Current Medicinal Chemistry - Volume 29, Issue 13, 2022

Background: The carboxylic acid moiety is an important functional group which features in the pharmacophore of some 450 drugs. Unfortunately, some carboxylic acid-containing drugs have been withdrawn from market due to unforeseen toxicity issues. Other issues associated with the carboxylate moiety include reduced metabolic stability or limited passive diffusion across biological membranes. Medicinal chemists often turn to bioisosteres to circumvent such obstacles. Objective: The aim of this review is to provide a summary of the various applications of novel carboxylic acid bioisosteres which have appeared in the literature since 2013. Results: We have summarised the most recent developments in carboxylic acid bioisosterism. In particular, we focus on the changes in bioactivity, selectivity or physicochemical properties brought about by these substitutions, as well as the advantages and disadvantages of each isostere. Conclusion: The topics discussed herein highlight the continued interest in carboxylate bioisosteres. The development of novel carboxylic acid substitutes which display improved pharmacological profiles is a testament to the innovation and creativity required to overcome the challenges faced in modern drug design.

Caffeinated beverages are the most widely consumed beverages globally with coffee and tea as the two most prominent sources of caffeine. Caffeine content varies across different types of beverages. In addition to caffeine, coffee and tea have other biologically active compounds, and all may affect general and cardiovascular (CV) health. Moderate caffeine consumption (<300-400 mg/day), regardless of the source, is considered safe by both European and US Health Authorities, as it is not associated with adverse health and CV effects, while it may confer certain health benefits. There is a nonlinear association between coffee ingestion and CV risk; moderate coffee drinking is inversely significantly associated with CV risk, with the highest benefit at 2-4 cups per day, while heavy coffee drinking might confer increased risk. With regards to tea, due to a lower caffeine content per serving, its consumption is only limited by the total caffeine daily intake. Both these caffeinated beverages, coffee and tea, have additional phenolic compounds, with anti-oxidant and anti-inflammatory activities, which confer cardioprotective benefits. Of the several coffee compounds, chloroacetic acids and melanoidins offer such beneficial effects, while diterpenes may have unfavorable effects on lipids. Most of the tea ingredients (polyphenols) are cardioprotective. A major concern relates to energy drinks with their much higher caffeine content which puts individuals, especially adolescents and young adults, at high health and CV risk. All these issues are herein discussed, including pertinent studies and meta-analyses, pathogenetic mechanisms involved and relevant recommendations from health authorities.

Doublecortin-like kinase 1 (DCLK1) has emerged over the last decade as a unique stem cell marker within gastrointestinal tissues. Evidence from mouse models shows that high Dclk1 expression denotes a population of cells that promote tissue regeneration and serve as potential cancer stem cells. Moreover, since certain DCLK1 isoforms are overexpressed in many cancers and not normal cells, targeting the expression or kinase activity of DCLK1 has the potential to inhibit cancer cell growth. Here, we review the evidence for DCLK1 as a prospective cancer target including its isoform-specific expression and mutational status in human cancers. We further discuss the challenges and current progress in the development of small molecule inhibitors of DCLK1.

Background: Cancer cells are usually recognized as foreign particles by the immune cells. Mounting evidence suggest an important link between toll-like receptors (TLRs) and carcinogenesis. This review article focused on the role of TLRs, especially TLR4, in breast cancer. Methods: Research data on TLRs and cancer was explored in PubMed, Scopus, Google Scholar and reviewed. Although some pioneer works are referenced, papers published in the last ten years were mostly cited. Results: TLRs are widely investigated pattern recognition receptors (PRR), and TLR4 is the most studied TLRs, implicated with the occurrence of several types of cancers, including breast cancer. TLR4 activation occurs via the binding of its ligand lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria. Upon LPS binding, TLR4 dimerizes and recruits downstream signalling and/or adapter molecules, leading to gene expression related to cancer cell proliferation, survival, invasion, and metastasis. Although LPS/TLR4 signalling seems a single signal transduction pathway, the TLR4 activation results in the activation of multiple diverse intracellular networks with huge cellular responses in both immune and cancer cells. The role of TLR4 in the growth, invasion, and metastasis of breast cancer is attracting huge attention in oncology research. Several clinical and preclinical studies utilize both TLR4 agonists and antagonists as a treatment option for cancer therapy, either as monotherapy or adjuvants for vaccine development. Conclusion: This review narrates the role of LPS/TLR4 signalling in breast cancer development and future prospects for targeting LPS/TLR4 axis in the treatment of breast cancer.

The unique features of the tumor microenvironment (TME) govern the biological properties of many cancers, including hematological malignancies. TME factors can trigger an invasion and protect against drug cytotoxicity by inhibiting apoptosis and activating specific signaling pathways (e.g. NF-B). TME remodeling is facilitated due to the high self-renewal ability of the bone marrow. Progressing tumor cells can alter some extracellular matrix (ECM) components which act as a barrier to drug penetration in the TME. The initial progression of the cell cycle is controlled by the MAPK pathway (Raf/MEK/ERK) and Hippo pathway, while the final phase is regulated by the PI3K/Akt /mTOR and WNT pathways. This review summarizes the main signaling pathways involved in drug resistance (DR) and some mechanisms by which DR can occur in the bone marrow. The relationship between autophagy, endoplasmic reticulum stress, and cellular signaling pathways in DR and apoptosis is covered in the TME.

Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved “pan” HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2–6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 μM and 7.7 μM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.

The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and is dynamically adjusted according to the energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis are discussed.

Scaffolds of metal-based compounds can act as pharmacophore groups in several ligands to treat various diseases, including tropical infectious diseases (TID). In this review article, we investigate the contribution of these moieties to medicinal inorganic chemistry in the last seven years against TID, including American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT, sleeping sickness), leishmania, and malaria. The most potent metal-based complexes are displayed and highlighted in figures, tables and graphics; according to their pharmacological activities (IC50 > 10μM) against Trypanosomatids and Plasmodium spp parasites. We highlight the current progresses and viewpoints of these metal-based complexes, with a specific focus on drug discovery.