Current Medicinal Chemistry

ISSN: 0929-8673




Current Medicinal Chemistry
Volume 17, Number 18, 2010


Contents



Plant and Animal Steroids a New Hope to Search for Antiviral Agents Pp. 1858-1873
V. Castilla, J. Ramírez and C.E. Coto
[Abstract] [Purchase Article] [PMID: 20377516 PubMed - indexed for MEDLINE]


Dipyridodiazepinone Analogs as Human Immunodeficiency Virus Type 1-Specific Non-Nucleoside Reverse Transcriptase Inhibitors: An Overview Pp. 1874-1898
M. Lv and H. Xu
[Abstract] [Purchase Article] [PMID: 20377515 PubMed - indexed for MEDLINE]


Recognition of Nucleic Acids by Toll-Like Receptors and Development of Immunomodulatory Drugs Pp. 1899-1914
A. Kužnik, G. Panter and R. Jerala
[Abstract] [Purchase Article] [PMID: 20377514 PubMed - indexed for MEDLINE]


Editor’s Choice
The Emerging Role of Nitrite as an Endogenous Modulator and Therapeutic Agent of Cardiovascular Function Pp. 1915-1925
B. Tota, A.M. Quintieri and T. Angelone
[Abstract] [Purchase Article] [PMID: 20377513 PubMed - indexed for MEDLINE]


The Chemistry of Mycophenolic Acid – Synthesis and Modifications Towards Desired Biological Activity Pp. 1926-1941
G. Cholewinski, M. Malachowska-Ugarte and K. Dzierzbicka
[Abstract] [Purchase Article] [PMID: 20377512 PubMed - indexed for MEDLINE]


Riluzole, Neuroprotection and Amyotrophic Lateral Sclerosis Pp. 1942-1959
B.C. Cheah, S. Vucic, A.V. Krishnan and M.C. Kiernan
[Abstract] [Full Text Article] [PMID: 20377511 PubMed - indexed for MEDLINE]


Quinoline-Based Antifungals Pp. 1960-1973
R. Musiol, M. Serda, S. Hensel-Bielowka and J. Polanski
[Abstract] [Purchase Article] [PMID: 20377510 PubMed - indexed for MEDLINE]


Phytoecdysteroids and Vitamin D Analogues – Similarities in Structure and Mode of Action Pp. 1974-1949
Noémi Tóth, Attila Hunyadi, Mária Báthori and Erno Zádor
[Abstract] [Purchase Article] [PMID: 20377509 PubMed - indexed for MEDLINE]




Abstracts


[Back to top] [Purchase Article] [PMID: 20377516 PubMed - indexed for MEDLINE]
Plant and Animal Steroids a New Hope to Search for Antiviral Agents
V. Castilla, J. Ramírez and C.E. Coto

Scientific literature provides evidence about the use of steroids as an adjunct treatment to antiviral therapies. Immunomodulatory activity of some steroids would account for the recovery in patients with herpetic and other viral infections. However, in vitro studies have demonstrated a direct antiviral effect of this kind of molecules. In this review we discuss recent reports about the mechanism of antiviral action of steroids from animal and plant origin. Chemical structures of most active compounds are also provided.


[Back to top] [Purchase Article] [PMID: 20377515 PubMed - indexed for MEDLINE]
Dipyridodiazepinone Analogs as Human Immunodeficiency Virus Type 1-Specific Non-Nucleoside Reverse Transcriptase Inhibitors: An Overview
M. Lv and H. Xu

According to World Health Organization (WHO)/Joint United Nations Programme on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (UNAIDS) Report in 2007, 33.2 million people are living with HIV, 2.5 million ones have been newly infected with HIV, and 2.1 million ones died from AIDS, including 330,000 children. Therefore, HIV/AIDS still remains a public health emergency and a leading cause of mortality worldwide. It is believed that reverse transcriptase (RT) is a crucial enzyme in the life cycle of HIV-1, and thereby RT has been the important drug target for antiretroviral (ARV) chemotherapy against AIDS. To our knowledge, dipyridodiazepinone analogs have been considered as one class of potential non-nucleoside reverse transcriptase inhibitors (NNRTIs), especially the structurally and chemically related nevirapine (Viramune®), which was the first NNRTI approved by the U. S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection for adults in 1996 and for children in 1998. This review mainly highlights the progress of synthesis and structure–activity relationship (SAR) of dipyridodiazepinone analogs; in the meantime, the mechanism of action is also presented. It will pave the way for the design and development of novel dipyridodiazepinone analogs as NNRTIs in AIDS chemotherapy in the future.


