Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 15, 2022

Proteolysis targeting chimeras (PROTACs) are an emerging class of targeted protein degraders that coopt the intracellular degradation machinery to selectively deplete their respective targets. PROTACs act as bifunctional degraders that comprise ubiquitin E3 ligase- and target-binding moieties connected by chemical linkers with appropriate physicochemical properties. Through this bivalent structure, PROTACs induce the degradation of their targets via proximity-based pharmacology. Compared to conventional inhibitors, PROTACs exhibit superior pharmacologic properties in terms of efficacy, potency, selectivity, the durability of response, and efficacy against undruggable proteins. Over the last few years, the scientific community has witnessed significant endeavors to advance this field and expand the armamentarium of PROTACs. In this perspective, we highlight these advances with an emphasis on emerging PROTAC variants, PROTACtability and degradability of protein targets, expression-guided PROTACs, multivalent PROTACs, preclinical resistance, candidates evaluated in clinical trials, and prospects for the use of PROTACs as a therapeutic modality.

Protein kinases are amongst the most focused enzymes in the current century to design, synthesize and formulate drugs that ought to be effective in the treatment of various disordered and diseased states involving either overexpression or deficiency situations. The ATP pocket on the kinases is the active binding site for most of the kinase inhibitors. However, the kinase mutations prevent the binding of kinase inhibitors to the ATP pocket. The enzyme becomes inactive even in the mutated state when the switch pocket site on the enzyme is occupied by switch pocket inhibitors. This review comprises detailed information regarding various classical protein kinases and switch pocket kinase inhibitors with their mechanism of action so that new molecules can be designed to encounter mutations in the kinase enzyme.

Liposomes are one of the most versatile drug carriers due to their functional properties, such as higher biocompatibility, the ability to encapsulate hydrophilic and hydrophobic products, and higher biodegradability. Liposomes are a better and more significant nanocarrier for cancer therapy. The key to developing a better cancer-targeted nanocarrier is the development of targeted liposomes using various approaches. Several traditional and novel liposome preparation methods are briefly discussed in this mini-review. The current state of liposome targeting, active and passive liposome targeting in cancer therapy, ligand directed targeting (antibody, aptamer, and protein/peptide-mediated targeting), and other miscellaneous approaches such as stimuli-responsive liposome-based targeting, autophagy inhibition mediated targeting, and curcumin loaded liposomal targeting are all discussed within. All of this gathered and compiled information will shed new light on liposome targeting strategies in cancer treatment and will pique the interest of aspiring researchers and academicians.

Metal based therapy is no new in biomedical research. In early days, the biggest limitation was the inequality among therapeutical and toxicological dosages. Ever since, Barnett Rosenberg discovered cisplatin, a new era has begun to treat cancer with metal complexes. Platinum complexes such as oxaliplatin, cisplatin, and carboplatin, seem to be the foundation of metal/s-based components to challenge malignancies. With advancement in the biomolemoecular mechanism, researchers have started developing non-classical platinum-based complexes, where a different mechanistic approach of the complexes is observed towards the biomolecular target. Till date, larger numbers of metal/s-based complexes were synthesized by overhauling the present structures chemically by substituting the ligand or preparing the whole novel component with improved cytotoxic and safety profiles. Howsoever, due to elevated accentuation upon the therapeutic importance of metal/s-based components, a couple of those agents are at present in clinical trials and several other are in anticipating regulatory endorsement to enter the trial. This literature highlights the detailed heterometallic multinuclear components, primarily focusing on platinum, ruthenium, gold and remarks on possible stability, synergism, mechanistic studies and structure activity relationships.

Despite modern medicine advances greatly, cancer remains a serious challenge to world health for which effective methods of treatment have hardly been developed yet. However, throughout recent years, rapid-developing nanotechnology has provided a new outlook on cancer therapy by transdermal drug delivery. By disrupting the stratum corneum, drugs are delivered through the skin and navigated to the tumor site by drug delivery systems such as nanogels, microneedles, etc. The superiorities include the improvement of drug pharmacokinetics as well as reduced side effects. This paper reviews the reported novel development of transdermal drug delivery systems for targeted cancer therapy. Advanced techniques for penetrating the skin will be discussed as well.

Background: Selenium nanoparticles (SeNPs) have gained a place in the biomedical field; they serve as chemotherapeutic agents for targeted drug delivery due to their capacity to exert distinct mechanisms of action on cancer and normal cells. The principle behind these mechanisms is the generation of reactive oxygen species (ROS), which accelerates apoptosis via the dysfunction of various pathways. SeNPs, when used in higher concentrations, induce toxicity; however, conjugation and surface functionalization are some techniques available to ameliorate their toxic nature as well as enhance their anticancer activity. Objectives: The primary goal of this analysis is to provide a thorough and systematic investigation into the use of various SeNPs in localized drug targeting for cancer therapy. This has been achieved by citing examples of numerous SeNPs and their use as a drug targeting agent for cancer therapy. Methods: All relevant data and information about the various SeNPs for drug targeting in cancer therapy were gathered from various databases, including Science Direct, PubMed, Taylor and Francis imprints, American Chemical Society, Springer, Royal Society of Chemistry, and Google Scholar. Results: SeNPs are explored due to their better biopharmaceutical properties and cytostatic behavior. Se, as an essential component of the enzyme glutathione peroxidase (GPx) and other seleno-chemical substances, might boost chemotherapeutic efficacy and protect tissues from cellular damage caused by ROS. SeNPs have the potential to set the stage for developing new strategies to treat malignancy. Conclusion: This review extensively analyzed the anticancer efficacy and functionalization strategies of SeNPs in drug delivery to cancer cells. In addition, this review highlights the mechanism of action of drug-loaded SeNPs to suppress the proliferation of cancer cells in different cell lines.

