Current Topics in Medicinal Chemistry - Volume 20, Issue 21, 2020

This editorial provides a brief overview of the thematic issue and the papers in it. The thematic issue is proposed to help chemists and biologists track the most recent advances in drug discovery and cancer diagnoses. The process of drug discovery involves the identification and validation of biological targets, the identification and optimization of lead compounds, preclinical development, and clinical trials. Cancer is a major public health problem in the world. The results of tissue diagnosis, blood tests, computed tomography scans, and cytogenetic analyses can provide informative clues about molecular changes and indicate proper prognoses. Timely detection of cancer significantly improves cancer outcomes by providing care at the earliest possible stage thus contributing greatly to the prevention and exacerbation and has become an important public health strategy in all settings. The collection of this thematic issue includes five articles. The first one reviews the current advances and limitations of deep learning in anticancer drug sensitivity prediction. The next review summarizes the most recent and high-quality research related to anticancer activities of Vitamin C. The third one reports the efficacy of two different sets of natural products (terpenoids and flavonoids) towards caspase-3 activity. The fourth one proposes a novel in silico method for predicting cancer biomarkers in human body fluids. The fifth article performs an in silico and in vitro investigation on isothymusin, which serves as a potential inhibitor of cancer cell proliferation.

Anticancer drug screening can accelerate drug discovery to save the lives of cancer patients, but cancer heterogeneity makes this screening challenging. The prediction of anticancer drug sensitivity is useful for anticancer drug development and the identification of biomarkers of drug sensitivity. Deep learning, as a branch of machine learning, is an important aspect of in silico research. Its outstanding computational performance means that it has been used for many biomedical purposes, such as medical image interpretation, biological sequence analysis, and drug discovery. Several studies have predicted anticancer drug sensitivity based on deep learning algorithms. The field of deep learning has made progress regarding model performance and multi-omics data integration. However, deep learning is limited by the number of studies performed and data sources available, so it is not perfect as a pre-clinical approach for use in the anticancer drug screening process. Improving the performance of deep learning models is a pressing issue for researchers. In this review, we introduce the research of anticancer drug sensitivity prediction and the use of deep learning in this research area. To provide a reference for future research, we also review some common data sources and machine learning methods. Lastly, we discuss the advantages and disadvantages of deep learning, as well as the limitations and future perspectives regarding this approach.

Treatment options for effective treatment of cancer with minimum off-target effects and maximum clinical outcomes have remained overarching goals in the clinical oncology. Vitamin C has remained in the shadows of controversy since the past few decades; burgeoning evidence has started to shed light on wide-ranging anticancer effects exerted by Vitamin C to induce apoptosis in drug-resistant cancer cells, inhibit uncontrolled proliferation of the cancer cells and metastatic spread. Landmark achievements in molecular oncology have ushered in a new era, and researchers have focused on the identification of oncogenic pathways regulated by Vitamin C in different cancers. However, there are visible knowledge gaps in our understanding related to the ability of Vitamin C to modulate a myriad of transduction cascades. There are scattered pieces of scientific evidence about promising potential of Vitamin C to regulate JAK-STAT, TGF/SMAD, TRAIL and microRNAs in different cancers. However, published data is insufficient and needs to be investigated comprehensively to enable basic and clinical researchers to reap full benefits and promote result-oriented transition of Vitamin C into various phases of clinical trials. In this review, we will emphasize on available evidence related to the regulation of oncogenic cell signaling pathways by Vitamin C in different cancers. We will also highlight the conceptual gaps, which need detailed and cutting-edge research.

Background: Caspase-3 is accountable for the execution of apoptosis. Recently, it has gained attention as a promising target for the discovery of natural products as anticancer agents. Methods: We examined the efficacy of two different sets of natural products (terpenoids and flavonoids) towards caspase-3 activity adopting in silico, cell-free and cell-based activity and real-time gene expression analysis. Results: It was observed that terpenes activate caspase-3 activity in both the cell-free and cell-based systems, which was supported by the gene expression analysis, binding energy and activation constant. Flavonoids’ action, however, was limited to the cell-based system and transcriptional regulation suggesting their indirect association, which enhanced the enzyme activity and up-regulated the expression of mRNA levels in the cells. Among the tested natural products, (+) carvone was observed to be the best activator of caspase-3 in K562 (34.4 μM), WRL-68 (22.3 μM), HeLa (18.7 μM), MCF-7 (39.4 μM) and MDA-MB-231 cell lines (45.1 μM). Conclusion: Overall, terpenoids have a persistent activation of caspase-3 in all the investigated systems, while flavonoids circuitously affect the enzyme activity.

Objective: Cancer is one of the most serious diseases affecting human health. Among all current cancer treatments, early diagnosis and control significantly help increase the chances of cure. Detecting cancer biomarkers in body fluids now is attracting more attention within oncologists. In-silico predictions of body fluid-related proteins, which can be served as cancer biomarkers, open a door for labor-intensive and time-consuming biochemical experiments. Methods: In this work, we propose a novel method for high-throughput identification of cancer biomarkers in human body fluids. We incorporate physicochemical properties into the weighted observed percentages (WOP) and position-specific scoring matrices (PSSM) profiles to enhance their attributes that reflect the evolutionary conservation of the body fluid-related proteins. The least absolute selection and shrinkage operator (LASSO) feature selection strategy is introduced to generate the optimal feature subset. Results: The ten-fold cross-validation results on training datasets demonstrate the accuracy of the proposed model. We also test our proposed method on independent testing datasets and apply it to the identification of potential cancer biomarkers in human body fluids. Conclusion: The testing results promise a good generalization capability of our approach.

