Mini Reviews in Medicinal Chemistry - Volume 23, Issue 1, 2023

Background: Benzocycloheptanone is the main structural feature of numerous famous natural pharmacophores such as Colchicine and Theaflavins. It has gained popularity in the field of medicinal chemistry, attributing to its broad-spectrum effect. Objective: Numerous research publications addressing the derivatization of the benzosuberone molecule have been published, and their biological and pharmacological features have been extensively addressed. Numerous derivatives have been discovered as lead compounds for the development of novel medications. Thus, the goal of this article is to summarize and analyze all published findings on the synthesis and biological assessment of the benzosuberone skeleton. Methods: All main databases including SciFinder, PubMed and google scholar were used with appropriate keywords to select related reported literature, and further bibliography in related literature was also used to find linked reports. Results: Synthetic routes to benzosuberone-based ring systems were identified from the literature and explained stepwise and after this, pharmacological activities of all benzosuberone derivatives are listed target-wise and a detailed structure-activity relationship is developed. Conclusion: The current review discusses numerous synthetic approaches for the synthesis of benzosuberone skeleton and its applications in many domains of medical chemistry. Compounds possessing the benzosuberone skeleton play an important role in the drug development process due to their wide range of biological actions such as anti-cancer, antibacterial, antifungal, antiinflammatory, and so on. The results of antibacterial screening and Structure-Activity Relationship (SAR) revealed that the compounds containing this skeleton with the piperazine and morpholine rings have antimicrobial potential when compared to the commercial antibiotic Norfloxacin. Despite extensive study to date, there is still room for the development of novel and efficient pharmacophores using the structure-based drug design technique.

PCSK9 is a strongly expressed protein in the liver and brain that binds to the LDLR and regulates cholesterol in the liver effectively. Other receptors with which it interacts include VLDLR, LRP1, ApoER2, and OLR1. PCSK9 gain-of-function results in lysosomal degradation of these receptors, which may result in hyperlipidemia. PCSK9 deficiency results in a lower amount of cholesterol, which reduces cholesterol's accessibility to cancer cells. PCSK9 regulates several proteins and signaling pathways in cancer, including JNK, NF-ΚЦ#146;, and the mitochondrial-mediated apoptotic pathway. In the liver, breast, lungs, and colon tissue, PCSK9 initiates and facilitates cancer development, while in prostate cancer cells, it induces apoptosis. PCSK9 has a significant impact on brain cancer, promoting cancer cell survival by manipulating the mitochondrial apoptotic pathway and exhibiting apoptotic activity in neurons by influencing the NF-ΚЦ#146;, JNK, and caspase-dependent pathways. The PCSK9 impact in cancer at different organs is explored in this study, as well as the targeted signaling mechanisms involved in cancer growth. As a result, these signaling mechanisms may be aimed for the development and exploration of anti-cancer drugs in the immediate future.

Cancer is the leading cause of death and the most significant determinant of life expectancy in almost every country in this twenty-first century. According to the World Health Organization (WHO), cancer is responsible for the leading cause of death globally. Benzophenone derivatives are found in a variety of naturally occurring compounds which are known to be pharmacologically efficacious against a variety of diseases, including cancer. Microtubules are thought to be a good target for cancer chemotherapies. Microtubule polymerization and depolymerization are induced by a variety of natural, synthetic, and semisynthetic chemicals having a benzophenone nucleus, affecting tubulin dynamics. Several medications that affect microtubule dynamics are in various stages of clinical trials, including Combretastatins (phase II), Vincristine (clinically approved), Paclitaxel (in clinical usage), and epothilone (phase III), and only a few have been patented. Benzophenone derivatives target the colchicine binding site of microtubules, damage them and cause cell cycle arrest in the G2-M phase. Belonging to this class of molecules, phenstatin, a potent inhibitor of tubulin polymerization, has shown strongly inhibit cancer cell growth and arrest the G2/M phase of the cell cycle by targeting the colchicine binding site of microtubules. In the present manuscript, we described the benzophenone as tubulin polymerization inhibitors, their Structure-Activity Relationships (SARs) and molecular docking studies that reveal its binding affinity with the colchicine binding site.

Alzheimer’s disease or senile dementia is principally acknowledged by the gradual accumulation of neurotoxic amyloid- β protein in the brain and is considered as the initial event of the phenomenon of this asymptomatic ailment. It prompts the decline in cognitive performance, standard psychiatric functioning, and neuronal transmission across the brain. Significant inferences were withdrawn by utilizing the recently introduced disease-modifying anti- amyloid- β immunotherapy developed after performing the clinical and preclinical controlled trials to cure the neurodegenerative malady. This strategy is worthwhile because of the clinical relevance and specific targeted approach that exhibited the quenched immunotherapeutic effects and encouraged clinical findings. In vitro fabricated, anti- amyloid- β recombinant monoclonal antibodies are passively employed to promote clearance and antagonize the aggregation and synthesis of neurotoxic and degenerative aggregates of amyloid-β. Thus, passive immunotherapy has an adequate impact on treating this disorder, and currently, some other monoclonal pharmacological molecules are under clinical trials to defeat this severe exacerbation with more efficacy and clinical benefits. This review compendiously discusses the anti-amyloid-β immunotherapy, which will provide a more proficient framework to be employed as a potential therapeutic approach.

