Medicinal Chemistry - Current Issue

Overexpression of HDAC8 was observed in various cancers and inhibition of HDAC8 has emerged as a promising therapeutic approach in recent decades.

This review aims to facilitate the discovery of novel selective HDAC8 inhibitors by analyzing the structural scaffolds of 66 known selective HDAC8 inhibitors, along with their IC50 values against HDAC8 and other HDACs.

The inhibitors were clustered based on structural symmetry, and common pharmacophores for each cluster were identified using Phase. Molecular docking with all HDACs was performed to determine binding affinity and crucial interacting residues for HDAC8 inhibition. Representative inhibitors from each cluster were subjected to molecular dynamics simulation to analyze RMSD, RMSF, active site amino acid residues, and crucial interacting residues responsible for HDAC8 inhibition. The study reviewed the active site amino acid information, active site cavities of all HDACs, and the basic structure of Zn²⁺ binding groups.

Common pharmacophores identified included AADHR_1, AADDR_1, ADDR_1, ADHHR_1, and AADRR_1. Molecular docking analysis revealed crucial interacting residues: HIS-142, GLY-151, HIS-143, PHE-152, PHE-208 in the main pocket, and ARG-37, TYR-100, TYR-111, TYR-306 in the secondary pocket. The RMSD of protein and RMSF of active site amino acid residues for stable protein-ligand complexes were less than 2.4 Å and 1.0 Å, respectively, as identified from MD trajectories. The range of Molecular Mechanics Generalized Born Surface Area (MM-GBSA) ΔG predicted from MD trajectories was between -15.8379 Å and -61.5017 Å kcal/mol.

These findings may expedite the rapid discovery of selective HDAC8 inhibitors subject to experimental evaluation.

Due to interdisciplinary research, many innovative concepts have been merged that seemed to be impractical. Recently, medicinal organometallic chemistry has made remarkable progress, but the latency of these compounds has not been fully exploited. This systematic review has examined the published literature on anticancer organometallic chemistry across countries, science fields, and organizations involved in organometallics research for cancer.

The study data related to anticancer organometallics were searched from Scopus between 1985 and 2022. Biblioshiny and VOS Viewers were used to analyze and visualize patterns in scientific literature derived from Scopus.

Publications on organometallic compounds have been found to contribute to, on average, 1.02% per year, accounting for 94.3% of the total scholarly work published in the last two decades since 2003. However, research productivity has been found to be steadily improved, with 81.5% of all publications produced between 2011 and 2022. The countries possessing the highest published work have been found to be China, the UK, and Germany. The leading institutions, the University of Warwick, United Kingdom, and the University of Auckland, New Zealand, have topped the list of organizations with the most publications. Although the use of medicinal organometallics for cancer has become widespread over the last two decennaries, there has been a notable influx of groundbreaking scientific publications in recent years.

The findings of this study may enable researchers to envision potential future scenarios for scientific collaborations involving the utilization of organometallics in the treatment of cancer. This study may provide aspiring and current researchers with the necessary tools and knowledge to effectively pursue their research endeavors for scientific collaborations investigating the use of anticancer organometallics in the medicinal field. The areas, such as ruthenium with reactive oxygen species and angiogenesis, represent opportunities for future investigation and innovation.

In this current study, a new series of triazolo-triazine derivatives were designed and synthesized as potential anticancer agents.

The antiproliferative activity of the new compounds was evaluated against four different cancerous cell lines (MDA-MB-231, HCT-116, A549, and HT-29) using an MTT assay. To evaluate the mechanism of action, the ability of the best compound in apoptosis induction and DNA damage was evaluated using the flow cytometry technique and comet assays. Furthermore, molecular docking simulation was used to investigate their interactions with the two targets, VEGFR2 and c-Met kinases.

Results showed that 6-(4-bromophenyl)-3-((4-methoxybenzyl)thio)-[1,2,4]triazolo[4,3-b][1,2,4]triazine (8c) demonstrated the best anti-proliferative activity against the human colorectal carcinoma cells HCT-116 with an IC50 value of 38.7 ± 1.7 µM. In silico evaluations showed that the triazolo-triazine scaffold, along with the methoxy substitution of compound 8c, was involved in creating effective H-bond interactions in the active site of both targets.

