Mini Reviews in Medicinal Chemistry - Volume 11, Issue 13, 2011

The serine/threonine kinase Akt, also known as protein kinase B (PKB), plays a key role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a prominent feature of many human cancers and Akt is overexpressed or activated in all major cancers. For these reasons, Akt is considered as an attractive target for cancer therapy. In the past few years, several series of compounds with diverse structural features have been reported as Akt inhibitors, such as, ATP-competitive inhibitors, Phosphatidylinositol (PI) analogs, and allosteric inhibitors. Although most of the inhibitors exhibited potent inhibitory activities at nanomolar concentrations against Akt, some of them have shown unfavorable selectivity against other protein kinases especially PKA and PKC. This review will focus on the recent advances in the development and biological evaluation of selective ATP-competitive inhibitors for Akt. We will summarize the novel approaches toward the developments of selective ATP-competitive inhibitors, expecting to give information to design new ATP-competitive inhibitors with high selectivity, bioavailability, and potency.

The 5-HT7 receptor (5-HT7R), characterized in 1993, is the most recently described member of the serotonin family. Since its discovery, 5-HT7R has been the subject of extensive research due to its widespread distribution in the brain, suggestive of multiple central roles. The focus of this review is to illustrate the literature concerning developments of the last few years (2007-2010) towards the discovery of novel and selective 5-HT7R ligands, agonists, antagonist and inverse agonists.

Berberine is an isoquinoline alkaloid isolated from Chinese herbs such as Coptidis Rhizome. This paper is a systematic review of the structural modifications of berberine for different biological activities such as antitumor, antimicrobial, anti-Alzheimer's disease, antihyperglycemic, anti-inflammatory and antimalaria. The current review would provide some useful information for further studies on structural modification of berberine for discovering new drug leads.

1,3,4-oxadiazole, a privileged structure, endows its derivatives with broad and potent biological functions, especially in antiviral activities, including anti-HIV, anti-HCV, anti-HBV, anti-HSV activities, etc. Molecular modeling and pharmacokinetic studies have demonstrated that the introduction of 1,3,4-oxadiazole ring to the inhibitors can change their polarity, flexibility as well as metabolic stability, and 1,3,4-oxadiazole scaffold can also act as acceptors of hydrogen bonds formation, which make it possible to be used as a isosteric substituent for amide or ester groups. This review focuses on the recent advances in the synthesis of 1,3,4-oxadiazole ring and mainly the discovery, biological activities investigations and structural modifications of several distinct classes of 1,3,4-oxadiazoles as potent antiviral agents. In addition, the binding models of some representative 1,3,4-oxadiazoles were also discussed, which provide rational explanation for their interesting antiviral activities, and also pave the way for further optimization of 1,3,4- oxadiazole based antiviral agents.

Caveolae are highly enriched in numerous membrane-bound proteins and caveolin-1 is their major component. Caveolae and caveolin proteins are involved in a variety of cellular processes including lipid homeostasis, endocytosis, signal transduction, and tumorigenesis. Breast cancer is one of the most common cancers in women throughout the world. Clinical studies have shown that the correlation of caveolin-1 expression with tumor progression varies with tumor type. The data presented here extend the findings that caveolin-1 suppresses breast cancer but there are controversial studies. The potential function of caveolin-1 in scaffolding signaling factors also demonstrates the importance of its expression control and modulation, correlating with physiological or pathological conditions. Based on current research, this review presents the current understanding of their function and the involvement of caveolin-1 in breast cancer pathogenesis.

Sesquiterpenoids are a group of naturally occurring 15-carbon isoprenoid compounds that are mainly found in higher plants, microorganism and marine life. Many of them provided encouraging leads for chemotherapeutics. In this review, the sesquiterpenoids are classified according to the ring numbering system and the functional groups presented in the core structures as acyclic, mono-, bi-, and tricyclic derivatives, and a current overview of sesquiterpenoids as potential cytotoxic anticancer agents is provided.

MicroRNAs (miRNAs) are approximately 22 nucleotide endogenous RNA molecules which exert their functions by base pairing with messenger RNAs (mRNAs), thereby regulating protein-coding gene expression. In eukaryotic cells, miRNAs play important roles in regulating biological processes such as proliferation, differentiation, apoptosis, and stem cell self-renewal. miRNAs are encoded by the genome, and more than 1,000 human miRNAs have been identified so far. miRNAs are predicted to target -60% of human mRNAs and are expressed in all animal cells. Unique expression domains, targets, and gain- and loss-of-function phenotypes of particular miRNAs have important implications for directed to control differentiation of stem cell populations. Many cancers show variations in miRNA levels, and more specifically an overall downregulation, when compared to their normal counterparts. Therefore, miRNAs may be used as potential therapeutic agents to correct aberrant transcript levels found in the signaling pathways of cancer. This review examines the most recent acquisition on the role of miRNAs in regulating the cell cycle, with particular emphasis on their effects on cell proliferation and differentiation. The second part explores specifically the role of these factors in the physiological regulation of embryonic stem cells, of cellular reprogramming and their involvement in the activation of stem cells in adult tissues. In the third part, the article discusses some issues that relate to the role of miRNAs in the development of neoplastic diseases, focusing on aspects of the genetic and transcriptional alterations that determine the beginning and the development of tumor process, with emphasis on, looking to emphasize their involvement in the activation of adult cancer stem cells.