Mini Reviews in Medicinal Chemistry - Volume 17, Issue 3, 2017

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder, characterized, in most cases, by the presence of the Bcr-Abl fusion oncogene. Bcr-Abl is a constitutively active tyrosine kinase that is responsible for the malignant transformation. Targeting the Bcr-Abl kinase is an attractive treatment strategy for CML. First and second generation Bcr-Abl inhibitors have focused on targeting the ATP-binding domain of the kinase. Mutations in that region are relatively resistant to drug manipulation. Therefore, non-ATP-competitive agents have been recently developed and tested. In the present study, in an attempt to aid the design of new chemotypes with enhanced cytotoxicity against K562 cells, 3D pharmacophore models were generated and 3D-QSAR CoMFA and CoMSIA studies were carried out on the 33 novel Abl kinase inhibitors (E)-α-benzylthio chalcones synthesized by Reddy et al. A five-point pharmacophore with a hydrogen bond acceptor, two hydrophobic groups and two aromatic rings as pharmacophore features, and a statistically significant 3D-QSAR model with excellent predictive power were developed. The pharmacophore model was also used for alignment of the 33 compounds in a CoMFA/CoMSIA analysis. The contour maps of the fields of CoMFA and CoMSIA models were utilized to provide structural insight into how these molecules promote their toxicity. The possibility of using this model for the design of drugs for the treatment of β-thalassemia and sickle cell disease (SCD), since several Bcr-Abl inhibitors are able to promote erythroid differentiation and γ-globin expression in CML cell lines and primary erythroid cells is discussed.

Despite the introduction of more than 15 third generation antiepileptic drugs to the market from 1990 to the moment, about one third of the epileptic patients still suffer from refractory to intractable epilepsy. Several hypotheses seek to explain the failure of drug treatments to control epilepsy symptoms in such patients. The most studied one proposes that drug resistance might be related with regional overactivity of efflux transporters from the ATP-Binding Cassette (ABC) superfamily at the blood-brain barrier and/or the epileptic foci in the brain. Different strategies have been conceived to address the transporter hypothesis, among them inhibiting or down-regulating the efflux transporters or bypassing them through a diversity of artifices. Here, we review scientific evidence supporting the transporter hypothesis along with its limitations, as well as computer-assisted early recognition of ABC transporter substrates as an interesting strategy to develop novel antiepileptic drugs capable of treating refractory epilepsy linked to ABC transporters overactivity.

The small molecule nitric oxide (NO) plays important roles in many vital physiological and pathophysiological processes, including the modulation of cardiovascular processes, and key functions in the immune, nervous e respiratory systems. Several pathological conditions, such as sexual dysfunction and hypertension, are associated with deficiencies in the NO production or its inactivation. Due to the relative instability of NO in biological system, there is an increasing interest in the preparation of NO carriers as an efficient platform to carry and deliver therapeutic and relevant amounts of NO in biomedical applications. Among these approaches, NO-releasing nanomaterials have been described as promising strategy that could promote the spatio-temporal production of NO, in several pharmacological applications. The scope of this review is to point out the recent advances in the synthesis of versatile NO-releasing nanomaterials based on several materials, including polymeric nanoparticles, dendrimers, liposomes, solid lipid nanoparticles, metallic nanoparticles, silica nanoparticles, and carbon nanotubes. Although important progress in this area, some drawbacks still need to be overcome in order to translate these research innovations into practical applications. In this scenario, this review describes the state of the art of versatile nanostructured NO donors and their biomedical applications.

Nanotechnology has provided powerful tools to improve the chemotherapy of cancer. Different nanostructures have been developed which deliver the anticancer drugs more selectively to tumor than to healthy tissues. The result has generally been the increase in efficacy and safety of classical anticancer drugs. In recent years, several studies have focused not only on the delivery of anticancer drugs to tumors, but also on delivering the drugs to specific organelles of cancer cells. Endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria, and nucleus have been the targets of different nanostructured drug delivery systems developed with the goal of circumventing drugresistance, increasing drug efficacy, and so on. So far, the results described in the literature show that this strategy may be used to improve chemotherapy outcomes. In this review a discussion is presented on the strategies described in the literature to deliver anticancer drugs to specific organelles of cancer cells by using nanostructures.