Background: Since centuries plant-based compounds are known for the treatment of cancer in both traditional and contemporary medicine. The problems like target non-specificity and toxicity are well-known regarding anticancer drugs. Therefore, target specific search of novel entities is constant. Isothymusin is a dimethoxy, trihydroxy flavone present in plants like Ocimum sanctum, and Limnophilla geoffrayi. There are limited reports available on the anticancer potential of isothymusin. Objectives: The effects of isothymusin on redox status, cell cytotoxicity, and targets involved in the promotion and progression of the cancer cells have been investigated. Methods: Antiproliferative efficacy was evaluated by MTT, Neutral Red Uptake, and Sulforhodamine-B assays. The spectrophotometric methods were adopted to study the effect against selected targets. Redox activity was assessed by in vitro antioxidant assays and the interaction study, ADMET profiling, and toxicity assessments were done in silico. Results: Isothymusin scavenges the radicals, i.e., DPPH and nitric oxide with moderate ferric reducing potential. It affected the proliferation of leukemia, colon, skin, and breast cancer cell lines by more than 50% but moderately affected prostate, kidney, lung, hepatic, and breast adenocarcinoma (up to 48%). Isothymusin inhibited the enzymes associated with the promotion stage of cancer, including cycloxygenase- 2 and lipoxygenase-5. Additionally, it also inhibited the activity of proliferation markers like cathepsin- D, dihydrofolate reductase, hyaluronidase, and ornithine-decarboxylase. Besides, in silico studies supported the in vitro enzyme inhibition assays outcome. Toxicity studies showed promising results of chemical descriptors and non-skin-irritant, moderate ocular-irritancy, and in vitro Ames test confirmed non-mutagenic nature. Conclusion: Isothymusin showed radical scavenging and anti-proliferative activities, which may be taken up as a phytochemical lead for the synthesis of analogues possessing enhanced anticancer potential.

Aims: A series of 8-methoxy ciprofloxacin- hydrazone/acylhydrazone hybrids were evaluated for their activity against a panel of cancer cell lines including HepG2 liver cancer cells, MCF-7, doxorubicin- resistant MCF-7 (MCF-7/DOX) breast cancer cells, DU-145 and multidrug-resistant DU145 (MDR DU-145) prostate cancer cells to seek for novel anticancer agents. Background: Ciprofloxacin with excellent pharmacokinetic properties as well as few side effects, is one of the most common used antibacterial agents. Notably, Ciprofloxacin could induce cancer cells apoptosis, and cell cycle arrest at the S/G2 stage. The structure-activity relationship reveals that the introduction of the methoxy group into the C-8 position of the fluoroquinolone moiety has resulted in a greater binding affinity to the binding site, and 8-methoxy ciprofloxacin derivatives have proved a variety of biological activities even against drug-resistant organisms. However, to the best of our current knowledge, there are no studies that have reported the anticancer activity of 8-methoxy ciprofloxacin derivatives so far. Furthermore, many fluoroquinolone-hydrazone/acylhydrazone hybrids possess promising anticancer activity. Thus, it is rational to screen the anticancer activity of 8-methoxy ciprofloxacin derivatives. Objective: To enrich the structure-activity relationship and provide new anticancer candidates for further investigations. Methods: The desired 8-methoxy ciprofloxacin-hydrazone/acylhydrazone hybrids 5 and 6 were screened for their in vitro anticancer activity against liver cancer cells HepG2, breast cancer cells MCF-7, MCF7/DOX, prostate cancer cells DU-145 and MDR DU-145 by MTT assay. Results: Some of 8-methoxy ciprofloxacin-hydrazone hybrids showed potential activity against HepG2, MCF-7, MCF-7/DOX, DU-145 and MDR DU-145 cancer cell lines, low cytotoxicity towards VERO cells and promising inhibitory activity on tubulin polymerization. Conclusion: Compounds 5d and 5f showed promising anticancer activity, low cytotoxicity, and potential tubulin polymerization inhibitory activity, were worthy of investigation. Other: The structure-activity relationship was enriched.

Cancer, which has been cursed for human beings for long time is considered as one of the leading causes of morbidity and mortality across the world. In spite of different types of treatments available, chemotherapy is still deemed as a favored treatment for the cancer. Unfortunately, many currently accessible anticancer agents have developed multidrug resistance along with fatal adverse effects. Therefore, intensive efforts have been made to seek for new active drugs with improved anticancer efficacy and reduced adverse effects. In recent years, the emergence of heterocyclic ring-containing anticancer agents has gained a great deal of attention among medicinal chemists. 1,3- oxazole is a versatile heterocyclic compound, and its derivatives possess broad-spectrum pharmacological properties, including anticancer activity against both drug-susceptible, drug-resistant and even multidrug-resistant cancer cell lines through multiple mechanisms. Thus, the 1,3-oxazole moiety is a useful template for the development of novel anticancer agents. This review will provide a comprehensive overview of the recent advances on 1,3-oxazole derivatives with potential therapeutic applications as anticancer agents, focus on the chemical structures, anticancer activity, and mechanisms of action.

Indole alkaloids, which are abundant in nature, are a significant source of pharmacologically active compounds. Indole alkaloids have the potential to exert anticancer activity via various antiproliferative mechanisms, and some of them, such as Vinblastine and Vincristinem, have already used in clinics or under clinical evaluations for the treatment of cancers. Therefore, indole alkaloids occupy an important position in the discovery of novel anticancer agents. This review emphasizes the recent development of indole alkaloids as potential anticancer agents, their structure-activity relationship, and mechanisms of action covering the articles published from 2015 to 2020.