Global efforts invested in the prevention and treatment of cancer need to be repositioned to develop safe, effective, and economic anticancer therapeutics by adopting rational approaches of drug discovery. Drug repurposing is one of the established approaches to reposition old, clinically approved off-patent noncancer drugs with known targets into newer indications. The literature review suggests a key role of drug repurposing in the development of drugs intended for cancer as well as noncancer therapeutics. A wide category of noncancer drugs such as, drugs acting on CNS, anthelmintics, cardiovascular drugs, antimalarial drugs, anti-inflammatory drugs, have come out with interesting outcomes during preclinical and clinical phases. In the present article, a comprehensive overview of the current scenario of drug repurposing for the treatment of cancer has been focused. The details of some successful studies along with examples have been included followed by associated challenges.

Cancer persists as the world's leading cause of mortality, thereby making it a compelling condition to research and potentially develop prevention options. Anticancer therapies such as chemotherapy, surgery and radiation therapy are becoming highly futile and tend to have achieved a clinical deficit due to massive side effects, toxicities, and limited specificity. Anticancer agents from natural sources, such as aquatic fishes, terrestrial mammals, animal venoms, and amphibians, have mainly been focused on in recent researches. Edible marine fishes contain high contents of fatty acids, vitamins, and proteins, also having bioactive compounds. Fish derivatives naturally have the potential to target cancer cells while being less hazardous to normal tissues, making them a better choice for cancer prevention and therapy. In this review, we mainly focused on the bioactive compounds identified in marine fishes which have significant biological properties including anticancer effects, also discuss the mechanism of action.

Leukemia is common among both women and men worldwide. Besides the fact that finding new treatment methods may enhance the life quality of patients, there are several problems that we face today in treating leukemia patients, such as drugs’ side effects and acquired resistance to chemotherapeutic drugs. Berberine is a bioactive alkaloid found in herbal plants (e.g., Rhizoma coptidis and Cortex phellodendri) and exerts several beneficial functions, including anti-tumor activities. Furthermore, berberine exerts antiproliferative and anti-inflammatory effects. Up to now, some studies have investigated the roles of berberine in different types of leukemia, including acute myeloid leukemia and chronic lymphocytic leukemia. In this review, a detailed description of the roles of berberine in leukemia is provided. We discuss how berberine involves different molecular targets (e.g., interleukins and cyclins) and signaling pathways (e.g., mTOR and PI3K) to exert its anti-tumor functions and how berberine is effective in leukemia treatment when combined with other therapeutic drugs.

Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is most valuable for exploring novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs, including etoposide, sorafenib, cisplatin, and triclosan, against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs.

Background: The Coccoloba uvifera L. species is currently considered an important source of compounds of high biological value such as lupeol. This is related to different and important biological activities to human health. Objective: The objective of this study was to encapsulate the C. uvifera extract in nanofibers made with the biopolymers gelatin (G)/high-grade polymerization agave fructans (HDPAF) in the proportions 1:0, 1:1, 1:2, 1:3 and 0:1, through the electrospinning process, in addition to evaluating the antimutagenic and antiproliferative properties of the encapsulated extract. Methods: The physicochemical characteristics of the nanofibers were evaluated, as well as the antiproliferative and antimutagenic activities of the encapsulated and unencapsulated extract. SEM evaluation shows nanofibers of smooth, continuous morphology and nanometric size (50-250 nm). The TGA, FTIR-ATR, HPLC-MS analyses reveal the presence of the extract in the nanofibers. Results: The extract did not show a mutagenic effect during the development of the Ames test, on the other hand, the MTT test showed the antiproliferative effect at the concentrations of 50 and 100 μg/mL of extract. Conclusion: The extract of C. uvifera loaded in nanofibers elaborated by electrospinning with the G/HDPAF biopolymers conserves its antimutagenic and antiproliferative properties.

Background: Oral squamous cell carcinoma (OSCC) is a rampant cancer type in head and neck cancers with a poor prognosis and a high recurrence rate. Eugenol shows an anticancer effect in a variety of cancers, but it has been rarely studied in oral squamous cell carcinoma (OSCC). Objective: The purpose of this study was to explore the role of Eugenol in OSCC and the underlying mechanism. Methods: After different concentrations of Eugenol (0, 200, 400, and 800 μM) treatment, the viability, proliferation, migration, and invasion of OSCC cell line SCC9 were measured by CCK-8, colony formation, wound-healing, and transwell assays, respectively. TUNEL staining was employed to detect apoptosis. Western blotting was used to evaluate gene expression at the protein level. Molecular docking was used to identify the target of Eugenol. Results: Eugenol decreased the proliferation and reduced the abilities of invasion and migration along with the expression of matrix metalloproteinases (MMP) 2 and MMP9 in SCC9 cells. On the contrary, the ratio of apoptotic cells was increased by Eugenol. In addition, Eugenol down-regulated B cell lymphoma-2 (Bcl-2) expression, but up-regulated BCL-2 associated X (Bax), cleaved caspase 3, and cleaved poly-ADP ribose polymerase (PARP) expression. Meanwhile, Eugenol exerted its effect on SCC9 cells in a concentration-dependent manner. Eugenol could bind to macrophage migration inhibitory factor (MIF), the expression of which was down-regulated after Eugenol treatment. Besides, overexpression of MIF reversed all the effects of Eugenol on OSCC cells. Conclusion: In summary, Eugenol suppressed the malignant processes of OSCC cells by targeting MIF, which could guide the clinical application of Eugenol in OSCC.