Anti-Cancer Agents in Medicinal Chemistry - Volume 20, Issue 14, 2020

Background: Cancer is a dreadful disease causing thousands of deaths per year worldwide, which requires precision diagnostics and therapy. Although the selection of therapeutic regimens depends on the cancer type, chemotherapy remains a sustainable treatment strategy despite some of its known side-effects. To date, a number of natural products and their derivatives or analogues have been investigated as potent anticancer drugs. These drug discoveries have aimed for targeted therapy and reduced side-effects, including natural therapeutic regimens. Objective: This review introduces a prospective fungal-derived polyphenol, Hispolon (HIS), as an anticancer agent. Accordingly, this review focuses on exploring the anticancer effect of hispolon based on information extracted from databases such as PubMed, ScienceDirect, MedLine, Web of Science, and Google Scholar. Methods: A literature search in PubMed, ScienceDirect, MedLine, Web of Science, and Google Scholar was accomplished, using the keyword ‘Hispolon’, pairing with ‘cancer’, ‘cytotoxicity’, ‘cell cycle arrest’, ‘apoptosis’, ‘metastasis’, ‘migration’, ‘invasion’, ‘proliferation’, ‘genotoxicity’, ‘mutagenicity’, ‘drug-resistant cancer’, ‘autophagy’, and ‘estrogen receptor. Results: Database-dependent findings from reported research works suggest that HIS can exert anticancer effects by modulating multiple molecular and biochemical pathways, including cell cycle arrest, apoptosis, autophagy, inhibition of proliferation, metastasis, migration, and invasion. Moreover, HIS inhibits the estrogenic activity and exhibits chemoprevention prospects, possibly due to its protective effects such as anticancer and anti-inflammatory mechanisms. To date, a number of HIS derivatives and analogues have been introduced for their anticancer effects in numerous cancer cell lines. Conclusion: Data obtained from this review suggest that hispolon and some of its derivatives can be promising anticancer agents, and may become plant-based cancer chemotherapeutic leads for the development of potent anticancer drugs, alone or in combination with other chemotherapeutic agents.

Background: Lung cancer is among the most common cancers worldwide, responsible for 13% of all new cancer cases. Also, it is the leading cause of cancer death among both men and women. In this scenario, an effective and efficient treatment is required. Objective: Production of two gold nanoparticles: 198Au and 99mTc-Au. The first one has been produced from irradiation of the 197Au in order to produce a beta-emitter gold nanoparticle for cancer therapy. The second one has been produced from the radiolabeling of gold nanoparticles with technetium 99 metastable in order to produce imaging nanoagent. Methods: The 198Au nanoparticles were produced by irradiation and identified by hyper-purity germanium (HPGe). They were then evaluated in vitro in order to confirm the behavior on cell proliferation of lung cancer cell lines by the MTT methodology using A549 cells. The 99mTc-Au nanoparticles were produced by directradiolabeling with 99mTc and evaluated in vivo as intralesional nanoagent. Results: The results showed that in both cases, all the nanoparticles have performed their duties with excellence. The 198Au nanoparticles were capable to kill lung cancer cells, while 99mTc-Au was capable to image the tumor after intralesional injection. In addition, 99mTc-Au nanoparticles were useful for biodistribution assay imaging, showing the main organs responsible for the nanoparticle uptake in healthy animals. Conclusion: Both gold nanoparticles showed to be a highly efficient nanoagent for both: therapy and diagnosing of lung cancer.

Background: We previously demonstrated that isovitexin (apigenin-6-C-glucoside, ISOV) suppressed the stemness of human Hepatocellular Carcinoma (HCC) cells. However, the mechanism of its action remains to be deciphered. Objective: The current study was to examine whether ISOV regulates the miR-34a expression and hence suppresses the stemness of HCC SK-Hep-1 cells. Methods: After identification of the stemness, apoptosis resistance and decreased miR-34a expression of spheres from SK-Hep-1 cells (SK-SC), we utilized transfection of a miR-34a mimic or inhibitor to investigate the effects of ISOV on miR-34a, Bcl-2, Bax and Mcl-1 expression in order to understand the mechanism underlying ISOV-mediated repression of stemness and promotion of apoptosis. Results: Our results demonstrated that SK-SC displayed higher stemness and resistance to apoptosis, as well as reduced miR-34a levels compared to SK-Hep-1 cells. ISOV suppressed sphere and colony formation, and decreased CD44+ cell populations. In addition, ABCG2, ALDH1, and NANOG mRNA levels were decreased, while there was a concomitant increase in miR-34a levels. With regards to apoptosis-related proteins, ISOV increased Bax protein levels, and reduced Bcl-2 and Mcl-1 protein levels in SK-SC. Importantly, there was a cooperative effect when miR-34a was overexpressed in the presence of ISOV in SK-SC, and down-regulation of miR-34a attenuated the effects of ISOV in SK-Hep-1 cells. Conclusion: We suggest that ISOV-mediated miR-34a upregulation induces apoptosis and suppresses the stemness of SK-SC. Our data indicate that ISOV exhibits therapeutic potential for the treatment of HCC.

