Current Medicinal Chemistry (v.18, #28)
Monocyclic β-Lactams: New Structures for New Biological Activities by P. Galletti, D. Giacomini (4265-4283).
The azetidinone core-structure offers a unique approach to the design and synthesis of new derivatives with unique biologicalproperties. During the last two decades researches convincingly demonstrated that the prospect of structural modifications of monocyclicβ-lactams with specific substituents is an effective procedure for the detection and improvement of important pharmacological effects differentfrom antibacterial activity. As a matter of fact, new β-lactam compounds demonstrated biological activity as inhibitors of a widerange of enzymes. This review reports the latest developments on monocyclic β-lactam compounds activity as anticancer, antitubercular,HFAAH inhibitors, HDAC inhibitors, anti-inflammatory drugs (tryptase inhibitors), Cathepsin K inhibitors, and vasopressin inhibitors.We attempted to highlight the intertwined relationships between structural features and biological activities, by analysing groups anchoredon the three positions of the azetidinone ring as sources of molecular diversity.
New Therapeutic Strategy for Mood Disorders by R. Crupi, A. Marino, S. Cuzzocrea (4284-4298).
The development of new treatments for mood disorders, as anxiety and depression, is based on identification of neural substratesand the mechanisms underlying their etiology and pathophysiology. The heterogeneity of mood disorders indicates that its originmay lie in dysfunction of multiple brain regions (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex).The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests the contribute of new neurons to thebiology of mood disorders that is still under debate. The production of new neurons, referred to as neurogenesis, occurs throughout life indiscrete brain areas such as the dentate gyrus (DG) of the hippocampus and the subventricular zone/olfactory bulb. Findings describingthat neurogenesis process in DG is increased by antidepressants, like fluoxetine, and it is required for the behavioral effect of antidepressants,lead to a new strategy and drugs for the treatment of mood disorders. As many patients display poor response to therapy, researchon depression and antidepressant drugs is necessary. In this regard, focusing on neurogenesis and neuroplasticity processes in experimentalmodels is particularly interesting for the understanding of the pathophysiology of mood disorders and should define the role of adultbornneurons in hippocampal physiology. Different classes of drugs are currently prescribed for the treatment of mood disorders. Amongthem selective serotonin reuptake (SSRIs), monoamine oxidase inhibitors (MAOIs), specific norepinephrine reuptake inhibitors (SNRIs)and tricyclic acids (TCA) alleviate symptoms of mood disorders. Here we review different strategies that may be adopted for impairingmood disorders and that may be further developed for innovative therapeutic approaches.
Alzheimer’s Disease: Emerging Trends in Small Molecule Therapies by T. Mohamed, P.P.N. Rao (4299-4320).
Alzheimer’s disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by thesystemic collapse of cognitive function and formation of dense amyloid plaques and neurofibrillary tangles. AD pathology is derivedfrom the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such asAricept® and Exelon®, only offer symptomatic relief without any disease-modifying effects. It is now clear that in order to prevent therapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional one drug, onetarget approach. This review will focus on the recent advances in medicinal chemistry aimed at the development of small moleculetherapies that target various AD pathological routes such as the cholinesterases (AChE and BuChE), amyloidogenic secretases (β/γ-secretase), amyloid-β aggregation, tau phosphorylation and fibrillation and metal-ion redox/reactive oxygen species (ROS). Some notablering templates will be discussed along with their structure-activity relationship (SAR) data and their multiple modes of action. Theseemerging trends signal a paradigm shift in anti-AD therapies aimed at the development of multifunctional small molecules as diseasemodifyingagents (DMAs).
Targeting Opioid and Neurokinin-1 Receptors to Treat Alcoholism by F.D. Rodriguez, R. Covenas (4321-4334).
