Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 18, Issue 15, 2018

Introduction: The understanding of cancer has evolved into a complex disease, which has heterogeneous characteristics between different patients, and more than that, a broad range of genetically distinct cells in the same tumor. Chronic and non-transmissible diseases such as cancer have become even more important worldwide and advances in their characterization and properties are running out. In a suitable setting, early diagnosis of cancer and proper treatment are essential to overcome the barriers of tumor healing and quality assurance of the patient's life. The studies included in the analysis were independently retrieved by the authors. The text words included “Non-Small Cell Lung Cancer,” “NSCLC,” “biomarkers in NSCLC” and “gene in NSCLC”.” We were used to perform a systematic literature search in the PubMed and Web of Science databases. There was limit on the start date for published articles (2001), and the search ended in December 2017. For a more comprehensive analysis, articles were only in English. Non-small Cell Lung Cancer (NSCLC) Microenvironment: This review focuses on lung cancer, especially NSCLC, one of the most worldwide common cancer types, showing the importance of tumor microenvironment in this disease. NSCLC Biomarkers: This review shows a molecular aspect of NSCLC biomarkers used in clinical approaches, such as EGFR, KRAS, MET, indicating mutations that are crucial for cancer progression and related to treatment properties. We also describe 11 drugs commonly used in cancer treatment that are correlated with the patient genetic profile. Conclusion: This review highlights the importance of molecular diagnosis of mutations in lung cancer, driving to individualized therapy with the intent of getting a better response to treatment and improving patients’ quality of life.

Background: Nanotechnology pictures a breakthrough in the domain of cancer therapy owing to its novel properties and functions. This technology is quite amendable as it allows the scientists to engineer drug nanoparticles of dimensions 10nm – 500nm permitting them to pass via leaky vasculature of tumorigenic microenvironment with higher specificity, reduced cytotoxicity and effective release without any after effects. The central part of the review zooms onto the role of nanoparticles and their targeted delivery for the cure of cancer. Methods: The novel and various versatile nanoparticle platforms viz. polymeric (drug-conjugates, micelles, dendrimers), Lipid-based (liposomes, solid nanoparticle, nanostructured lipid carrier, lipid-polymer hybrid), and stimuli-sensitive (thermoresponsive, ultrasound, pH-responsive, hydrogel) etc. have been designed for a persistent, précised nanodrug delivery and the co-delivery of collegial drug conjugates leading to the formation of safer release of myriad of drugs for cancer chemoprevention. Results: The review concerns about tracing and detailing the drug delivery systems of cancer nanotechnology. Conclusion: Nanotechnology is bestowed with the design, depiction, fabrication, and application of nanostructures, and devices with their controlled delivery together with the imaging of the selected target site and drug release at the specific site of action.

Background: Cisplatin (CDDP), a small molecule platinum-based compound, is an effective anticancer drug used against a wide range of human neoplasms. Long-term clinical use of CDDP is however limited due to the development of drug resistance and the possible incidence of serious side effects including nephrotoxicity and ototoxicity. The mechanisms underlying resistance of cells to CDDP are complex, and among them, the cytoprotective involvement of proteins referred to as Heat Shock Proteins (HSP) seems potentially important. Methods: We searched various electronic databases including PubMed and selected the reports concerning the contribution of HSPs to CDDP resistance of cancer cells and to minimize the CDDP-induced nephrotoxicity and ototoxicity. Results: This critical review of data collected so far summarizes the results on the major HSPs: HSP27/HSPB1, HSP70/HSPA1, HSP90/HSPC and GRP78/HSPA5, because only these have been the subject of the most intense research in the matter discussed here. We also provide relevant information concerning some other HSPs, namely HSPA9/mortalin, HSPA2, HSP110 and DNAJ. A possible role of HSPs in counteracting CDDP-induced neprho- and ototoxicity is mentioned. Conclusions: This review shows that no universal relationship between the levels of expression of HSPs and sensitivity of cancer cells to CDDP can be confirmed. Multiple observations indicate however that such correlation can rather manifest as a molecular or cellular context-dependent phenomenon. Thus, HSPs can be viewed as an important component of the multifactorial, complex response of cancer cells to CDDP. However, to strengthen such a conviction, more extensive studies are needed.

