Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 10, 2023

Background: The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in radiotherapy for cancer treatment. These radiations can cause damage to the cell membrane, lipids, proteins, and DNA and generate free radicals. Evidence reports stated that radiotherapy accounts for 17-19% of secondary malignancies, labelling this treatment option a double-edged sword. Objective: Radioprotective molecules are used for mitigating radiotherapy's side effects. These agents show free radical scavenging, antioxidant, collagen synthesis inhibition, protease inhibition, immune stimulation, increased cytokine production, electron transfer, and toxicity reduction properties. The most frequently used amifostine has an array of cancer applications, showing multitarget action as nephroprotective to cisplatin and reducing the chances of xerostomia. Many other agents, such as metformin, edaravone, mercaptopropionylglycine, in specific diseases, such as diabetes, cerebral infarction, cystinuria, have shown radioprotective action. This article will discuss potentially repurposed radioprotectors that can be used in the clinical setting, along with a brief discussion on specific synthetic agents like amifostine and PrC-210. Methods: Rigorous literature search using various electronic databases, such as PubMed, ScienceDirect, Scopus, EMBASE, Bentham Science, Cochrane Library, etc., was made. Peer-review research and review papers were selected, studied, reviewed, and analysed. Conclusion: Safety and risk-free treatment can be guaranteed with the repurposed agents. Agents like metformin, captopril, nifedipine, simvastatin, and various others have shown potent radioprotective action in various studies. This review compiled repurposed synthetic radioprotective agents.

Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9/NF-ΚB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumourassociated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.

Background: Kaurane-type diterpenoids, obtained from various natural sources, have shown many biological activities, including anti-inflammatory and antitumor effects. Caracasine, an ent-kaurane diterpenoid isolated from the flowers of Croton micans, was shown to induce apoptosis in leukaemia cell lines. Objective: The present study aimed to ascertain the compound’s mechanism of cell death induction using two leukaemia cell lines, Jurkat E6.1 (T cell) and HL-60 (promyeloblast cells). Methods: Cell death in Jurkat and HL60 cells were evaluated by flow cytometry for apoptosis with annexin-V/PI, mitochondrial membrane potential disturbance, changes in cell cycle, CD95 expression, caspase activation, Nuclear Factor kappa B inhibition, and differentiation into a neutrophil-like cell (dHL60). Results: Caracasine (10 μM) increased the G0/G1 phase in Jurkat and arrested the cell cycle in the S phase in HL60. Caracasine increased CD95 expression (p<0.01 in Jurkat and p<0.05 in HL60) and caspase-8 activation (p<0.001 in Jurkat and p<0.05 in HL60). Caspase-9 was activated in both cell lines (p<0.001) along with the decline in mitochondrial Δψm (p<0.05 in Jurkat and p<0.001 in HL60). In HL60 cells, the kaurane induced neutrophil differentiation was assessed by CD40 expression and reactive oxygen species production. In Jurkat cells, caracasine inhibited the NF-ΚB pathway in cells pretreated with PHA to activate the NF-ΚB pathway, suggesting a possible role in inflammatory diseases. Conclusion: Caracasine induced apoptosis through the intrinsic and extrinsic pathways in both cell lines were evaluated which could be the leading structure for new anti-leukemic and anti-inflammatory drugs.

Introduction: Tubulin polymerization inhibitors induce cancer cell death; therefore, they can be developed as chemotherapeutic agents. We hypothesized that hybrid compounds, including the trans-stilbene moiety contained in resveratrol and penta-1,4-dien-3-one contained in curcumin, could inhibit tubulin polymerization. Methods: Twenty-six hybrid stilbene and pentadienone compounds were designed and synthesized. The cytotoxicity of the hybrid compounds against MDA-MB-231 human breast cancer cells was determined using a clonogenic long-term survival assay. The relationship between cytotoxicity and structural properties was evaluated. Biological activities, including inhibition of tubulin polymerization and cell cycle progression, were investigated to select compounds with excellent anticancer properties. The molecular binding mode between the selected compound and the α, β-tubulin dimers was investigated. Results: Twenty-six hybrid stilbene and pentadienone compounds were designed and synthesized. Among them, compound 13 exhibited the highest inhibitory effect on the clonogenicity of MDA-MB-231 cells. Compound 13 induced the destabilization of tubulins and inhibited cell cycle progression at the G2/M phase. Through in silico molecular docking analysis, compound 13 was predicted to bind to the colchicine binding site of α, β-tubulin. Conclusion: The stilbene and pentadienone hybrid compound 13 has a binding mode similar to that of colchicine. Compound 13 inhibited the clonogenicity of MDA-MB-231 cells through a mechanism that destabilizes tubulin polymerization, leading to cell cycle arrest at the G2/M phase.