Background: Combretaceae is a large family comprising of 500 species and 20 genera distributed in subtropical and tropical regions of the world. Conocarpus genus is an ornamental tree native to coastal and riverine areas of East Africa and is also planted as an ornamental plant in different areas of Pakistan. This genus has proved medicinal value as a cytotoxic, antibacterial, antiprotozoal, anti-leishmanial, antifungal and antidiabetic agent. Objective: The current study was designed to screen the selected pharmacological attributes of sulphur containing novel compound isolated from Conocarpus lancifolius using a series of in vitro and molecular docking models. Materials and Methods: After collection and authentication of plant material, methanolic extract was prepared from which various secondary metabolites were qualitatively examined. The compound was isolated using open column chromatography and the structure was established with spectroscopic techniques such as UV-visible, infrared spectroscopy, proton nuclear magnetic resonance (1H-NMR), 13C NMR (BB, DEPT-135, 90), twodimensional correlation techniques (HMBC, HSQC) and mass spectrometry (HRMS) respectively. C. lancifolius extract and isolated compound were studied for cytotoxic and antifungal potentials using in vitro Sulforhodamine B (SRB) and disc diffusion methods, respectively. Molecular docking studies were conducted to check the interaction of the isolated compound with major oncogenic proteins. Results: Qualitative phytochemical screening revealed the presence of saponins, steroids, flavonoids, anthraquinones, and cardiac glycosides while alkaloids were absent in C. lancifolius extract. Isolated compound was characterized as lancifoliate, which showed cytotoxic activity towards a variety of cancer cell lines including murine lymphocytic leukemia (P-388, IC50 = 2.65μg/ml), human colon cancer (Col-2, IC50 = 0.84μg/ml), human breast cancer (MCF-7, IC50 = 0.72μg/ml) while no cytotoxic activity was observed towards human lung cancer (Lu-1), rat normal glioma cells (ASK, IC50 = 11.6μg/ml) and human embryonic kidney cells (Kek293, IC50 = 6.74μg/ml) respectively. Minimum Inhibitory Concentration (MIC) of Lancifoliate towards Aspergillus fumigatus, Aspergillus nigar (skin sample), Aspergillus flavus (pleural fluid) and Candida albicans (urine and blood samples) was found to be 54.5, 44.8, 43.5, 22.4 and 20.2μg/ml respectively. Moreover, docking results are in strong agreement with our experimental finding, which has identified lancifoliate to be a more potent antiproliferative agent than previously known compound ellipticine. Conclusion: C. lancifolius extract and lancifoliate possess potent cytotoxic and antifungal properties and thus has potential to be further studied. To the best of our knowledge, this is the first study that highlights isolation, identification and pharmacological activities of lancifoliate from Conocarpus lancifolius.

Background and Purpose: Green nanotechnology is an interesting method for the synthesis of functional nanoparticles. Because of their wide application, they have set up great attention in recent years. Objective: The present research examines the green synthesis of Ag and zero-valent iron nanoparticles (AgNPs, ZVINPs) by Feijoa sellowiana fruit extract. In this synthesis, no stabilizers or surfactants were applied. Methods: Eco-friendly synthesis of Iron and biogenic synthesis of Ag nanoparticles were accomplished by controlling critical parameters such as concentration, incubation period and temperature. Scanning Electron Microscopy (SEM), Transmission Electron Microscope (TEM), Energy-Dispersive X-ray Spectroscopy (EDS), Fourier-Transform Infrared (FT-IR) spectroscopy, X-ray Diffraction analysis (XRD), Dynamic Light Scattering (DLS) and UV-Vis were applied to characterize NPs. The cytotoxicity of NPs was investigated in two cell lines, MCF-7 (breast cancer) and AGS (human gastric carcinoma). A high-performance liquid chromatography (HPLC) analysis was also performed for characterization of phenolic acids in the extract. Results: Both NPs displayed powerful anticancer activities against two tumor cell lines with little effect on BEAS-2B normal cells. Synthesized AgNPs and ZVINPs inhibited the growth of all selected bacteria. Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumonia, Staphylococcus aureus, Enterococcus faecalis, Acinetobacter baumannii and Escherichia coli have been studied in two stages. We initially examined the ATCCs followed by clinical strain isolation. Based on the results from resistant strains, we showed that nanoparticles were superior to conventional antibiotics. DPPH (diphenyl-1-picrylhydrazyl) free radical scavenging assay and iron chelating activity were used for the determination of antioxidant properties. Results showed a high antioxidant activity of scavenging free radicals for ZVINPs and powerful iron-chelating activity for AgNPs. Based on the HPLC data, catechin was the major phenolic compound in the extract. Conclusion: Our synthesized nanoparticles displayed potent cytotoxic, antibacterial and antioxidant activities.