Alcoholism is a multifarious and ongoing disease tightly related to the amount of alcohol ingested, the drinking pattern, thehistory of alcohol drinking and the individual features, such as some genetic traits. Worldwide alcohol is the necessary cause of approximately60 diseases and causes circa 2.5 million deaths every year. Studies show that alcohol interacts with brain neurotransmission in acomplex manner. Dopaminergic, GABAergic, serotonergic, cholinergic and glutamatergic systems are all key participants in the action ofethanol on the brain. Furthermore, several neuropeptides, such as endogenous opioid peptides, substance P, corticotropin-releasing hormone,or the appetite-regulating peptides (eg., neuropeptide Y, ghrelin or orexin) also play a role in alcohol drinking. Treatment of alcoholuse disorders (AUD) is based on the application of combined approaches, including pharmacological intervention directed to differentmolecular targets. Results, however, are variable, not always satisfactory, and not applicable to all stages and pathologies or to all patients.New strategies focused on the control of neuropeptide performance in the brain are being explored and may be an advance in thetherapy of alcoholism. The application of treatments ad personam represents a challenge that currently stimulates research in differentrealms, including epidemiology, psychology, chemistry, biochemistry, cell biology and pharmacology. In this review the potential valueand application of ligands that modulate the function of opioid and neurokinin-1 receptors in alcoholism therapy is analyzed.
Hypoxia Inducible Factor-1 as a Target for Neurodegenerative Diseases by Z. Zhang, J. Yan, Y. Chang, S. ShiDu Yan, H. Shi (4335-4343).
Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension.HIF-1, a heterodimer consisting of a constitutively expressed β subunit and an oxygen-regulated α subunit, regulates a series ofgenes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The activity of HIF-1 is controlledby post-translational modifications on different amino acid residues of its subunits, mainly the alpha subunit. Besides in ischemicstroke (see review ), emerging evidence has revealed that HIF-1 activity and expression of its down-stream genes, such as vascular endothelialgrowth factor and erythropoietin, are altered in a range of neurodegenerative diseases. At the same time, experimental and clinicalevidence has demonstrated that regulating HIF-1 might ameliorate the cellular and tissue damage in the neurodegenerative diseases.These new findings suggest HIF-1 as a potential medicinal target for the neurodegenerative diseases. This review focuses on HIF-1α proteinmodifications and HIF-1’s potential neuroprotective roles in Alzheimer’s (AD), Parkinson’s (PD), Huntington’s diseases (HD), andamyotrophic lateral sclerosis (ALS).
Evaluation of Anticonvulsants for Possible Use in Neuropathic Pain by A.M. Waszkielewicz, A. Gunia, K. Sloczynska, H. Marona (4344-4358).
Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy,neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin,gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepilepticdrugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned outthat 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is alreadya phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity.Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain.This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathicpain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), theBennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine,gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproicacid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has beendiscussed.
Promoting Adult Hippocampal Neurogenesis: A Novel Strategy for Antidepressant Drug Screening by H.-C. Yan, X. Cao, T.-M. Gao, X.-H. Zhu (4359-4367).
Major depression is a common mood disorder that affects overall health; currently, almost all of the available antidepressantshave the same core mechanisms of action through promotion of serotonin or noradrenaline function in the brain. The major limitation oftoday’s antidepressants is that chronic treatment (3 - 6 weeks) is required before a therapeutic benefit is achieved. More effective andfaster treatments for depression are needed. Adult neurogenesis is the birth of new neurons, which continues postnatally and into adulthoodin the brains of multiple species, including humans. Recently, a large body of evidence gives rise to the hypothesis that the antidepressanteffect and increases in adult hippocampal neurogenesis may be causally related. Multiple classes of antidepressants increase hippocampalneurogenesis in a chronic, but not acute, time course. This effect corresponds to the therapeutic time lag associated with currentantidepressants. In addition, antidepressants are not effective in behavioral models of depression when hippocampal neurogenesis is prevented.This review examines the current understanding of adult neurogenesis and the evidence of the causal relationship between antidepressanteffects and adult hippocampal neurogenesis. We also present our recent research findings, which support a promising strategyfor enhancing adult hippocampal neurogenesis that might be a new approach for the development of novel antidepressants.
Current Inhibitors of Checkpoint Kinase 2 by T.N.T. Nguyen, J.J. Tepe (4368-4374).