Background: Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women. Even after diagnosis, the prognosis cannot be concluded since patients can develop resistance to therapy, which favors tumor growth, invasion and metastasis. In recent years, research has focused on identifying significant markers that can be used to determine the prognosis. Melatonin can act through G protein– coupled MT1 receptor, which controls selected protein kinases, influences the levels of transcription factor phosphorylation, specific genes expression, proliferation, angiogenesis, cell differentiation, migration, and indirectly controls the transport of glucose in cancer cells. It is known that glucose enters the cells by glucose transporters, such as GLUT1 which shows wide tissue distribution and appears to be altered in human breast carcinoma. High GLUT1 expression is associated with increased malignant potential, invasiveness and poor prognosis in some cancers including breast cancer. Objective: The aim of this study was to evaluate the expression of MT1 receptor and GLUT1 in breast tumors and correlate with molecular subtypes and prognostic characteristics. Method: Protein expression was performed by an immunohistochemical procedure with specific antibodies and positive and negative controls. Results: We found that MT1 high expression was associated with good prognosis subtype (Luminal A), while GLUT1 high expression was related to poor prognosis subtype (triple-negative). In addition, we found high expression of MT1 in ER+ and the inverse in GLUT1 expression. GLUT1 is also highly expressed in tumor ≥20mm. Conclusion: These results indicate MT1 and GLUT1 as potential targets for breast cancer subtypes and prognosis.

Background: Cancer is one of the leading diseases responsible for deaths in the society. According to the American cancer society, there will be 95,270 new cases of colon cancer in the U.S. in 2016. When a normal cell turns cancerous they develop into tumours, which produce various pro-inflammatory and inflammatory cytokines and chemokines that attract leukocytes to the site of growth. The main aim of this paper is to introduce readers about the increased number of cancer patient, effects of cancer and need of research on same. Methods: The target molecules were prepared by reacting pyrazolealdehyde with appropriate aromatic ketone by using polyethylene glycol (PEG-300) as green solvent and catalyst to yield chalcone. Furthermore, the reaction of chalcones with thiosemicabazide yields asymmetric 1-thiocarbamoyl pyrazoles. All the newly synthesized compounds were in vitro screened for their anticancer activities against Colon SW-620 by employing the sulforhodamine B (SRB) assay method. Also all the synthesized compounds tested for in vitro antioxidant and anti-inflammatory activity by using known literature methods. Results: Preliminary in vitro evaluation indicated that most of the compounds 4c, 4d and 4e possess distinct cytotoxicity profile against Colon SW-620 cell line compared to standard drug adriamycin. All the tested compounds showed good to excellent antioxidant activity against one or more reactive (H2O2, DPPH, SOR and NO) radical scavenging species. Additionally, all the synthesized compounds were screened for their in vitro antiinflammatory activity. Compounds 4a, 4b and 4e shows potent anti-inflammatory activity as compared to diclofenac sodium as a standard reference. Conclusion: New anti- Colon SW-620 cancer agents are the need of time, we trust that 1-thiocarbamoyl pyrazole derivatives 4c, 4d and 4e constitute an interesting template for the evaluation of new anticancer agent also antioxidant and anti-inflammatory work may provide an interesting insight for further development

Background: For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Methods: Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Result: Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 μM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 μM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 μM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). Conclusion: The obtained results encourage considering these three compounds as novel anticancer prototypes.

Background: Acetylation of core histones is governed by opposing actions of a variety of histone acetyltransferases (HATs) and Histone Deacetylases (HDACs). Deregulation of histone acetylation has been causally linked to cancer development and progression, and can be potentially reversed by drug treatments. HDAC inhibitors (HDACis) have the anti-cancer effects such as induction of cell cycle arrest, promotion of cell apoptosis, and inhibition of metastasis. Many of these HDACis are currently in clinical development. Methods: To screen for novel compound with HDACis activity, cell-based strategy has been developed in current work. The interaction of HDACs and TCFs was determined by reporter assay, and Natural products library (A10) was screened by our system in colon cancer cells. Results: Based on the interaction of HDACs and TCFs, compounds with HDACis activity could be easily picked out from Natural products library (A10) by using this screening system. Finally, a compound Wsu-18 was preliminarily identified as a potential HDACis. Conclusion: These data suggest our screening system for HDACis was efficient and promising, and it is suitable for screening other small molecular chemical libraries.

Background: Malignant melanoma is an agressive tumour related to the overproduction of melanin, which provides colors of skin, eyes and hair. In addition contributing to the risk of malignant melanoma, abnormal production of melanin has many drawbacks, including hyperpigmentation, post-inflammatory pigmentation, melasma and skin aging. Kojic acid is currently employed in order to lighten skin pigmentation and provide depigmentation. Objective: Mannich bases of kojic acid with the structure of 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/ methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylmethyl-4H-pyran-4-one (compounds 1-23) were synthesized by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in the presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives, nucleophilic substitutions were carried out. Method: Cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5 human lung cell lines were investigated by sulphorhodamine B assay. Control agents were vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. Results: Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 μM) than the FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. Conclusion: Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.