Background: The strategic development of therapeutic agents, capable of being targeted at their active sites, has been a major goal in treatment of cancer. The delivery of drugs for tumors has as its main challenge the development of safe and effective drugs, since the goal of chemotherapy is to eliminate the tumor completely without affecting healthy cells. The aim of present study was to investigate the antioxidant, anticancer activities of zidovudine and its α-O-glycosylated derivative obtained by biosynthesis of a filamentous fungi, Cunninghamela echinulata. Methods: An evaluation of the cytotoxic potential of zidovudine and its α-O-glycosylated was performed in fibroblasts and melanoma cells by the tetrazolium reduction method (MTT) and the antioxidant activity of this derivative was observed. Results: The antioxidant activity of zidovudine demonstrated an electrochemical oxidation potential of 0.91V, while the α-O-glycosylated derivative did not exhibit any antioxidant activity. The zidovudine exhibited low cytotoxicity for melanoma and fibroblast cells, while the α-O-glycosylated derivative presented better cytotoxicity on melanoma cells at a concentration of 10mg. mL-1. Conclusion: This study demonstrates the specific cytotoxicity of the glycoconjugate and suggests that glycosylation by biosynthesis can be a useful strategy for obtaining new anticancer compounds.

Introduction: Prostate cancer is a serious threat to men’s health so it is necessary to develop technics for early detection of this malignancy. The purpose of this research was the evaluation of a new^99mTc-labeled GnRH analogue as an imaging probe for tumor targeting of prostate cancer. Methods: ^99mTc-labeled-DLys6-GnRH analogue was prepared based on HYNIC as a chelating agent and tricine/ EDDA as coligands for labeling with ^99mTc. HYNIC was coupled to epsilon amino group of DLys6 through aminobutyric acid (GABA) as a linker. Radiochemical purity and stability in normal saline and serum, were determined by TLC and HPLC methods. Furthermore, calculation of protein-binding and partition coefficient constant were carried out for ^99mTc labeled peptide. The cellular experiments including receptor binding specificity and affinity were studied using three prostate cancer cell lines LN-CaP, DU-145 and PC-3. Finally, the animal assessment and SPECT imaging of radiolabeled GnRH analogue were evaluated on normal mice and nude mice bearing LN-CaP tumor. Results: The GnRH conjugate was labeled with high radiochemical purity (~97%). The radiolabeled peptide showed efficient stability in the presence of normal saline and human serum. The in vitro cellular assays on three prostate cancer cell lines indicated that the radiotracer was bound to LN-CaP cells with higher affinity compared to DU-145 and PC-3 cells. The Kd values of ^99mTc- HYNIC (tricine/ EDDA)-Gaba-D-Lys6GnRH were 89.39±26.71, 93.57±30.49 and107.3±18.82 in LN-CaP, PC-3 and DU-145 cells respectively. The biodistribution studies in normal mice and LN-CaP tumor-bearing nude mice showed similar results including rapid blood clearance and low radioactivity accumulation in non-target organs. High kidney uptake proved that the main excretion route of radiopeptide was through the urinary system. The tumor uptake was 1.72±0.45 %ID/g at 1h p.i. decreasing to 0.70±0.06%ID/g at 4h p.i. for ^99mTc-HYNIC-Gaba-D-Lys6GnRH. The maximum tumor/ muscle ratio was 2.30 at 1h p.i. Pre-saturation of receptor using an excess of unlabeled peptide revealed that the tumor uptake was receptor mediated. The results of the SPECT image of LN-CaP tumor were in agreement with the biodistribution data. Conclusion: Based on this study, we suggest LN-CaP as a favorable cell line for in vivo studies on GnRH analogues. Moreover, this report shows that ^99mTc-HYNIC (tricine/EDDA)-Gaba-D-Lys6GnRH may be a suitable candidate for further evaluation of prostate cancer.