[Back to top] [Purchase Article] [PMID: 20377514 PubMed - indexed for MEDLINE]
Recognition of Nucleic Acids by Toll-Like Receptors and Development of Immunomodulatory Drugs
A. Kužnik, G. Panter and R. Jerala

Microbial as well as endogenous nucleic acids are recognized by a group of endosomal Toll-like receptors TLR3, TLR7, TLR8 and TLR9. Recent discoveries significantly improved our understanding of molecular mechanism of their activation and their physiological role. Those include recognition of dsRNA through two nucleic acid binding sites of TLR3 ectodomain, activation of TLR9 by phosphodiester backbone of ssDNA, independent of the nucleotide sequence and phosphorothioate modified bonds, and the role of proteolysis in activation of TLR9. In addition, proteins that chaperone nucleic acids, such as HMGB1 or LL-37, have been described to mediate TLR activation. There is growing evidence that supports involvement of endosomal TLRs in a number of autoimmune diseases, suggesting a therapeutic potential of immunomodulatory endosomal TLR ligands. So far, inhibitory nucleic acids against TLR7, TLR8 and TLR9 as well as small compounds targeting downstream signal transduction of single or several endosomal TLRs have been reported. TLR-targeting drugs have been included in clinical trials as vaccine adjuvants or as therapeutic agents for the treatment of diseases, ranging from cancer, infections, asthma and allergy to autoimmune diseases.


[Back to top] [Purchase Article] [PMID: 20377513 PubMed - indexed for MEDLINE]
The Emerging Role of Nitrite as an Endogenous Modulator and Therapeutic Agent of Cardiovascular Function
B. Tota, A.M. Quintieri and T. Angelone

Recently, the circulating anion nitrite (NO₂^-), the largest physiological reservoir of nitric oxide (NO) in the body, has revealed itself as a signalling molecule mediating numerous biological responses. Since it was estimated that as much as 70% of plasma nitrite originates from nitric oxide synthases (NOSs), mainly in the endothelium by endothelial NOS, nitrite is considered an index of NOSs activity. Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. In mammalian blood, nitrite, present at nanomolar concentrations, can be reduced to bioactive NO along a physiological oxygen and pH gradient either non-enzymatically (acidic disproportionation) or by a number of enzymes including xanthine oxidoreductase, NOS, mitochondrial cytochromes and deoxygenated haemoglobin and myoglobin. The various NO-dependent nitrite-induced biological responses include hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion, and regulation of protein and gene expression.

Since NO is a major paracrine-autocrine cardiovascular modulator and nitrite acts mainly as an endocrine store of NO, it is not surprising that NO₂^- exerts important cardiovascular actions both under normal and physio-pathological conditions.

In the interdisciplinary framework of the NO cycle concept, this review illustrates the actions exerted by nitrite on the cardiovascular system. Since the majority of the NO₂^- -oriented studies focused on the systemic and regional control of blood flow both under physiological and ischemia/reperfusion conditions, we will firstly consider this issue. Secondly, the nitrite-induced effects on myocardial contractile and relaxation processes will be discussed, emphasizing the biomedical interest of nitrite as a new therapeutic agent. The importance of cardiac myoglobin as nitrite-reductase able to exert cardioprotection through a novel function, in addition to its role as classical respiratory protein, will be highlighted. Finally, using recent data from others and our labs, we will emphasize the importance of fish and amphibian heart models with diverse morphologies and blood supply for providing remarkable insights on “ancestral” functions of the nitrite-NO system in vertebrates, which, in turn, may help to expand its actual significance in human physiology.