Polo-like kinase 4 (PLK4), a serine/threonine kinase, is a member of the PLK family. As a key regulator of the cell cycle, PLK4 controls centrosome duplication and mitosis. Abnormal PLK4’s function can induce centrosome amplification, leading to tumorigenesis, therefore, PLK4 has been regarded as a promising target for cancer therapy, and PLK4 inhibitors have potentials to treat multiple cancers and other PLK4-associated human disorders, such as myelodysplastic syndrome. In addition, PLK4 may function as a DNA-damage sensitizer, therefore improving the efficacy of chemotherapy. To date, some small-molecule inhibitors with different chemical scaffolds targeting PLK4 have been reported, among which, CFI-400945 has entered clinical trials for the treatment of various solid tumors, myeloid leukemia, and myelodysplastic syndrome. In this review, the structure and biological functions of PLK4 with other homologous PLKs are compared; the roles of PLK4 in different cancers are reviewed; and PLK4 inhibitors disclosed in patent or literature are summarized. Used alone or in combination with other anticancer drugs in preclinical and clinical studies, PLK4 inhibitors have shown significant efficacy in the treatment of different cancers, demonstrating that PLK4 could be a critical target for cancer diagnosis and therapy. However, our understanding of PLK4 is still limited, and novel mechanisms of PLK4 should be identified in future studies.

Urolithins are microbial metabolites derived from berries and pomegranate fruits, which display anti-inflammatory, anti-oxidative, and anti-aging activities. There are eight natural urolithins (urolithin A-E, M5, M6 and M7), which have been isolated by now. Structurally, urolithins are phenolic compounds and belong to 6H-dibenzo [b,d] pyran-6-one. They have drawn considerable attention because of their vast range of biological activities and health benefits. Recent studies also suggest that they possess anti-SARS-CoV-2 and anticancer effects. In this article, the recent advances in the synthesis of urolithins and their derivatives from 2015 to 2021 are reviewed. To improve or overcome the solubility and metabolism stability issues, the modifications of urolithins are mainly centered on the hydroxy group and lactone group, and some compounds have been found to display promising results and the potential for further study. The possible modes of antitumor action of urolithin are also discussed. Several signaling pathways, including PI3K-Akt, Wnt/β-catenin pathways, and multiple receptors (aryl hydrocarbon receptor, estrogen and androgen receptors) and enzymes (tyrosinase and lactate dehydrogenase) are involved in the antitumor activity of urolithins.

Long non-coding RNA (lncRNA) is a novel kind of RNA transcript with lengths greater than 200 nucleotides. Functionally, lncRNAs lack the potential to encode peptides or proteins. Previous studies unveiled that lncRNA participated in numerous physiological and pathological processes, including cancer, aging, and immune responses. Newly discovered long noncoding RNA zinc finger protein, Friend of GATA (FOG) family member 2antisense 1 (ZFPM2-AS1), located on the 8q23 chromosome, acts as a tumor stimulator in various cancer types, including Breast Cancer (BC), Colorectal Cancer (CRC), Esophageal Squamous Cell Carcinoma (ESCC), Gastric Cancer (GC), glioma, hepatocellular carcinoma (HCC), Lung Adenocarcinoma (LUAD), melanoma, non-small cell lung cancer (NSCLC), Retinoblastoma (RB), Small Cell Lung Cancer (SCLC) and thyroid cancer. Accumulative evidence also elucidated that ZFPM2-AS1 dysregulation was related to tumor proliferative, migratory, invasive, anti-apoptotic, and pro-epithelial-tomesenchymal Transition (EMT) effects, larger tumor volume, higher tumor weight, advanced tumor stage, high rates of lymphatic metastasis, distant metastasis, poor prognosis, histological differentiation, higher TNM (tumor, node, metastases) stage, depth of tumor invasion, reduced overall and disease- free survival, vein invasion, and shorter 5-year overall survival. Mechanistically, ZFPM2-AS1 acted as a ceRNA to play its oncogenic role. Thus, this study summarized the specific mechanisms of the lncRNA ZFPM2-AS1 in the aforementioned cancer types to reveal its novel application in cancer diagnosis, treatment, and prognosis.

Soluble epoxide hydrolase is a class of α/β-fold hydrolase enzymes that exist in numerous organs and tissues, including the liver, kidney, brain, and vasculature. This homodimer enzyme is responsible for degrading epoxyeicosatrienoic acids to the less active vicinal diols, dihydroxyeicosatrienoic acids by adding a molecule of water to an epoxide in the cytochrome P450 pathway. Soluble epoxide hydrolase was firstly assayed and characterized by Hammock and colleagues about 40 years ago. Upholding high epoxyeicosatrienoic acid blood levels by inhibiting soluble epoxide hydrolase has been proposed as a hopeful strategy to treat renal and cardiovascular diseases, inflammation, and pain. Therefore, developing novel soluble epoxide hydrolase inhibitors has been an attractive research topic for many years. Regarding this issue, some carbamates, heterocycles, amides, and ureas have been proposed; however, rapid metabolism, low solubility, high melting point, and weak pharmacokinetic characteristics are challenges posed to the researchers. In this review, we have focused on the role of the soluble epoxide hydrolase in the metabolic pathway of arachidonic acid, and categorized the most representative soluble epoxide hydrolase inhibitors into two main classes of synthetic and natural compounds. The structures have been evaluated and an exemplary structure-activity relationship has been provided for further development of potent inhibitors at the end. According to our findings, urea-based inhibitors were preferred to the amide-based scaffolds due to the better fitting into the active site. An aromatic linker is a suitable bridge to connect primary and secondary pharmacophores compared with aliphatic linkers.