Current Medicinal Chemistry - Volume 28, Issue 13, 2021

This review outlines the discovery and development of a novel series of 1-[4-2- aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-piperidones (5-8) as potential drug candidates over the last 15 years in our laboratory. Many of these compounds demonstrate excellent cytotoxic properties and are often more potent than contemporary anticancer drugs. Two highly important features of many of these molecules are first, the greater tumour-selective toxicity and second, the ability of these molecules to act as modulators of multi-drug resistance. The modes of action of some of the potent compounds are by apoptosis induction, generation of reactive oxygen species, activation of certain caspases and affecting mitochondrial functions. These molecules also display promising antimalarial and antimycobacterial properties. In a short term toxicity study, these molecules are well tolerated in mice. Structure-activity relationships and a drug delivery system along with pharmacokinetic studies and metabolic stability of these compounds, have been presented. The positive characteristics associated with the series (5-8) warrant their further evaluations as candidate antineoplastic drug candidates.

Background: Triterpenes are a large group of secondary metabolites mainly produced by plants with a variety of biological activities, including potential antitumor effects. Hepatocellular carcinoma (HCC) is a very common primary liver disease spread worldwide. The treatment can consist of surgical intervention, radiotherapy, immunotherapy and chemotherapeutic drugs. These drugs mainly include tyrosine multikinase inhibitors, although their use is limited by the underlying liver disease and displays side effects. For that reason, the utility of natural compounds such as triterpenes to treat HCC is an interesting line of research. No clinical studies are reported in humans so far. Objective: The aim of the present work is to review the knowledge about the effects of triterpenes as a possible coadjuvant tool to treat HCC. Results: In vitro and xenograft models have pointed out the cytotoxic and anti-proliferative effects as well as improvements in tumor growth and development of many triterpenes. In addition, they have also shown to be chemosensitizing agents when co-administered with chemotherapeutic agents. The mechanisms of action are diverse and involve the participation of mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, and the survival-associated PI3K / Akt signaling pathway. However, no clinical studies are still reported in humans. Conclusion: Triterpenes could become a future strategy to address HCC or at least improve results when administered in combination with chemotherapeutic agents.

Targeted therapy has been recently highlighted due to the reduction of side effects and improvement in overall efficacy and survival from different types of cancers. Considering the approval of many monoclonal antibodies in the last twenty years, cancer treatment can be accomplished by the combination of monoclonal antibodies and small molecule chemotherapeutics. Thus, strategies to combine both drugs in a single administration system are relevant in the clinic. In this context, two strategies are possible and will be further discussed in this review: antibody-drug conjugates (ADCs) and antibody-functionalized nanoparticles. First, it is important to better understand the possible molecular targets for cancer therapy, addressing different antigens that can selectively bind to antibodies. After selecting the best target, ADCs can be prepared by attaching a cytotoxic drug to an antibody able to target a cancer cell antigen. Briefly, an ADC will be formed by a monoclonal antibody (MAb), a cytotoxic molecule (cytotoxin) and a chemical linker. Usually, surface-exposed lysine or the thiol group of cysteine residues are used as anchor sites for linker-drug molecules. Another strategy that should be considered is antibody-functionalized nanoparticles. Basically, liposomes, polymeric and inorganic nanoparticles can be attached to specific antibodies for targeted therapy. Different conjugation strategies can be used, but nanoparticles coupling between maleimide and thiolated antibodies or activation with the addition of ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) (1:5) and further addition of the antibody are some of the most used strategies. Herein, molecular targets and conjugation strategies will be presented and discussed to better understand the in vitro and in vivo applications presented. Also, the clinical development of ADCs and antibody-conjugated nanoparticles are addressed in the clinical development section. Finally, due to the innovation related to the targeted therapy, it is convenient to analyze the impact on patenting and technology. Information related to the temporal evolution of the number of patents, distribution of patent holders and also the number of patents related to cancer types are presented and discussed. Thus, our aim is to provide an overview of the recent developments in immunoconjugates for cancer targeting and highlight the most important aspects for clinical relevance and innovation.

Background: Air ions (AIs) are clusters of ionized particles present in the atmosphere, carrying an electrical charge of negative or positive polarity. Past speculations suggested that exposure to positive air ions may be harmful, while exposure to negative air ions (NAIs) may be associated with beneficial health effects. Increasing attention has been directed towards investigating the potential effect of NAIs on human brain activities since initial observations of their beneficial effects on some cognitive processes and mood. Aims: Given the paucity and scattered literature, our paper aims to review the available studies on potential positive effects of NAIs exposure on cognitive performances and depression. Discussion: The review of the literature seems to confirm the effects of NAIs on several brain functions. Indeed, a significant association between NAIs exposure and both well-being and high cognitive performances has been described. Furthermore, exposure to high concentrations of NAIs could be related to the improvement of depressive symptoms. Conclusion: A growing evidence of data, although not yet conclusive, would suggest that NAIs might improve cognitive processes. These findings require specific and urgent controlled trials adopting systems based on AIs release to possibly prevent and treat cognitive dysfunctions present in a broad range of neuropsychiatric conditions.

Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.

Background: Ghrelin, a unique 28 amino acid peptide hormone secreted by the gastric X/A like cells, is an endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin-GHSR signaling has been found to exert various physiological functions, including stimulation of appetite, regulation of body weight, lipid and glucose metabolism, and increase of gut motility and secretion. This system is thus critical for energy homeostasis. Objective: The objective of this review is to highlight the strategies of ghrelin-GHSR based intervention for therapy of obesity and its related metabolic diseases. Results: Therapeutic strategies of metabolic disorders targeting the ghrelin-GHSR pathway involve neutralization of circulating ghrelin by antibodies and RNA spiegelmers, antagonism of ghrelin receptor by its antagonists and inverse agonists, inhibition of ghrelin O-acyltransferase (GOAT), as well as potential pharmacological approach to decrease ghrelin synthesis and secretion. Conclusion: Various compounds targeting the ghrelin-GHSR system have shown promising efficacy for the intervention of obesity and relevant metabolic disorders in animals and in vitro. Further clinical trials to validate their efficacy in human beings are urgently needed.

Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.