Objective: Metastasis phenotype is considered as the main challenge in colon cancer therapeutic methods. Furthermore, the side effects of conventional colorectal cancer treatment methods have attracted a lot of attention into natural ingredients. The aim of the study was to assess the molecular mechanism of verbascoside as natural bio-compound in human HT29 colon cancer cells. Methods: HT29 cells were cultured in RPMI-1640 medium containing 10% FBS and 1% penicillin/ streptomycin at 37°C and 5% CO2. HT-29 cells were treated with different concentrations of verbascoside (10, 20, 30, 40, 50, 70, 100 μg/ml) for 24 hours, then MTT assay was used to calculate 50% inhibitory concentration. The migration of the colon cancer cells was evaluated by scratch assay. To evaluate involved antiproliferative mechanism, Rac-1 (Ras-related C3 botulinum toxin substrate 1) and HIF-1α (hypoxia-inducible factor-1α) related gene expression were evaluated by Real Time PCR. Results: The results showed that verbascoside inhibited HT29 colon cancer cell proliferation dose-dependently and IC50 was evaluated as 50 μg/ml (***P<0.001). The results of wound healing assay demonstrated verbascoside decreased cell migration in a dose dependent manner. In the IC50 treated HT29 cells metastatic progression was significantly suppressed as **P<0.01. The results of Real Time PCR showed an attenuating effect of verbascoside on Rac-1, Zeb-1 (zinc finger E-box binding homeobox 1), Arp2 (Actin-Related Proteins), Pak1 (p21 (RAC1) activated kinase 1), VEGF (Vascular endothelial growth factor) and HIF-1α as Epithelial-Mesenchymal Transition markers. The down regulation of mRNA levels was Rac-1= 15.38, HIF-1 α = 16.66, Pak-1, Arp-2= 6.25, VEGF=24.39, Zeb-1=35.71 in HT29 cells treated with IC50 concentration of verbascoside. Conclusion: Colorectal cancer cells induce Rac-1 and HIF-1α overexpression which plays an important role in the activation and progression of cell motility, angiogenesis and metastasis. Overall results showed that verbascoside elucidated significant anti-metastatic and anti-invasion activities through suppression of Rac-1, HIF-1α, and Zeb-1 signaling pathway and it may be a suitable candidate to overwhelm colon cancer metastatic phenotype.

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

Background: Amino acids conjugated with heterocyclic molecules are well known for their effective bioactive properties. In search of effective anticancer agents, a series of xanthone linked amino acids 2-23 were synthesized and tested for in vitro anticancer activity. Methods: In vitro anticancer activity of the synthesized xanthone linked amino acids 2-23 are tested against three different cancer cell lines MCF-7, MDA-MB-435 and A549 by MTT assay and validated by DNA binding and molecular docking approaches. Doxorubicin and ethidium bromide used as standard and positive control respectively. Results: Compounds 7, 8 and 9 exhibited potent anticancer activity against tested cancer cell lines and DNA binding study using methyl green. In the molecular docking study, binding interactions of the most active compounds 7, 8 and 9 were confirmed to molecular surface of DNA. Conclusion: Structure-Activity Relationship (SAR) showed that the aromatic and hydrophobic amino acids (phenylalanine, tyrosine, and tryptophan) favoured the DNA binding studies and anticancer activity whereas, aliphatic amino acids showed least anticancer activity.

Background: Arsenic trioxide (As2O3), which has been shown to be effective in treating leukemia and other solid tumors, was strictly restricted in clinical application due to its severe toxicity. The present study was performed to explore whether the combination of As2O3 and artemisinin could produce a more powerful anticancer effect and reduce the toxicity of As2O3. Method: MTT assay was performed to detect the cell viability of A549, Hela and HepG2 cells treated with As2O3 and artemisinin. Combination Index (CI) analysis was carried out to evaluate the synergistic effect of As2O3 and artemisinin. Wound healing assay was performed to evaluate the migration rate. Fluorescent microscopy measurements and flow cytometry were used to evaluate the apoptosis. Result: Reactive Oxygen Species (ROS) was detected with DCFH-DA. The cell proliferation assay indicated that artemisinin significantly enhanced the inhibitory effect of As2O3 in a dose and time-dependent manner (P<0.01). Combination Index (CI) analysis further demonstrated that combining artemisinin with As2O3 generated synergistic effects in A549 (CI=0.65±0.05), Hela (CI=0.68±0.07) and HepG2 (CI=0.47±0.01) cells. The combination of these two drugs also evidently reduced the cell migration rate. Artemisinin also enhanced the apoptosis, necrosis in As2O3- treated A549 and Hela cells. Combination of As2O3 and artemisinin significantly induced more apoptosis (22.1%) than As2O3 (5.68%) or ART (5.93%) alone in Hela cells. In addition, ROS levels were increased obviously by combining artemisinin with As2O3. Conclusion: The present study indicated that combining artemisinin with As2O3 would be a novel therapeutic strategy for cancer therapy.

