Mini Reviews in Medicinal Chemistry - Volume 12, Issue 4, 2012

The key role of proteins and amino acids in the structure and function of living matter has stimulated extensive studies. Modified amino acids with enhanced biological activity, proteolitic stability and bioavailability are of increasing interest in protein design and engineering as drug candidates. In the last few years, several efforts have been devoted to the synthesis of amino acids having unusual side chains and unnatural chirality, commonly referred to as “nonproteinogenic” or “unnatural” amino acids, even though some of them can be isolated from natural sources. In this review we describe recent advances in the amino acid side-chain transformations and backbone modifications by oxidative and fluorination procedures.

Drug delivery to the central nervous system (CNS) is a timely and challenging issue: 95percnt; of the pharmacological drugs cannot be delivered to the brain. This is mainly due to the blood-brain barrier (BBB), a highly selective boundary that hampers the passage of most compounds into the CNS. To overcome this problem, several approaches exist to deliver a therapeutic drug to the brain that takes into account not only the chemical properties of the drug but also the type of transport used at the BBB. One of those strategies is the glucose-mediated drug delivery which will be the focus of the present review. Glucose-mediated drug delivery requires the attachment of glycosyl moieties to a drug and the use of endogenous glucose transporters as a way to circumvent the blood-brain barrier. Glycosylated drugs display improved cell penetrability, enhanced biodistribution, stability and low toxicity. Examples such as glycosylation of ibuprofen and different opioids result in an enhanced central effect and will be discussed.

Substituted hydroxymethylenebisphosphonic acid derivatives – either as dronic acids or their dronate sodium salts, are important pharmaceuticals in the treatment of diseases arising from excessive bone-resorption. Potential has also been identified in areas ranging from parasite-growth inhibition to immunological and cancer therapeutics. Representative clinically relevant N-heterocyclic derivatives include zoledronic and risedronic acids. The biochemical background and mechanism of action of these drugs are discussed, along with trends in structural development and future prospects. Synthetic routes to dronates are then summarized. The most popular route to valuable dronic acids involves the 3- component condensation of a substituted acetic acid, phosphorous acid, and phosphorus trichloride. However, the protocols recorded in the literature are very diverse. This review gives a critical account of reported methods, explores the contradictions and suggests a practical synthetic procedure after clarifying the inconsistencies described. Possible mechanisms of the reaction are also discussed.

Nanotechnology is a rapidly emerging drug-delivery system that makes possible the controlled release of small molecules, and nanodelivery of therapeutic molecules using nanoparticles or nanogels represents a major improvement for more focused delivery of such therapeutic molecules. The delivery of insulin for the control of diabetes mellitus (DM) and aldose reductase inhibitor (ARI) for diabetic complications may provide better treatment of diabetes. A structural overview of aldose reductase including computational docking experiments with HAR-1, various ARIs, aldose-keto reductase, and nanodelivery of insulin, ARI's, and drug molecules are described.

Dihydropyrimidinones (DHPMs) are a series of highly valuable small molecules possessing versatile pharmaceutical properties. Although the first one-pot synthesis of DHPMs had been reported more than 100 years ago, the fascinating achievement in DHPMs-based pharmacology during the past century promoted durative interests to the pharmacological and related studies of the scaffold, which lead to the discovery of many new biological functions of DHPMs. Recent pharmacological development on DHPMs-based molecules have been summarized in this review.

Genistein is the most abundant isoflavone in soybeans. It has exhibited diverse biological activities, among these, its anticancer effects is most noteworthy. Through regulating critical cell cycle genes, genistein can inhibit cancer cell growth in vivo and in vitro. It has been reported that genistein can inhibit activation of NF-κB and Akt signaling pathways to induce cell apopt1osis, both pathways are well known for their function to maintain a balance between cell survival and apoptosis. In order to find out more outstanding anticancer isoflavone agents, against cancers extended synthesis of genistein derivatives has been carried out. Some of these synthetic compounds demonstrated higher anticancer activity with lower doses. Based on these results, genistein and its synthetic derivatives may be an emerging new type of anticancer agents.