Indole and spiro-fused oxindole frameworks widely exist in a variety of natural bioactive products, pharmaceuticals, and drug candidates, featuring unique functions in the regulation of proliferation, infiltration, and metastasis of cancer cells. In recent years, significant progress in proteolysis targeting chimeric (PROTAC) technology that employs ubiquitin-proteasome system (UPS) to eliminate disease-associated proteins has been witnessed, thus opening a promising avenue to the discovery of new indole-related drugs. In this review, we focus on summarizing the achievements of small molecule PROTACs that involve indole/spirofused oxindole scaffolds in the part of ligands of the protein of interest (POI). Current challenges and future directions in this promising field are discussed at the end of this review. For the convenience of readers, our review is divided into five parts according to the types of target proteins. We hope this review could bring a quick look and some inspiration to researchers in relevant fields.

Lupeol (LP) and Mangiferin (MG) have beneficial effects on health. However, their pharmacokinetic properties can affect their bioavailability when administered orally. Therefore, their incorporation as a vehicle in a hybrid matrix of ZnO and PLGA could contribute to improving bioavailability. Methods: This study aimed to develop this matrix and evaluate the optical and bioactive properties obtained by the solvent emulsion and evaporation methods. These were subjected to processes to evaluate their bioactivity in relation with topoisomerase. Results: Functionalized treatment number 15 (TF15) showed the best results in studies of controlled release and encapsulation efficiency of lupeol (LP) and mangiferin (MG) (60.01 ± 1.24% and 57.71 ± 1.94%). The best treatment showed behavior as a topoisomerase II inhibitor (18.60 ± 1.55). The nanoparticles developed in this study did not show a cytotoxic effect on BEAS-2B, while HepG2, showed a decrease in viability (IC50 1549.96 ± 174.62 μg/mL). However, although the hemolytic activity is not shown after 1 h of exposure, morphological alterations caused by TF15 are observed at concentrations of 2500 and 1250 μg/mL. Conclusion: The TF15 treatment shown maintaining antitopoisomerasa activity does and does not cytotoxixity for healthy cells and slows down the growth of cancer cells.

Background: Carbonic Anhydrases (CAs) are a family of metalloenzymes that catalyze the reversible interconversion of CO2 and water to bicarbonate and proton. CA isoforms I, II, IX, and XII are considered physiologically and pharmacologically relevant. Objective: The objective of this study is to synthesize potent and selective tumor-associated CA IX and XII inhibitors. Methods: A library of 17 coumarin derivatives clubbed with piperazine and benzyl moiety was designed, synthesized and evaluated for its inhibitory effects and selectivity profile towards physiologically and pharmacologically relevant CA isoforms I, II, IX, and XII. Results: All the derivatives were found to be active against the tumor-associated isoforms IX and XII. The most active compound against hCA (human Carbonic Anhydrase) IX was found to possess a Ki of 229 nM, while the one against hCA XII had a Ki of 294.2 nM. Additionally, two of the compounds were found to have exquisite selectivity towards the off-target hCA I and II isoforms. Moreover, they were found to be approximately 20-fold more selective towards hCA IX than XII. The selectivity of the compounds was further investigated via molecular modeling techniques. Conclusion: Coumarin-piperazine hybrids were identified as potent and selective CA IX and XII inhibitors. Molecular modeling techniques provided interesting cues pertaining to observed selectivity.

Objective: We reported herein the synthesis of novel arylazo derivatives 3a-e incorporating isoquinoline moiety. Methods: A coupling reaction of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile 1 with diazotized heterocyclic amines 2 in ethanol in the presence of sodium acetate to give arylazo derivatives 3a-e. Results: Cytotoxic effect of five arylazo derivatives on breast carcinoma MCF7 and hepatocellular carcinoma HepG2 was carried out, followed by molecular and functional-based assays, to estimate the anticancer effect of these compounds. The fibroblast growth factor receptor (FGFR) and epithelial growth factor receptor (EGFR) were found to interact and bind with the compounds 3a and 3d through several hydrophobic and hydrogen bonds, which were validated by molecular docking. Conclusion: The two promising compounds 3a and 3d demonstrated various anticancer potential activities on tumorigenesis, cytotoxicity, and apoptotic effects, exhibited in the deregulation of the expression of different genes involved in apoptotic and anti-apoptotic mechanisms, cell cycle arrest at G2/M, and induction of apoptosis in both cell lines.