Background: Bone Marrow (BM) has the self-renovation capacity and has been used recently in tumor medicine. Chlorambucil [CHB] is ordinarily utilized chemotherapy to treat varieties of malignancy patients. This investigation intended to gauge the effectiveness of BM as an in-vivo antimutagenic against CHB. Methods: The experimental design relies upon four classes; each class contains ten adult male albino rats as follows: control, rats infused orally with CHB for fourteen days, rats intravenously infused with BM through a tail vein one time, rats infused the mix of CHB and BM.The Anticancer capability of BM was assessed by cytogenetic assay and mitotic index. The declarations of the apoptosis- related genes were examined by RT-qPCR examination. Results: The present experiment demonstrated a curative effect of BM against the cytotoxic impact of CHB. Infusion of BM after chemotherapy helps to diminish the chromosomal aberration; increment mitotic index and decline the Bax/Bcl2 proportion compared with [CHB] class gather that prompts expanding the survival rate of influenced cells with chemotherapy cytotoxicity. Conclusion: The present study shows that bone marrow transplantation together after CHB infusion helps to increase genomic stability by diminishing structural chromosome abnormalities, diminishing the Bax/Bcl2 proportion and increasing the mitotic index.

Background: Microbial infections have been the major cause of morbidity and mortality for the centuries and continue to present the formidable challenge to the human health. Several studies have been performed to explore the antimicrobial potential of various synthesized chalcone derivatives. The morpholine derivatives are also gaining considerable importance due to diverse biological activities. Hybridization of morpholine and chalcone moiety together can be the useful approach for the development of new effective antimicrobial agents. Methods: A new series of morpholine based heterocyclic diazenyl chalcones (MD1-MD21) was synthesized, characterized and evaluated for antimicrobial potential by tube dilution and agar diffusion methods. The most active derivatives were also evaluated for cytotoxicity towards mouse fibroblast cell line (L929) and the human lung cancer cell line (A549) and for haemolysis to check the toxicity on human red blood cells. Results: MD-6 was found highly active against different microbial strains, particularly S. typhi, E. coli, A. niger and C. albicans having the MIC in the range of 1.95 μg/ml to 3.91 μg/ml. MD-9 and MD-21 were also found to have good antimicrobial activity. The most active diazenyl derivatives exhibited very low cytotoxicity towards L929 cell line (IC50 ranges from 360 μg/ml - 902.3 μg/ml) and A549 cell line (IC50 ranges from 35.42 μg/ml - 216.4 μg/ml) as compared to the standard drug 5-FU (IC50 ranges from 1 μg/ml - 2 μg/ml) against these cell lines. The active derivatives showed haemolysis of 10-15% up to 150 μg/ml concentration. Conclusion: MD-6, MD-9 and MD-21 were found to be most active antimicrobial agents. These derivatives demonstrated high safety profile by exhibiting very low cytotoxicity and also revealed their safety for human blood cells with haemolysis of 0.2-5.5% at their antimicrobial concentration.

Background: Cisplatin-based treatment often leads to therapeutic failure because the acquisition of cisplatin resistance. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Objective: Celastrus orbiculatus is a traditional Chinese medicine from Celastraceae family with multiple pharmacological activities. We previously found that the ethyl acetate extract of Celastrus orbiculatus (COE) exhibited significant antitumor activity in gastric cancer. Here, we asked whether COE could increase the sensitivity of cisplatin. Methods: We use CCK8 assay to show synergistic cytotoxicity of COE and cisplatin. Then, PI single staining and FITC-Annexin V/PI double staining were used to observe apoptotic cells through flow cytometry. The proteins of caspase signaling pathway were examined by Western blotting. Results: COE and cisplatin showed synergistic cytotoxicity in a dose-dependent manner in BGC 823 and SGC 7901 gastric cancer cells, and COE could increase the number of apoptotic cells upon cisplatin treatment in vitro. Moreover, our results indicated that COE could enhance cisplatin–induced activation of caspase-8 or caspase- 9/caspase-3/PARP1 signaling pathways. The xenograft study further confirmed that COE increased the sensitivity of cisplatin in vivo. Conclusion: Our findings provided new evidence that COE could increase the sensitivity of cisplatin on the antitumor effect.