Medicinal Chemistry Reviews - Online (Discontinued) - Volume 1, Issue 2, 2004

Wound healing is a complex process that can be compromized by both endogenous and exogenous factors. The old dictum “I dressed the wound, God healed it” is from the past. There is ample evidence now to suggest that local wound management greatly affects the orderly progression of the healing cascade and determines the quality of its final outcome. The perfect wound dressing would relieve pain, provide a moist wound environment, shield the wound from further damage, remove necrotic debris, promote granulation tissue formation and protect the wound from bacterial contamination. There are currently hundreds of topical preparations and dressings on the market to aid in wound management. Over the years, biologically neutral agents that would allow the healing process to proceed unhindered by providing optimal conditions, have replaced older preparations proven to affect negatively wound healing. Bio-pro-active products are being developed and will be the future generation of local wound care agents in future. In any event, the bestinformed choice for the patient must always be made. However, surgical vascular and soft tissue reconstruction should not be overlooked whenever indicated by insisting on unsuccessful local wound therapies.

This review discusses current understanding of organophosphate induced delayed polyneuropathy (OPIDP) with emphasis on molecular mechanisms, pathogenesis and possibilities for prevention / therapy. OPIDP is a rare toxicity caused by certain organophosphorus compounds (OP) characterized by degeneration of some long axons in the central and peripheral nervous system that appear about 2-3 weeks after exposure. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). NTE can be inhibited by two types of inhibitors: a) phosphates, phosphonates, and phosphoramidates, which cause OPIDP when >70% of the enzyme is inhibited, and b) phosphinates, carbamates, and sulfonyl halides, which inhibit NTE and cause either protection from or promotion of OPIDP when given before or after a neuropathic OP, respectively. The ability of a NTE inhibitor to cause OPIDP, besides its affinity for the enzyme, is related to its chemical structure and residue left attached to NTE. If such residue can undergo the aging reaction i.e. the loss of alkyl group bound to the enzyme, those OPs usually have high potency to cause OPIDP. Protection from neuropathic doses of OP inhibitors is obtained when NTE is inhibited with nonageable inhibitors. Promotion of OPIDP involves another site besides NTE because it might occur when all NTE is affected. It is now known that this other site is similar to NTE in that it is also sensitive to mipafox but at much higher concentrations. Promotion affects either progression or expression of OPIDP after the initial biochemical effect on NTE. There were some recent observations that development of OPIDP in hens can be influenced by atropine, oximes and methylprednisolone when they are given before or soon after neuropathic OPs.

The developments in the area of inhibition of different serine enzymes by βlactams have been reviewed recently [1]. Since then, the following advances have been made: development of synthetic methodology for the preparation of enantiomerically pure lactams, whose inhibiting properties have been previously established; preparation of novel antibacterial cephams; synthesis of prodrugs containing dual inhibitors of PBPs and βlactamases; and the discovery of monocyclic βlactams, whose mode of action and structure-activity profiles differ dramatically from those of traditional βlactam drugs.

Temozolomide (TMZ) is a methylating agent with promising antitumour activity against primary or secondary brain tumours. Through the generation of a reactive intermediate, TMZ interacts with DNA at different base site positions, generating a wide spectrum of methyl adducts represented mainly by N-methylpurines (70%) while, at a lesser extent, by N3-methyladenine (9%) and O6-methylguanine (5%). The antitumour activity of TMZ has been primarily attributed to O6- methylguanine, since tumour cell sensitivity inversely correlates with the levels of O6-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Even though the pharmacokinetics properties, favourable toxicity profile and antitumour activity against a broad range of tumour types render TMZ an attractive agent in oncology, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of clinical response in cancer patients. Thus, different strategies aimed at counteracting resistance and increasing the efficacy of TMZ have been designed and for many of them investigation is still underway. Herein, we provide an update on the latest findings of preclinical and clinical studies on TMZ in combination with resistance or biological modulators and anticancer drugs with different mechanisms of action.

Macrolides, an old class of antibiotics, have attracted intense interest in recent years because of their diverse non-antibiotic properties. Among these properties, their immunomodulating effects were most extensively examined. In this review, their broad range of effects on the immune system as shown by various in-vitro, ex-vivo, and in-vivo experiments and clinical studies are discussed. It is now evident that various macrolides can modulate the innate immune system, with greater effects from 14- and 15-membered than the 16-membered derivatives. In vitro studies have demonstrated that macrolides modulate the production of various cytokines, including IL-1, IL-2, IL-6, IL-8 and TNF-α, and functions of macrophage-monocytes, neutrophils, and lymphoctyes. Moreover, the human airway smooth muscles and secretions are also affected by these drugs. Although results from in-vitro studies appear to depend on the use of individual drugs and experimental conditions, they provide clues to the mechanisms of modulating different pathways of the immune system. On the other hand, animal and clinical studies, which summarize the effects of individual pathways, concluded that many macrolides are useful in a wide variety of clinical situations, from treatment of inflammatory lung diseases to application in transplantation. As for adaptive immunity, limited data were available but attenuation by macrolides was also reported in preliminary studies. Owing to their diverse effects on the immune system and inconclusive results from different in-vitro studies, the mechanism of their immunomodulation is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It may be more valuable for future studies to concentrate on the genetic basis for mechanisms on one hand, and additional areas of clinical applications on the other.

