl inhibitors. Src is a family of nonreceptor tyrosine kinases, fundamental for cell development, growth, replication, adhesion, motility and is overexpressed in a wide number of human cancers. Recently it was demonstrated that Src is increased in hematopoietic cells expressing Bcr-Abl and is involved in the oncogenic pathway that causes CML. For this reason and also for the development of resistance to classical Bcr-Abl inhibitors, various dual Src/Abl inhibitors have been recently synthesized and tested. This mini review will be focused on the latest finding on this matter.

Cisplatin is routinely employed for the treatment of testicular, ovarian cancer and head/neck tumors. Typical doses administrated to patients are 100 mg/day for up to five days. It is believed that the mechanism of action appears to be the binding of cis-Pt(NH3)2 unit to DNA at two neighboring guanine bases. In the years following the introduction of cisplatin, the design of new platinum anticancer drugs concentrated mainly on direct cisplatin analogies, which sticked to the set of structure-activity relationships summarized by Clear and Hoeschele in 1973. Lately, some pioneering strategies towards the synthesis of novel platinum anticancer drugs based on the improved understanding of the mechanism of platinum resistance have emerged. Those are based on either changing the coordinated nitrogen ligand or altering the leaving groups. Other strategies have been shifted to discover “non classical” drugs that can act in a way different from cisplatin. Abnormal structures that violate the empirical structure-activity relationships of platinum compounds and multinuclear complexes are examples of these compounds. Several review articles appeared during recent years dealing with the synthesis, preclinical screening, and mechanism of action of platinum-based anticancer drugs. In this review, the progress in the field of anticancer chemistry based on unconventional platinum antitumor agents during the last 10 years will be highlighted. Most of the complexes that illustrate the recent and the previous prominent strategies will be presented.