Current Medicinal Chemistry (v.20, #22)
Targeting Heat Shock Proteins in Prostate Cancer by W. Hessenkemper, A. Baniahmad (2731-2740).
Heat shock proteins (HSPs) and chaperones are highly conserved stress-induced factors. They regulate not onlyprotein folding and stability but are also actively involved in protein transport and transcriptional regulation. HSPs havecytoprotective roles and are essential for cancer cell survival. Noteworthy, HSPs are often upregulated in cancer. Therefore,HSPs emerged as drug targets for cancer therapy. Especially for prostate cancer (PCa) therapy, a battery of differentcompounds has been identified that act with different modes to inhibit PCa growth. The androgen receptor (AR) is a majorplayer in PCa progression and is a well-known interacting factor of HSPs. Since the AR function is very dependent onHSP activity, many emerging compounds address the AR-associated HSPs as novel drug targets. Here, we provide an insightinto the different classes of HSPs, their association with the human AR, the role of HSPs in human PCa developmentand review also the targeting of HSPs in human PCa. Further, the function and the underlying molecular mechanisms ofspecific compounds that are currently under investigation for the use against PCa growth will be comprehensively summarized.
Endomorphin Derivatives with Improved Pharmacological Properties by Pegah Varamini, Joanne Blanchfield, Istvan Toth (2741-2758).
Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment ofsevere pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratorydepression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathicpain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociceptionin rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, nativeendomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins sufferfrom poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier.Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesizedwith the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation.In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associatedwith endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in additionto application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approachesthat resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effectsare also discussed giving an insight into the development of opioid peptides with an improved side effect profile.
The Fate of Nanocarriers As Nanomedicines In Vivo: Important Considerations and Biological Barriers to Overcome by M. Moros, S. Mitchell, V. Grazu, J.M. de Fuente (2759-2778).
Many pharmaceuticals on the market suffer from two significant limitations to their activity: lack of specificitytoward the pathological site and poor aqueous solubility. Both factors therefore require the application of a large total doseof a drug to achieve high local concentration, causing numerous off-target toxic effects. Consequently, the grand aim oftargeted drug delivery - the often-referred "magic bullet" - promises to improve drug concentration at the target site andmaximize therapeutic response. Nanomaterial drug delivery systems have been explored extensively in the recent yearsfor just this purpose. In the field of medicine, nanocarriers (NCs) have the potential to improve the biodistribution andpharmacokinetic characteristics of drugs, thereby reducing side effects while improving the therapeutic effect of drugs.Many nanomaterials are exquisitely designed and possess potent properties, yet it is extremely important to note that ageneral understanding of the interaction of nanomaterials with biological systems is essential for any such model propertiesto be effective in vivo, since the body presents a host of biological 'barriers' that will be encountered drug NCs. Thisreview offers a general overview of the different biological obstacles that a NC must negotiate before it can carry out itsdesired role as a medicinal agent. From this standpoint we suggest aspects that should be considered for the rational designof novel nanomaterials possessing physicochemical properties that are appropriate for therapeutic or theragnostic applications.
Platelets and Atherothrombosis: Causes, Targets and Treatments for Thrombosis by T. Siddiqui, A. Kumar S., D. Dikshit (2779-2797).
Arterial thrombosis is the acute complication that develops on the chronic lesions of atherosclerosis and reasonsheart attack and stroke, today the most common causes of mortality in developed countries. According to the WHO, 17.1million people died world wide of cardiovascular diseases (CVD), per year, accounting for one-third of all deaths globally.On the basis of current estimates from the American Heart Association, more than 60 million people in the UnitedStates alone have one or more forms of cardiovascular disease, and a high proportion of these individuals are at increasedrisk of arterial thrombosis. The involvement of platelets in atherogenesis and the subsequent formation of occlusivethrombi depend on platelets' adhesive properties and the ability to respond to stimuli with rapid activation. Byunderstanding the multifaceted mechanisms involved in platelet interactions with vascular surfaces and aggregation, newapproaches can be tailored to selectively inhibit the pathways most relevant to the pathological aspects ofatherothrombosis. The present review aims to describe the haemostasis phenomenon along with the centrality of theplatelet in atherothrombosis, and briefly looks at the efficacy of reported antiplatelet agents.
