Current Medicinal Chemistry - Current Issue

The heterogeneous disease, breast cancer (BC), is a frequently detected cancer today, including hormone receptor-positive (HR+), human epidermal growth factor receptor-2-positive (HER2+), and triple-negative (ER-, PR-, HER2-) BC. Advanced endocrine therapies could improve about 85% HR+ BC patient survival. Still, 20% - 30% of cases of endocrine therapy resistance are observed. For all kinds of breast cancer, drug resistance is a common and dangerous phenomenon, comprised of two types: de novo resistance and acquired resistance (prolonged exposure). According to recent works of literature, the PI3K/AKT/mTOR pathway has become an emerging target for overcoming drug resistance in BC therapy due to its close association with tumour growth and resistance from current therapies. Activation of the PI3K/AKT/mTOR pathway was found to promote multidrug resistance by elevating drugs’ outflow. The first orally active PI3K inhibitor, Alpelisib (BYL-719) in fulvestrant combination, was approved for treating HR+/ HER2− metastatic BC. Therefore, utilizing PI3K/mTOR/AKT inhibitors in combination with currently available strategies could be an optimistic approach to overcoming drug resistance and resensitizing drug-resistant tumor cells of BC. Here, in this perspective, BC cancer therapies related to drug resistance, the involvement of PI3K/AKT/mTOR pathway in drug resistance and multi-drug resistance, and the role of PI3K/AKT/mTOR inhibitors in getting rid of drug resistance have been illuminated.

Obesity is the most pervasive metabolic disorder, further linked with many other diseases, including diabetes, hypertension, cardiovascular disorders, and sleep apnea. To control the increasing weight of obese individuals, experts usually recommend exercise and lifestyle alterations, but medication and surgeries are also advised in severe cases. FDA-approved obesity-controlling drugs are effective but possess certain adverse effects, including dry mouth, drug abuse, dysregulation in monoamine neurotransmitters, insomnia, and many more. Medication processes are expensive; researchers have focused on safer and more effective alternative approaches than pharmaceutical drugs. Historically, a diverse array of herbal plants has been used due to their therapeutic effect, as in vitro and in vivo experimentations have proved the effectiveness of herbal plants without associated mortality. In this review, we present various herbs with their metabolically active secondary metabolites, including Berberis vulgaris L, Rhizoma Coptidis, Radix Lithospermi, Aloe vera, Clerodendrum multiflorum Burm f., Astragalus membranaceus (Fisch), Boerhaavia diffusa, Achyranthes aspera L., etc. All of these herbs are responsible for anti-obesity, anti-diabetic, and anti-inflammatory effects. Most previously published clinical trials and animal studies have confirmed the significant potential of these herbal plants and their active ingredients to reduce weight by decreasing the accumulated fats in the body have also been discussed in this review. Thus, it is concluded that scientists must consider and utilize these natural treasures for safe, effective, and cost-effective treatment. It will open new and novel ways for treatment regimes.

Neurodegenerative diseases (NDDs) comprise a large number of disorders that affects the structure and functions of the nervous system. The major cause of various neurodegenerative diseases includes protein aggregation, oxidative stress and inflammation. Over the last decade, there has been a gradual inclination in neurological research in order to find drugs that can prevent, slow down, or treat these diseases. The most common NDDs are Alzheimer's, Parkinson's, and Huntington's illnesses, which claims the lives of 6.8 million people worldwide each year and it is expected to rise by 7.1%. The focus on alternative medicine, particularly plant-based products, has grown significantly in recent years. Plants are considered as a good source of biologically active molecules and hence phytochemical screening of plants will pave way for the discovering new drugs. Neurodegeneration has been linked to oxidative stress, either as a direct cause or as a side effect of other variables. Therefore, it has been proposed that the use of antioxidants to combat cellular oxidative stress within the nervous system may be a viable therapeutic strategy for neurological illnesses. In order to prevent and treat NDDs, this review article covers the therapeutic compounds/metabolites from plants with the neuroprotective role. However, these exhibit other beneficial molecular functions in addition to antioxidative activity, making them a potential application in the management or prevention of neurodegenerative disorders. Further, it gives the insights to the future researchers about considering the peptide based therapeutics through various mechanisms for delaying or curing neurodegenerative diseases.