The dramatic increase in allergic disease is now an enormous healthcare burden in many countries. Because most current treatment strategies are directed only at controlling the symptoms of these common, disabling and potentially life threatening conditions, there is now a pressing need to define strategies which can directly target, reverse or even prevent the underlying immunological processes. Recent technological advances have provided a better understanding of underlying disease processes and offered new potential therapeutic targets. Optimal treatment strategies permanently modify underlying inflammatory allergic immune responses (immunotherapy) with long-term alleviation of symptoms and minimal side effects. Although these processes are still not completely understood, methods of modifying allergen recognition by the immune system have already been successful. Here, we review recent developments and future directions in allergen immunotherapy and adjunctive therapies. Specifically, we address the molecular mechanisms of allergen immunotherapy, newer routes, and new techniques including allergen modification, allergen gene vaccination, CpG immunostimulation and peptide immunotherapy. Other non-allergen specific molecular targets (including receptor, cytokine and IgE targets) that may complement specific immunotherapy are also discussed. Ideally these methods will eventually be replaced by strategies targeting the prevention of allergic responses (immunoprophylaxis).

The review describes different aspects of the host immune response to Trichinella. The role of antibodies, T cells, mast cells, eosinophils and neutrophils, respectively, in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both in vivo and in vitro. A section is also devoted to the principal escape mechanisms of host immune response, described in Trichinella, some of which only are shared by other parasites, some others peculiar of this parasite. The antigenic composition of the different stages is the topic of another section, which wants to give an overview of the main antigens described up to now. Finally, the perspectives for vaccination are discussed.

The limitations of cisplatin as an anticancer drug have stimulated the search for other antitumour-active platinum complexes with improved pharmacological properties. The two main goals in the search for new platinum anticancer agents are the reduction of the dose-limiting toxicities of cisplatin and the circumvention of cisplatin resistance. However, it should be noted that this has proven to be a difficult task. In fact, less than 1% of the thousand of platinum complexes tested for pre-clinical antitumour activity have entered clinical trials in the past 30 years. Nonetheless, at present, several new platinum complexes are in clinical trials; a proof of the continued belief that platinum complexes may still fulfil the needs for novel antitumour drugs. This review will focus on the three main innovative bioinorganic approaches found in the platinum anticancer-field, namely, (1) compounds with a slowed down kinetic of activation, (2) compounds with carrier ligands, and (3) compounds that bind differently to DNA as compared to cisplatin. In the latter class, special attention is paid to dinuclear and polynuclear platinum complexes.

This article is an update of our recent review on βlapachone [1]. Since then two dozen references on β- lapachone that have direct relevance to cancer appeared. These are summarized here. Nearly 300 references on β lapachone are currently listed by PubMed.

5-Lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes (LTs), proinflammatory mediators, which are mainly released from myeloid cells. Whereas LTB4 is a potent chemotactic and chemokinetic agent for leukocytes, the cysteinyl (cys) LTs C4, D4 and E4 cause vascular permeability and smooth muscle contraction. In view of these properties, LT synthesis inhibitors have been hypothesised to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxide; nevertheless activation of cellular 5-LO in response to external stimuli is rather incompletely understood. Intensive research revealed that on cell stimulation, 5-LO redistributes to the nuclear membrane where it colocalises with 5-lipoxygenase-activating protein and cytosolic phospholipase A2. Accumulating data suggest that phosphorylation of 5-LO by p38 MAPK-regulated MAPKAP-kinases and extracellular signal-regulated kinases 1 / 2 regulates cellular 5-LO activity and influences redistribution of the enzyme in the cell. In addition, the cellular redox tone regulates 5-LO product formation, and 5-LO reactions may be influenced by cellular proteins physically interacting with 5-LO. This review highlights the determinants of cellular 5-LO activity and summarises the molecular pharmacology of 5-LO.

Benzamide riboside (BR) is a novel anticancer agent exhibiting pronounced activity against several human tumor cell lines via the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) that catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. Phosphorylation of BR to its 5'-monophosphate derivative appears to be ubiquitous in most cells catalyzed by the enzymes, adenosine kinase, nicotinam ide nucleoside kinase and 5' nucleotidase. BR 5'-monophosphate is then converted to the active metabolite benzamide adenine dinucleotide (BAD) by NMN adenylyltransferase, the rate-limiting enzyme in the biosynthesis of NAD. As BAD is more potent in the inhibition of IMPDH than BR and BR 5'-monophosphate, cytotoxicity of BR is closely connected with intercellular metabolism to BAD. However, intracellular BAD level is also affected by BADase activity, a phosphodiesterase which hydrolyzes BAD to BR-5'-monophosphate and AMP. A recent study demonstrates enzymatic deamination of BR to non-cytotoxic benzene carboxylic acid (BR-COOH) as the main hepatic BR biotransformation product in rat liver. As the IMPDH inhibitors tiazofurin and ribavirin exhibit predominant accumulation and biotransformation in liver, hepatic metabolism may be an important factor also for BR activation and inactivation and should be considered in human liver during cancer therapy when BR is used as a single drug or in combination with other anticancer agents.

Endocannabinoids are lipid mediators, isolated from brain and peripheral tissues, which exhibit “cannabimimetic activity” by binding to cannabinoid receptors. The biological actions of anandamide (Narachidonoylethanolamine; AEA), a prominent endocannabinoid, are terminated through an AEA membrane transporter and an AEA-hydrolase (fatty acid amide hydrolase; FAAH). Recently, we have reviewed the potential of inhibitors of endocannabinoid degradation as therapeutic agents. In particular, we discussed the role of oxidative metabolites of AEA generated by lipoxygenases as powerful inhibitors of FAAH. Here, we shall supplement recent information on the oxidative metabolism of endocannabinoids, and on their potential therapeutic applications.