Our results showed that compound 8c significantly increased cell death through apoptosis induction and caused a significant increase in genotoxicity. Furthermore, it was found that the tested compound 8c, with a selectivity index of 1.74, possessed selective antiproliferative activity towards the colorectal cancer cell line HCT-116 compared to the normal fibroblast cell line. These findings could be useful in the development of novel VEGFR2/c-Met dual-targeted inhibitors in the future.

Alternative and complementary applications of newly synthesized chemicals have enhanced the prospect of finding curative treatments for hepatocarcinogenesis and pancreatic cancer.

The current study investigated the curative effect of the newly synthesized drug 4-methyl-N-((4-(trifluoromethoxy) phenyl) carbamoyl) benzenesulfonamide (3) against diethyl nitrosamine (DEN) (50 mg/kg) and carbon tetrachloride (CCl4) (2 mg/kg)-induced hepatocellular carcinoma (HCC) and pancreatic cancer in male rats using doxorubicin as a reference drug.

The findings demonstrated that the DEN/CCl4 treatment produced oxidative stress, as evidenced by an increase in MDA and a reduction in GSH levels. A temporary decline in antioxidant and total antioxidant capacity (TAC) was detected. An increase in the levels of TNF-α and other inflammatory markers, interleukin-6 (IL-6) and B-cell lymphoma 2 (Bcl-2), was found. Our findings showed that the liver and pancreas had significantly higher levels of hepatocellular carcinoma biomarkers, namely α-fetoprotein and α-L-Fucosidase (α-FU). Changes in the biomarkers of hepatic function were also seen, with elevated levels of γ-glutamyltransferase (GGT), alkaline phosphatase (ALP), and transaminases (AST, ALT). Our findings were supported by immuno-histochemical and pathological examinations, which revealed considerable improvement in liver and pancreatic tissues after treatment with medication 3 when compared to normal healthy rats.

The new synthetic medication 3 could be an effective chemotherapeutic method for treating DEN and CCl4-induced HCC and pancreatic cancer.

In many types of cancer, uncontrolled growth and proliferation of cells occur due to abnormalities in their genes, mutations of pro-apoptotic proteins, or upregulation of anti-apoptotic proteins. Triazolinedione and pyrrole derivatives are compounds with anti-microbial, anti-fungal, anti-inflammatory, and anti-cancer activities. Pyrrole and its derivatives are critical heterocycle compounds that are significant in anticancer studies and highly preferred in research.

This study aimed to investigate the effects of dihydropyrrole derivatives substituted with triazolinedione on the MCF-7 (breast cancer) cell line’s apoptosis, ER stress, and heat shock genes.

The mRNA levels of apoptosis, ER stress, and heat shock proteins were assessed by qRT-PCR method in the MCF-7 cell line. The investigation of ADMET features, crucial pharmacokinetic indices for the potential candidacy of compounds as drugs, has been meticulously designed. In silico-induced molecular docking studies were conducted to further explore the interaction and elucidate the orientation of hybrid compounds within the active sites of BCL-2, PARP, HSP70, HSP90, and GRP78.

It was determined that the compounds caused cell death by modulating apoptotic (compound IV), ER stress, and heat shock proteins (compounds XI and XVI) through up- and down-regulation. Our findings have pointed to the effects of triazolinedione-substituted dihydropyrrole derivatives, exhibiting antitumor activity on apoptosis, ER stress, and heat shock genes in the MCF-7 cell line.

The compounds investigated in this study have been found to be promising for anticancer research.

Casein Kinase 2 (CK2), discovered as one of the earliest protein kinases, is a ubiquitous Ser/Thr protein kinase-specific to acidic environments. CK2 has been implicated in regulating diverse cellular processes and has been linked to the onset of various diseases, including cancer.

Consequently, modulating CK2 function has emerged as a potential therapeutic strategy. However, currently, available CK2 inhibitors or modulators often lack sufficient specificity and potency.

The results were validated through QSAR of curcumin derivatives, Pharmacophore modeling, virtual screening performed for filtered curcumin-like featured derivatives from the database, and Molecular Docking approaches. Since there is a solved crystal structure of high-resolution X-ray crystal structures of Human protein kinase CK2 alpha in complex with ferulic aldehyde.

Also, structure-based virtual screening was performed against a total of 3253 compounds from different libraries, and only the top 4 best-hit compounds with exceptional docking scores exceeding > -7 kcal/mol (more than 7 kcal/mol) were screened and analyzed. However, to validate their therapeutic potential, these compounds require in-vitro evaluation to assess their CK2 targeting ability.