Current Medicinal Chemistry (v.20, #32)

Neuroprotective Properties of Curcumin in Alzheimer’s Disease - Merits and Limitations by Dawn Chin, Patricia Huebbe, Kathrin Pallauf, Gerald Rimbach (3955-3985).
As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especiallydementias such as Alzheimer’s disease, pose one of the largest challenges to the modern health care system. Sincethere is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popularcandidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcumalonga (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory,anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly,the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulationin the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility,poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currentlybeing made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, althoughmany have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses,which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion havenot been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease,as well as its limitations will be discussed in detail.

Despite being the most abundant type of biopolymers in Nature, the biological relevance of carbohydrates hassystematically been underrated for decades, associating them far less sophisticated functions (structural or energysourcing) than those unraveled for polynucleotides and proteins. The inherently large and complex diversity of carbohydratesand glycoconjugates, together with the lack of efficient technologies to either isolate them from natural sources orproduce them synthetically in useful amounts, have burdened the appreciation of their utmost importance in the most fundamentalbiological processes. For these reasons, carbohydrate-mediated transmission of biological information waslargely unexplored. However, over the decades, it became clear that the expression of complex carbohydrates is critical inthe development of living systems. Nature uses this diverse repertoire of structures as codes in fundamental biologicalprocesses such as cellular differentiation, cellular signaling, fertilization or immune response, among many others. Theurgency to elucidate the glycan code in terms of structure-function relationships has fuelled chemical biology approachesuncovering new frontiers in molecular biology, for which the term glycobiology had to be coined in the early 1980s'.Novel strategies for assembling oligosaccharides, glycoproteins, glycolipids and a range of glycoconjugates have flourishedever since providing access to glycomaterials for interrogating and interfering glycan function. This account focuseson the major breakthroughs made on the strategies during the last decades to synthetically reproduce the overwhelmingglycodiversity, emphasizing on the dazzling array of concepts and techniques which development was required to copewith the task. In the first place, a succinct overview of the structural and functional diversity of biologically relevant saccharidesand glycoconjugates will be given. Then, a selection of the most relevant strategies that composes the complexand diversity-oriented toolbox that modern carbohydrate synthesis consists on will be dissected. Finally, a selection of themost recent applications of this synthetic toolbox to chemical biology will be captured.

Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants (ASIA) - Animal Models as a Proof of Concept by Paola Cruz-Tapias, Nancy Agmon-Levin, Eitan Israeli, Juan-Manuel Anaya, Yehuda Shoenfeld (4030-4036).
ASIA syndrome, “Autoimmune (Auto-inflammatory) Syndromes Induced by Adjuvants” includes at least fourconditions which share a similar complex of signs and symptoms and have been defined by hyperactive immune responses:siliconosis, macrophagic myofasciitis syndrome, Gulf war syndrome and post-vaccination phenomena. Exposureto adjuvants has been documented in these four medical conditions, suggesting that the common denominator to thesesyndromes is a trigger entailing adjuvant activity. An important role of animal models in proving the ASIA concept hasbeen established. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely usedto understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development ofnew diagnostic, predictive and therapeutic methods. In the current review we wish to unveil the variety of ASIA animalmodels associated with systemic and organ specific autoimmune diseases induced by adjuvants. We included in this reviewanimal models for rheumatoid arthritis-like disease, for systemic lupus erythematosus-like disease, autoimmune thyroiddisease-like disease, antiphospholipid syndrome, myocarditis and others. All these models support the concept ofASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants.

Molecular Basis of Bicarbonate Membrane Transport in the Male Reproductive Tract by R. L. Bernardino, T. T. Jesus, A. D. Martins, M. Sousa, A. Barros, J. E. Cavaco, S. Socorro, M. G. Alves, P. F. Oliveira (4037-4049).
Bicarbonate (HCO3-) membrane transport systems are crucial players in the physiology of several tissues. Themolecular basis of HCO3- membrane transport is of major physiological relevance since this ion is involved in the establishmentof intracellular and extracellular ionic composition, osmolariy and pH. The membrane HCO3- transporters are dividedin two main families: solute carrier 4 (SLC4) and solute carrier 26 (SLC26), although HCO3- concentration can alsobe regulated by the cystic fibrosis transmembrane regulator (CFTR). In most tissues the SLC4 family represents the majorityof HCO3- transporters members, which can be divided in two subgroups: the Na+-dependent and the Na+-independent transporters. The SLC26 family consists of ten members that can transport diverse ions besides HCO3-.In the male reproductive tract, HCO3- transport occurs in several processes in order to assure a correct pursuance of thespermatogenetic event and spermatozoa capacitation, being also necessary for egg fertilization. Indeed, the formation ofcompetent spermatozoa, the maintenance of an adequate ductal luminal milieu and spermatozoa capacitation are highlydependent of ionic balance and pH. Perturbations in these processes result in reduced male reproductive health and consequentlymale subfertility and/or infertility. Thus, it is imperative to understand HCO3- transport dynamics in order to identifyand counteract possible alterations related with reduced male fertility caused by pathological conditions. Herein, wewill review the major families and subfamilies of HCO3- membrane transport, discussing the molecular basis of HCO3-transport in the male reproductive tract and its role in male-associated subfertility and/or infertility.

