Mini Reviews in Medicinal Chemistry - Volume 9, Issue 3, 2009

The linear naphtho-γ-pyrone (LNGP) moiety is a naturally occurring scaffold with broad biological activity ranging through antimicrobial, antiviral, insecticidal and anti-estrogenic activity. This review, the first of its kind, surveys the chemical literature in an effort directed toward assembling data that will facilitate the construction of activity profiles associated with this emerging class of compounds. The structural and associated biological information has been presented in tabular format with all structures revealed throughout the document and referencing that will allow the reader to rapidly access the literature pertaining to a specific activity or structural class.

The antimicrobial, the in vitro and in vivo antineoplastic activities, mechanism of action, the structural and thermal properties of a pharmaceutically novel and small organometallic silver (I)-tartaric acid complex synthesized by the author given the title name Aliargentumycine or AAgM are reviewed here.

The naturally-occurring dipeptide carnosine (β-alanyl-L-histidine) and the tripeptide glutathione (L-γglutamyl- L-cysteinylglycine) are found extensively in animal tissues such as brain and skeletal muscle. Central functions for excitation and sedation of them and their derivatives were screened.

Lipopolysaccharide (LPS) or endotoxin, the major constituent of the outer membrane of Gram negative bacteria, has been implicated as the bacterial product responsible for the clinical syndrome of sepsis. LPS binding to the host receptor Toll-like receptor 4 (TLR4) triggers an inflammatory reaction characterised by the release of large number of inflammatory mediators that allow the host to respond to the invading pathogen. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. Despite decades of efforts in supporting therapies , sepsis remains the leading cause of death amongst critically ill patients. Unfortunately, the major factor contributing to the high morbidity and mortality of sepsis is the lack of the effective targeted treatment. Indeed, over 30 drugs for the treatment of sepsis have been developed: many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since sepsis relies on the cross talk of several cytokines and the block of a single factor has been proven to be ineffective. More successful strategies include those modulating the early phase of LPS signalling such as the ones that prevent the binding of LPS to host cells and the subsequent cascade of detrimental events. In this light, effective LPS antagonists would represent invaluable tools to efficaciously manage sepsis. This review discusses the evolution of naturally occurring and synthetic LPS antagonists with emphasis on the development of several natural new molecules.

Rheumatoid arthritis (RA) is a systematic inflammatory and intractable disease, which progressively affects multiple joints. Recent findings strongly suggest a key role of WNT signaling in the disease initiation and progression. In this review, we discuss the role and possibility of treatment by targeting WNT signaling.

Endometriosis is an enigmatic, debilitating disease which affects as many as 15% of all women of reproductive age and is characterized by pelvic pain and infertility. Current treatment regimes used to manage the disease do so by inducing a hypoestrogenic state. While the absence of circulating estrogen levels lead to a regression of the disease, this hypoestrogenism also induces many unpleasant side-effects. As such, these and other shortcomings of current drug therapies emphasize their limitations and the necessity for the development of novel endometriosis treatments. In this review, current therapies which target the biochemistry of the implant are discussed with emphasis on aromatase inhibitors, antiangiogenic compounds and vascular-disrupting agents.

The heptahelical G protein coupling receptors oligomerize extensively via transmembrane domains, in association with heterotrimeric G proteins. This provides higher affinity for agonists, conformational stability necessary for signal transduction, and protection from intracellular proteinases. The oligomerization is relevant to organismic pathophysiology and could be targeted by natural or modified agonists. For Supplement material, please see the online version of the article.

The interest in the microwave assisted organic synthesis has been growing during the recent years. It results from an increasing knowledge of fundamentals of the dielectric heating theory, availability of an equipment designed especially for the laboratory use as well as the discovery of the special techniques of the microwave syntheses. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry and this aspect is of great importance in high-speed combinatorial and medicinal chemistry. In this contribution, the current state of the art is summarized providing examples of the most recent applications in the field of microwave assisted synthesis of biologically active compounds both in heterocyclic and in peptide and peptidomimetic optimization.

Currently the only treatment for celiac disease is adherence to a strict gluten-free diet; however, compliance with this diet is complex and other alternatives are called for. Herein, we review recent developments in the design of novel therapeutic strategies to counteract the pathogenic effects of the interactions between gluten peptides and their specific biological targets.

The concentration of lysophospholipids (LPL) increases under pathological conditions and, thus, LPL attract diagnostic and pharmacological interest. LPL are particularly interesting because they possess pro- and anti-inflammatory properties and can be generated by phospholipases and reactive oxygen species (ROS). This review provides an overview of the mechanisms by which LPL are generated and how they can be determined. The effects of LPL as signaling molecules and their roles in different pathologies are discussed. The focus will be on lysophosphatidylcholine (LPC).

Transcription is considered to be a crucial step in the replication cycle of HIV-1. Tat regulates an early step of transcription elongation. The positive elongation factor P-TEFb, a heterodimer containing a catalytic subunit (CDK9) and unique regulatory cyclins (CycT1), is required for HIV-1 Tat transcriptional activation. This is a potential target for new HIV-1 transcription inhibitors. Without P-TEFb, transactivation is restrained and only short transcripts are generated. All the P-TEFb inhibitors can suppress the HIV-1 transactivation process by inhibition of CycT1, CDK9 or their interaction. Several low-molecular-weight compounds such as flavopiridol, roscovitine and the human small nuclear RNA 7SK which have been showed to possess potent anti-HIV activity by interfering with P-TEFb functions are reviewed in this article.

The human SIRT1 is a nuclear enzyme from the class III histone deacetylases (HDACs) which is widely distributed in mammalian tissues. A variety of SIRT1 substrates hints that this protein is involved in the regulation of diverse biological processes, including cell survival, apoptosis, gluconeogenesis, adipogenesis, lipolysis, stress resistance, muscle differentiation, and insulin secretion. This review emphasizes catalytic properties of SIRT1 and its role in apoptosis, insulin pathway, and neuron survival.

Prostate cancer (PCa) is a common cause of death in men and remains incurable in the androgen-refractory phase. Growing evidence has shown that the androgen receptor (AR) and signal transducers and activators of transcription 3 (STAT3) could be effective targets for androgen-refractory PCa therapy. Many strategies have been reported to inhibit the AR or STAT3 activities. In this review, we focus on the AR N-terminal domain and AR chaperones, as well as small molecule inhibitors to STAT3 with which we discuss some new approaches to target the AR and STAT3 as potential treatments for androgen-refractory PCa.