Checkpoint kinase 2 is a serine/threonine protein which functions as an important transducer in apoptosis or DNA repairfollowing activation by DNA damage. Inhibition of checkpoint kinase 2 is thought to sensitize p53-mutated or p53-deficient cancerouscells but protect normal tissue following DNA-damage caused by ionizing radiation or chemotherapeutic agents. The development ofcheckpoint kinase inhibitors for the treatment of cancer has therefore been a major objective in drug discovery over the past decade.Several inhibitors have been co-crystallized in the active site of checkpoint kinase 2 revealing important features of effective inhibitors.Some of these inhibitors have entered clinical trials in the last decade. This review describes and discusses the most recent inhibitors ofcheckpoint kinase 2 as reported in the literature, including an evaluation of biological activity.
Evolving Molecular Mechanism-Based Strategies for Control of Hepatocellular Carcinoma by K. Sato, M. Mori (4375-4388).
Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide. Unresectable or metastatic HCC has a poorprognosis, and systemic cytotoxic chemotherapy has failed to show a substantial benefit for patients with HCC. However, there has beenincreasing interest in developing novel molecularly targeted agents in HCC due to the accumulation of knowledge of cell signaling andmolecular carcinogenesis. Furthermore, some of these agents have proven to be efficacious in other traditionally challenging carcinomas,such as renal cell carcinoma. Recently, a phase III, randomized, placebo-controlled trial demonstrated that sorafenib, an oral multikinaseinhibitor of the vascular endothelial growth factor receptor and Ras kinase, improves overall survival (OS) in patients with advancedHCC. This seminal study described the first agent to improve OS in HCC and began a new era of molecule-targeted cancer therapies.Currently, many novel molecularly targeted agents are under evaluation in clinical trials. In this review, we comprehensively summarizethe molecular pathogenesis, targets, and signal transduction pathways involved in HCC. We also detail the current status of molecularlytargeted agents that are under clinical development in advanced HCC, including the mechanisms of action of these agents.
New Strategies in the Discovery of Novel Non-Camptothecin Topoisomerase I Inhibitors by Chunquan Sheng, Zhenyuan Miao, Wannian Zhang (4389-4409).
Topoisomerase I (Top1) represents an important target of active interest in developing novel anticancer agents. Camptothecinderivatives are the only class of clinically approved Top1 inhibitors and show potent efficacy in anticancer therapy. However, there arealso several major limitations for them, such as poor chemical stability, drug resistance, long infusions and side effects. To overcome thedrawbacks of the camptothecins, the discovery of non-camptothecin Top1 inhibitors has recently emerged as a promising field to findbetter antitumor agents. Non-camptothecin Top1 inhibitors are expected to possess better chemical stability, different therapeutic activitiesand antitumor spectrum, improved pharmacokinetics and lower toxicity. This review focuses on various strategies that were used inthe discovery of non-camptothecin Top1 inhibitors. In particular, the chemical scaffolds, structure-activity relationships and bindingmodes of the newly identified non-camptothecin Top1 inhibitors are discussed in detail.
Recent Progress in Medicinal Investigations on Trichosanthin and other Ribosome Inactivating Proteins from the Plant Genus Trichosanthes by E.F. Fang, T.B. Ng, P.C. Shaw, R.N.S. Wong (4410-4417).
Ribosome inactivating proteins (RIPs) are toxic RNA N-glycosidases that cleave an adenine-ribose glycosidic bond at positionadenine4324 with the conserved ricin/..-sarcin loop in the eukaryotic 28S ribosomal RNA. RIPs have captured the attention of botanists,biochemists, and drug discoverers, due to their diverse potent defensive activities, and inter alia, their antitumor and anti-HIV activities.Out of the 145 families of plants, Trichosanthes ranks among the top 5 genera with a good potential of use for discovery of anticancerdrugs. Trichosanthin (TCS) is a famous type I RIP purified from T. kirilowii that has been known for around 30 years. Based on the resultsof voluminous in vitro and in vivo investigations, TCS is considered a good candidate for the treatment of HIV/AIDS and neoplasms.Here we integrate recent progress of the research on the different medicinal activities of TCS. In addition to TCS, other promisingRIPs from the same species (such as TAP29 and trichoanguin), and from the same genus Trichosanthes are included. This reviewpresents a brief panorama of the studies on Trichosanthes RIPs. Regarding the debilitating nature of AIDS and different tumors, furtherunderstanding of these multifunctional proteins is worthwhile since it may help to open a novel therapeutic window for these stubborndiseases.