Background: Erianin is an active dibenzyl compound isolated from Dendrobium officinale and Dendrobium chrysotoxum and there are very few studies on molecular mechanisms and drug targets of erianin. In addition, there is no study investigating the anti-cancer effect of erianin on neuroblastoma cells. Objective: The aim of the study is to investigate the anticancer effect of erianin and the underlying mechanism of this effect on SH-SY5Y cells. Methods: The effects of erianin on cell viability, invasion and migration were determined by XTT, matrigel chamber and wound healing evaluation, respectively. Expression changes of miRNAs (microRNA) and apoptosis-related genes were evaluated by RT-PCR, and the apoptosis rate was supported by Annexin V evaluation. Results: Erianin significantly decreased cell proliferation, invasion and migration. Erianin administration caused apoptosis by significantly increasing , FADD (Fas-associated protein with death domain), BID (BH3 Interacting Domain Death Agonist) and DR5 (Death receptor 5) gene expressions. While the rate of total apoptotic cells was 45.35 ± 6.80% in SH-SY5Y cells treated with erianin, it was 0.133 ± 0.05% in the control group (p = 0.000). In addition, erianin administration significantly decreased the expressions of hsa-miR-155-5p (p = 0.014) and hsa-miR-223-3p (p = 0.004). Also, our study demonstrated for the first time the relationship between erianin and mi-RNAs in a cancer cell. Conclusion: Our study suggests that erianin may be a natural, safe and easily accessible drug candidate that can be used in the treatment of neuroblastoma.

Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx. Objective: Here, we aimed to understand better the molecular basis for arctigenin (ARG)'s ability to promote NPC 5- 8F cell invasion. Methods: We tested the effects of several doses of ARG on 5-8F cells that had been cultured in vitro. We estimated the metabolic activity of cells by The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay. We examined the influence on cell invasion, and migration using Transwell Evaluation. Real-time polymerase chain reaction analysis was used to determine the relative amounts of epidermal growth factor receptor (EGFR), Janus kinase 2 (JAK2), and transcriptional activator 3 (STAT 3) mRNA expression. Using western blotting, we looked at the level of phosphorylation of specific proteins like EGFR, phosphorylated EGFR, JAK2, and STAT 3. Results: Our findings revealed that ARG inhibited NPC 5-8F cell development in a dose-and time-dependent manner. The invasiveness and mobility of 5-8F cells were significantly suppressed when ARG was overexpressed in a tumor development model. Expression levels of EGFR, JAK2, and STAT 3 mRNA were considerably low in the experimental group. As a consequence of being treated with ARG, lower levels of EGFR, p-EGFR, p-JAK2, and p-STAT3 expression were observed. Conclusion: These results suggest that ARG may prevent NPC 5-8F cells from proliferating, migrating, and invading other tissues. There are a few potential molecular pathways, two of which are the inhibition of EGFR phosphorylation and the reduction of levels of phospho-JAK2 and phospho-STAT3.

Aim: Human carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are validated antitumor/ antimetastatic drug and tumor imaging targets with sulfonamide inhibitors and monoclonal antibodies in clinical development. Coumarins act as isoform-selective inhibitors of these isoforms over the cytosolic and mitochondrial ones. Methods: We report the synthesis and in vitro CA inhibitory evaluation of a large panel of coumarins incorporating pyrazole-1-carboxamide moieties. Compounds were fully characterized before the assessment of their inhibitory activity. A stopped-flow CO2 hydrase assay was performed for the biological test. Results: These coumarins did not inhibit the widespread, off-target isoforms CA I and II (KI >50 μM), but they were sub-micromolar CA IX/XII inhibitors with an interesting selectivity index higher than the reference compound. Selectivity between α- and β-class of CAs was also promising. Conclusion: These compounds may be used as leads for the rational design and development of non-sulfonamide CA IX/XII effective inhibitors.