Medicinal Chemistry of the Epigenetic Diet and Caloric Restriction by S. L. Martin, T. M. Hardy, T. O. Tollefsbol (4050-4059).
The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulationhave been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance becauseof the concept that external factors such as nutrition and diet may possess the ability to alter gene expression withoutmodifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane(SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending thehuman lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake whileconcurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging processthrough histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposedas two important mechanisms that modulate and potentially slow the progression of age-related diseases such ascardiovascular disease (CVD), cancer, obesity, Alzheimer’s and osteoporosis to name a few. While many investigatorshave examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases,their epigenetic effects and their medicinal chemistry.

This review explores the different aspects of constitutional factors in early life that modulate toxicokinetics andtoxicodynamics of low-dose mercury resulting from acute ethylmercury (etHg) exposure in Thimerosal-containing vaccines(TCV).;Major databases were searched for human and experimental studies that addressed issues related to early life exposure toTCV. It can be concluded that: a) mercury load in fetuses, neonates, and infants resulting from TCVs remains in blood ofneonates and infants at sufficient concentration and for enough time to penetrate the brain and to exert a neurologic impactand a probable influence on neurodevelopment of susceptible infants; b) etHg metabolism related to neurodevelopmentaldelays has been demonstrated experimentally and observed in population studies; c) unlike chronic Hg exposure duringpregnancy, neurodevelopmental effects caused by acute (repeated/cumulative) early life exposure to TCV-etHg remainunrecognized; and d) the uncertainty surrounding low-dose toxicity of etHg is challenging but recent evidence indicatesthat avoiding cumulative insults by alkyl-mercury forms (which include Thimerosal) is warranted. It is important to a)maintain trust in vaccines while reinforcing current public health policies to abate mercury exposure in infancy; b) generallysupport WHO policies that recommend vaccination to prevent and control existing and impending infectious diseases;and c) not confuse the ’need’ to use a specific ‘product’ (TCV) by accepting as ’innocuous’ (or without consequences) thepresence of a proven 'toxic alkyl-mercury' (etHg) at levels that have not been proven to be toxicologically safe.

Synthesis, Structure-Activity Relationship and Biological Activity of Acridine Derivatives as Potent MDR-Reversing Agents by Jianhong Wang, Tianwei Luo, Shaobin Li, Yahong Zhhang, Chaojie Wang, Jin Zhao (4070-4079).
Multidrug resistance (MDR) mediated by P-glycoprotein is one of the best characterized transporter-mediatedbarriers to successful cancer chemotherapy. In an attempt to find MDR-reversing agents, a series of novel acridine derivativeswere synthesized and evaluated for their in vitro antiproliferative activities against K562 and K562/ADM cells.Some of these compounds showed superior MDR-reversing activities than Amsacrine, the reference compound. Structureactivityrelationships (SAR) of these compounds indicated that the N, N-diethylamine moiety had an affect on the in vitroantiproliferative activity. Interestingly, the compounds bearing N, N-diethylamine moiety showed higher growthinhibitoryactivity against K562/ADM cells than K562 cells. The high duplex DNA binding affinity and inhibition oftopoisomerase of these acridine compounds are maintained which were confirmed by fluorescent quenching and DNAtopoisomerase II cleavage assay, respectively. Moreover, several compounds were examined for their ability to increasethe accumulation of rhodamine 123 in K562 and K562/ADM cells, and the result suggested that they may be inhibitors forP-glycoprotein. Our study suggested that acridine framework is a potentially interesting scaffold for developing novelMDR-reversing agents.

Co-Drug Strategy for Promoting Skin Targeting and Minimizing the Transdermal Diffusion of Hydroquinone and Tranexamic Acid by Pei-Wen Hsieh, Wei-Yu Chen, Ibrahim. A. Aljuffali, Chun-Che Chen, Jia-You Fang (4080-4092).
Hydroquinone and tranexamic acids (TXA) are skin-lightening agents with a hydrophilic nature and low skinabsorption. A high dose is needed for clinical use, resulting in a high incidence of skin irritation. Co-drugs formed by conjugatinghydroquinone and TXA were synthesized and their in vitro and in vivo skin absorption characteristics wereevaluated. The two synthesized co-drugs were 4-hydroxyphenyl 4-(aminomethyl)cyclohexanecarboxylate (HAC) and 1,4-phenylene bis(aminomethyl)cyclohexanecarboxylate (BAC). The co-drugs were chemically stable in aqueous solution,but rapidly degraded to the respective parent drug in esterases and skin homogenates. Compared to hydroquinone application,7.2- and 2.4-fold increments in the hydroquinone skin deposition were obtained with the in vitro application of HACand BAC. HAC and BAC led to 3- and 2-fold enhancements of equivalent TXA deposition compared to TXA administration.The in vivo experiment showed a further enhancement of co-drugs compared to the in vitro setup. The transdermalpenetration of co-drugs, especially BAC, was much lower than that of hydroquinone and TXA. This indicated high-levelskin targeting by the co-drugs. HAC and BAC revealed strong affinities for the viable epidermis/dermis. Hair follicles areimportant reservoirs for co-drug delivery. Daily administration of co-drugs to the skin did not generate irritation for up to7 days. Both co-drugs are superior candidates for treating skin hyperpigmentation.