[Back to top] [Purchase Article] [PMID: 20377512 PubMed - indexed for MEDLINE]
The Chemistry of Mycophenolic Acid – Synthesis and Modifications Towards Desired Biological Activity
G. Cholewinski, M. Malachowska-Ugarte and K. Dzierzbicka

Mycophenolic acid (MPA) is a basis for the immunosuppressive drugs used in clinic against rejection in solid organs transplantations. Since its physiological activity is very promising, numerous studies have been performed to establish mechanism of action, structure – activity relationship (SAR), synthesis of MPA derivatives to improve or extent its clinical use to anticancer one, especially. The reported methods for preparation of MPA analogues have been achieved by semi-synthetic approaches or total synthesis and accomplished by in vitro or / and in vivo evaluations. In this review we would like to bring together chemical aspects of these compounds and their implementations within biological activity, their synthesis and structural modifications referred to the structure-activity relationship (SAR).


[Back to top] [Full Text Article] [PMID: 20377511 PubMed - indexed for MEDLINE]
Riluzole, Neuroprotection and Amyotrophic Lateral Sclerosis
B.C. Cheah, S. Vucic, A.V. Krishnan and M.C. Kiernan

Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This ‘excitotoxicity’ theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na⁺ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na⁺ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.


[Back to top] [Purchase Article] [PMID: 20377510 PubMed - indexed for MEDLINE]
Quinoline-Based Antifungals
R. Musiol, M. Serda, S. Hensel-Bielowka and J. Polanski

Although the assortment of antifungal drugs is broad, the most commonly used agents have major drawbacks. Toxicity, serious side effects or the emergence of drug resistance are amongst them. New drugs and drug candidates under clinical trials do not guarantee better pharmacological parameters. These new medicines may appear effective; however; they may cause serious side effects. This current review is focused on the recent findings in the design of quinoline based antifungal agents. This field seems to be especially interesting as 8-hydroxyquinoline and its metal complexes have been well known as antifungals for years. Structural similarities between quinoline based antifungals and allylamines or homoallylamines, e.g. terbinafine is another interesting fact. Quinoline can be identified in a number of synthetic and natural antifungals, which indicates nature’s preference for this fragment and identifying it as one of the so-called privileged structures. We have discussed new trends in the design of quinolines with antifungal properties, their possible targets and the structure activity relationships within the antifungal series developed.


[Back to top] [Purchase Article] [PMID: 20377509 PubMed - indexed for MEDLINE]
Phytoecdysteroids and Vitamin D Analogues – Similarities in Structure and Mode of Action
Noémi Tóth, Attila Hunyadi, Mária Báthori and Erno Zádor

Phytoecdysteroids are plant steroids with identical or analogue structures to the molting hormone in arthropods. The ecdysteroids exert several beneficial effects on mammals, from which the most cited and deeply examined one is the increase of muscle size and strength. This shows similarities with the mode of action of the androgenic steroids but the ecdysteroids do not bind to the cytoplasmic/nuclear receptor of the mammalian steroids. These findings led to the hypothesis that ecdysteroids possibly bind to membrane bound receptors and they are likely to influence signal transduction pathways. Probably because of their closely related chemical structures, ecdysteroids exert some similar effects in vertebrates to those of the hormone 1α,25-dihydroxyvitamin D₃ (1,25D) which is produced in the kidney from 25-hydroxyvitamin D₃, after being converted in the liver from Vitamin D₃.

1,25D generates biological responses via both genomic and rapid, nongenomic mechanisms. Structure-activity relationship studies with different Vitamin D analogues could open the possibility to show that the two ways of action (genomic and nongenomic) can be influenced separately.

The connection between the Vitamin D status and muscle function is already well-described in clinical studies, and several efforts have been made to evaluate the effect of Vitamin D deficiency or supplementation on muscle morphological changes and the underlying molecular mechanisms.

This paper aims to summarize the main structural commonalities between the ecdysteroids, 1,25D and other Vitamin D analogues. The similarities in their effects and pathways that might be involved in the mechanism of action of these compounds will also be discussed.