Background: Pharmacoresistant epilepsy is a disabling neuronal disorder with harmful consequences that impact patient’s quality of life. Although psychiatric comorbidities are frequently present in patients with epilepsy, they are more common in those patients with pharmacoresistant epilepsy. Despite medical advances, the current existing therapeutic strategies for pharmacoresistant seizure control are not available for all patients and/or present disadvantages. Moreover, the conventional drug therapies for psychiatric comorbidities have several adverse effects. Therefore, in this field, nanotechnology arises as a novel tool for transporting drugs to the brain under pathological conditions with high efficiency and low side effects. Objective: Present an overview of nanotechnology as a novel, efficient and enhanced therapeutic strategy for controlling pharmacoresistant epilepsy and its associated psychiatric comorbidities. Conclusion: Nanotechnology emerges as a powerful tool for the control and/or treatment of pharmacoresistant epilepsy and its comorbidities in a more efficient and safer way than conventional treatments.

The Blood-Brain Barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu). Emphasis is made on two possible strategies to overcome the current limitations of in silico models: considering the prediction of brain penetration as a multifactorial problem, and increasing experimental datasets through accurate and standardized experimental techniques.

Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormonereleasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells.

The Janus kinases (JAKs) play a pivotal role in cytokine receptor signaling pathways via activation of downstream signal transducers and activators of transcription (STAT) pathway. Intracellular pathways that include JAKs are critical to immune cell activation and pro-inflammatory cytokine production. Selective inhibitors of JAKs are potentially disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis (RA). Each of the four members of the JAK family plays an individual role in the oncogenesis of the immune system, and therefore, the development of potent and specific inhibitors for each member is needed. Although there is a high sequence homology and structural identity of JAK1 and JAK2, such as a very similar binding mode of inhibitors at the ATPbinding site of enzymes, obvious differences surrounding the JAK1 and JAK2 ATP-binding sites provide a platform for the rational design of JAK2- and JAK1-specific inhibitors. In the present study, a dataset of 33 compounds characterized by a common scaffold of 2-amino-[1,2,4]triazolo[1,5-α]pyridine with well-defined in vitro activity values was computationally explored. Most of the compounds included in the dataset had higher ligand efficiency against JAK2 than JAK1. To improve further the selectivity of these triazolopyridines, Common Pharmacophore Hypotheses (CPHs) were generated and 3D-QSAR studies were carried out on them, in order to comprehend on the molecular features responsible for their selectivity. The proposed computational approach was applied in order to perform an in silico database virtual screening study with the aim to discover novel potent and selective JAK2 inhibitors.

Since the British scientist Michael Houghton along with George Kuo, Qui-Lim Choo (Chiron Corporation Emeryville), and Daniel W. Bradley (Centers for Disease Control and Prevention) codiscovered the causative agent of hepatitis C in 1989, so much progress has been made for the screening of blood donors and management of this chronic liver disease. In this regard, direct-acting antiviral agents (DAAs) have emerged as the potential “cure” of this slowly progressing and devastating disease. However, improvements are still clearly required since the anti-hepatitis C drugs currently available in the market are so extremely expensive (i.e. $94,500 for a 12-week course of treatment), that many patients will have a denied access to such drugs by their insurers. In the last few years, nanotechnology has emerged as a new platform for drug development, contributing significantly to the improvement of the administration and delivery of many drugs. Additionally, nanotechnologies can provide unique solutions even in poorer societies. This manuscript reviews the current knowledges on the available anti-hepatitis C drugs and the new drug candidates being investigated as well, and introduces the recent advances in nanocarrier-based delivery systems. Finally, the challenges in the development of drug delivery systems for the targeting of antiviral drugs to the liver are also discussed.

The discovery of disease modifying anti-Alzheimer’s molecules continues to be dared by: disease target multiplicity, downstream neurodegenerative biochemistry complexities, and genotype implications. A confluence of the above ingredients has contributed to a pipeline of creative molecules that regrettably underperform in clinical trials. Thus far, only five palliative pharmacotherapeutic agents, that is, four acetylcholine potentiating agents and an N-methyl-D-aspartate (NMDA) antagonist are clinically available. In this review we collectively describe the currently suggested targetable pathways for designing anti-Alzheimer’s agents (palliative and/or disease modifying). We are prompted to contribute in this manner out of a desire to simplify and consolidate, to a certain extent, the divergent target literature on Alzheimer’s drug discovery. We herein provide a summary update and perspective on realized and potentially druggable pharmacological targets for this CNS disorder. This article covers mostly the 2005-2015 medicinal chemistry/pharmacological/biological literature space on the subject.