Background: Cancer is the second leading cause of mortality worldwide. Despite several advances made in the treatment strategies, the cure for cancer remains still a challenge. Currently used treatment modalities pose several side effects and remain ineffective in the later stages. Thiazolidinediones (TZDs) have been shown to possess anti-cancer activity in several in vitro models. Objectives: The objective of this study was to assess the effect of novel synthesized thiazolidinedione derivatives on three selected cancer cell lines viz., human breast adenocarcinoma cell line (MCF-7), lung adenocarcinoma (A549) and colorectal carcinoma (HT29). This study also aimed to evaluate the anti-inflammatory and DNA binding activity of the synthesized derivatives. Methods: The synthesized thiazolidinedione derivatives were screened for their in vitro anti-cancer activity on the human breast adenocarcinoma cell line (MCF-7), lung adenocarcinoma (A549) and colorectal carcinoma (HT29) using the Methyl Thaizolyl Tetrazolium (MTT) Assay. They were also evaluated for in vitro antiinflammatory activity using albumin denaturation method, DNA binding activity and hemocompatibility. Results: Compounds 5a, 5b, 5d, 6c and 6d showed IC50 of 30.19, 41.56, 65.97, 60.16 and 50.41μM respectively on breast adenocarcinoma (MCF-7), IC50 of 49.75, 51.42, 65.43, 61.94 and 56.80μM on lung adenocarcinoma (A549) and 38.11, 45.58, 71.24, 53.15 and 51.25μM on colorectal carcinoma (HT29). In the hemolysis assay, compounds 5a and 5b were found to be nontoxic and nonhemolytic to human erythrocytes. Five compounds possessed significant anticancer and anti-inflammatory activity. Three of them are Mannich bases, whereas the remaining two are aryl acyl derivatives. Conclusion: The in vitro results (anticancer and anti-inflammatory) showed that the 4-chloro anilinomethyl substitution at third position and thiophenoethenyl at the fifth position of thiozolidinedione (5a) emerged as the most effective derivative on all the tested cancer cell lines. A higher DNA binding affinity of the test compounds was also found.

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

Background: Colon cancer is one of the major causes of morbidity and mortality worldwide. Cycle inhibiting factors (Cifs) have been shown to deamidate Nedd8, resulting in cell cycle arrest. Objective: To determine the antitumor effect of Cifs on colon cancer by using attenuated Salmonella typhimurium VNP20009. Methods: The VNP-SOPE2-cif and VNP-SOPE2-cif-C/A plasmids were transfected into attenuated Salmonella typhimurium VNP20009. The efficiency and specificity of the Cif promoter were validated in colon cancer SW480 cell lines. Western blotting was subsequently performed to evaluate cell cycle regulators, including P21, P27 and Wee1. In vivo, the antitumor effect of VNP20009 was evaluated in a colon cancer xenograft model. Results: Firstly, VNP-SOPE2-cif and VNP-SOPE2-cif-C/A were selectively expressed both in the bacterial and colon cancer cells. Cif expression in SW480 cells via the VNP tumor-targeted expression system induced the accumulation of Wee1, p21 and p27 expression. Moreover, tumor growth was significantly inhibited in the mice with VNP-SOPE2-cif compared to the mice with VNP with the empty construct. Conclusion: These results suggest that Cif gene delivered by VNP20009 is a promising approach for the treatment of colon cancer.

Background: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways. Objective: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer activities. Methods: Compounds were tested by cell-free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer, and L929 fibroblast cell lines. Results: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells, whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity. Conclusion: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells, and further research will enlighten the underlying mechanisms of their effects.

Background: Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATPBinding Cassette (ABC) transporters family. Physiologically, it exports toxins out of the cell, however, its overexpression leads to the phenomena of Multidrug-Resistance (MDR) by exporting a diverse range of compounds, which are structurally and chemically different from each other, thus creating a hurdle in the treatment of various diseases including cancer. The current study was designed to screen benzophenone sulfonamide derivatives as a class of inhibitors and potential anticancer agents for P-gp. Methods: A total number of 15 compounds were evaluated. These compounds were screened in daunorubicin efflux inhibition assays using CCRF-CEM Vcr1000 cell line that overexpressed human P-gp. Cytotoxicity assay was also performed for active compounds 11, 14, and 13. These scaffolds were then docked in the homology model of human P-gp using mouse P-gp as a template (PDB ID: 4MIM) and the recently published Cryo Electron Microscopy (CEM) structure of human mouse chimeric P-gp to find their interactions with specified residues in the binding pocket. Analysis was performed using Labview VI and Graph pad prism version 5.0. Results: Results revealed the potency of all these compounds in low nanomolar range whereas, compound 14 was found to be most active with IC50 value of 18.35nM±4.90 followed by 11 and 13 having IC50 values of 30.66nM±5.49 and 46.12nM±3.06, respectively. Moreover, IC50 values calculated for 14, 11 and 13 in cytotoxicity assay were found to be 22.97μM±0.026, 583.1μM±0.027 and 117.8μM±0.062, respectively. Docking results showed the interaction of these scaffolds in transmembrane helices (TM) where Tyr307, Tyr310, Tyr953, Met986 and Gln946 were found to be the major interaction partners, thus they might play a significant role in the transport of these scaffolds. Conclusion: Benzophenone sulfonamide derivatives showed IC50 values in low nanomolar range comparable to the standard inhibitor Verapamil, therefore they can be good inhibitors of P-gp and can serve as anticancer agents. Also, they have shown interactions in the transmembrane region sharing the same binding region of verapamil and zosuquidar.