Synthetic Approaches Towards the Marine Alkyl Purines by M. Gordaliza, P. Baraldi (2798-2811).
Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolatedfrom numerous genera of sponges (Agela sp, Raspailia sp). Nuttingins and malonganenones are tetraprenylatedpurine alkaloids from gordonian (Eplexura sp, Leptogorgia sp). Some of these alkaloids displayed broad spectrum activityincluding cytotoxic activity against several cancer cells. The review summarizes the synthesis of mono- or bi-cyclic diterpenoidsusually having a 9-methyladenine moiety.
Mechanisms of Herb-Induced Nephrotoxicity by T. Allard, T. Wenner, H. Greten, T. Efferth (2812-2819).
Herbal therapies gained much popularity among the general public, but compared to therapies approved by officialauthorities, toxicological studies are frequently not available for them. Hence, there may be inherent risks and thekidneys may be especially vulnerable to toxic effects. Herbs may induce nephrotoxicity by induction of apoptosis. Highoxalate contents in Star fruit (Averrhoa carambola L.) may induce acute nephropathy. Triptolide from Thunder God Vine(Triperygium wilfordii Hook) is a diterpenoid epoxide with induces reactive oxygen species and nephrotubular apoptosis.Cranberry juice is discussed as promoter of kidney stone formation (nephrolithiasis). Abuse of guaifenesin from Roughbark(Guaicum officinale L.) increases stone formation. Aristolochia acids from Aristolochia fangchi Y.C.Wu ex L.D.Chow & S.M. Hwang causes the well-known aristolochic acid nephropathy and carcinogenesis by DNA adduct formation.Carboxyatractyloside from Impila (Callilepsis laureola DC.) inhibits mitochondrial ATP synthesis. Acute allergic interstitialnephritis was diagnosed after intake of Peruvian Cat's claw (Uncaria tomentosa Willd. DC.). Whether or not WillowBark (Salix alba L.) induces analgesic nephropathwy is a matter of discussion. Other herbal therapies are considered to affectthe rennin-angiotensisn-aldosterone (RAA) system Ephedra sinica Stapf with its ingredient ephedrine. Devil's Claw(Harpagophytum procumbens DC. Ex Meisn.) and licorice (Glycyrrhiza glabra L.) may inhibit major renal transportprocesses needed for filtration, secretion, and absorption. Strategies to minimize nephrotoxicity include (1) quality controland standardization of herbal products, (2) research on the molecular modes of action to better understand pathophysiologicalmechanisms of herbal products as well as (3) clinical trials to demonstrate efficacy and safety.
Benzofuran-Based Estrogen Receptor α Modulators as Anti-Cancer Therapeutics: In Silico and Experimental Studies by Min Leow, Hui Li Chin, Peggy Yu, Kalyan Pasunooti, Raymond Xu Tay, Dawei Zhang, Ho Yoon, Xue-Wei Liu (2820-2837).
In the search for new estrogen receptor alpha (ERα) modulators, a trial molecular screening was conducted and5,6-dihydroxybenzofuran was identified as a possible drug target for ERα. The target molecular modelling molecule 1 anda series of 5,6-dihydroxybenzofurans have been synthesized and evaluated for their anti-proliferation activities againstMCF-7 and MDA-MB-231 cells. From the SAR studies, potential functional groups have been identified, the two hydroxylgroups at C-5 and C-6 and the phenyl ring at C-2, which showed considerable cytotoxicity in MCF-7 breast cancercells. In addition, the apoptotic abilities of the compounds have been measured in both MCF-7 ER(+) and MDA-MB-231ER(-) breast cancer cells. The results demonstrated that our compounds inhibit MCF-7 breast cancer cells via ER(+).These preliminary results provide valuable information towards the identification of important functional groups presenton 5,6-dihydroxybenzofuran, which could be a promising scaffold for designing novel ER ligands.