The search for effective methods of treatment and prevention of oncological diseases, despite the successes achieved in recent decades, remains one of the most urgent issues in modern medicine. It is known that chemotherapy and radiation therapy are based on the induction of cell death by increasing the intracellular concentration of reactive oxygen species (ROS). To increase the effectiveness of chemo- and radiotherapy, inducing and increasing oxidative stress in tumor cells has been proposed. A new class of promising adjuvants in combination with anticancer therapy, which has already been shown to be effective in preclinical and clinical studies, includes natural and synthetic polyphenols. Polyphenolic compounds not only exhibit antitumor activity but also significantly reduce the resistance of tumor cells to chemo- and radiotherapy. However, almost all chemotherapeutic drugs and regimens of radiation treatment have a damaging toxic effect on normal tissues, which significantly affects the quality of life of patients, and treatment options for managing these side effects are limited. In this regard, some of the most promising agents for the management of toxic side effects are natural polyphenols. This study discusses the possible molecular mechanisms and prospects for the clinical use of natural and synthetic polyphenolic compounds in chemo- and radiotherapy. In addition, the protective role/effect of polyphenols on the effects of chemo- and radiotherapy in tumor patients is discussed.

Gastric cancer (GC) represents a significant global health burden, ranking as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite recent advancements in GC treatment, the five-year survival rate for advanced-stage GC patients remains low. Consequently, there is an urgent need to identify novel drug targets and develop effective therapies. However, traditional drug discovery approaches are associated with high costs, time-consuming processes, and a high failure rate, posing challenges in meeting this critical need. In recent years, there has been a rapid increase in the utilization of artificial intelligence (AI) algorithms and big data in drug discovery, particularly in cancer research. AI has the potential to improve the drug discovery process by analyzing vast and complex datasets from multiple sources, enabling the prediction of compound efficacy and toxicity, as well as the optimization of drug candidates. This review provides an overview of the latest AI algorithms and big data employed in drug discovery for GC. Additionally, we examine the various applications of AI in this field, with a specific focus on therapeutic discovery. Moreover, we discuss the challenges, limitations, and prospects of emerging AI methods, which hold significant promise for advancing GC research in the future.

Several chronic liver injuries can result in liver fibrosis, a wound-healing response defined by an excessive buildup of diffuse extracellular matrix (ECM). Liver fibrosis may progress to liver cirrhosis, liver failure, or hepatocellular carcinoma. Many cellular routes are implicated in the fibrosis process; however, hepatic stellate cells appear to be the main cell type involved. Curcumin, a polyphenolic substance extracted from the Curcuma longa plant, has a diversity of pharmacologic impacts, including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic actions. The anti-fibrotic property of curcumin is less clear, but curcumin's ability to influence inflammatory cytokines, inflammatory pathways, the expression of pro-apoptotic (up-regulated) and anti-apoptotic (down-regulated) proteins, and its ability to lower oxidative stress likely underlie its anti-fibrotic properties. In this review, we investigate and analyze the impact of curcumin on several disorders that lead to liver fibrosis, and discuss the therapeutic applications of curcumin for these disorders.

The natural polyphenol, calebin-A, was recently discovered and identified as a novel phytopharmaceutical with anti-inflammatory, anti-tumor, and antiproliferative properties. Calebin-A occurs naturally in trace quantities in Curcuma longa/C cassia, commonly known as turmeric, from the Zingiberaceae family. Calebin-A is a curcumin analog or 'chemical cousin' of curcumin with a similar chemical structure. Although few research studies have been conducted on the pharmacological and therapeutic properties of calebin-A, it is a very promising molecule with a variety of pharmacological properties. Some studies have suggested that calebin-A is helpful in treating various cancers due to its inhibitory effect on cell growth and anti-inflammatory properties. Other studies have suggested that calebin-A may improve neurocognitive status associated with neurodegeneration caused by Alzheimer’s disease (AD) by inhibiting the aggregation of β-amyloid. Finally, several studies have proposed that calebin-A may potentially be therapeutically beneficial in treating patients with obesity. This novel compound downregulates nuclear factor (NF)-κB-mediated processes involved with cancer, such as tumor cell invasion, proliferation, metastasis, and, most profoundly, inflammation. Moreover, calebin-A influences the activities of mitogen-activated protein kinases (MAPKs) in cancer cells. The present review identifies and discusses the pharmacological and phytochemical properties of calebin-A, as well as its therapeutic benefits and limitations, for future scientists and clinicians interested in exploring calebin-A’s medicinal qualities.