scholarly journals The Fiber Knob Protein of Human Adenovirus Type 49 Mediates Highly Efficient and Promiscuous Infection of Cancer Cell Lines Using a Novel Cell Entry Mechanism

2020 ◽  
Author(s):  
Alexander T. Baker ◽  
James A. Davies ◽  
Emily A. Bates ◽  
Elise Moses ◽  
Rosie M. Mundy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Surface Potential ◽  
Human Adenovirus ◽  
Cancer Cell Lines ◽  
Cell Entry ◽  
Therapeutic Applications ◽  
Wide Range ◽  
Pseudotyped Vector ◽  
Entry Mechanism

The human adenovirus (HAdV) phylogenetic tree is diverse, divided across seven species and comprising over 100 individual types. Species D HAdV are rarely isolated with low rates of pre-existing immunity, making them appealing for therapeutic applications. Several species D vectors have been developed as vaccines against infectious diseases where they induce robust immunity in pre-clinical models and early phase clinical trials. However, many aspects of the basic virology of species D HAdV, including their basic receptor usage and means of cell entry, remain understudied. Here, we investigated HAdV-D49, which previously has been studied for vaccine and vascular gene transfer applications. We generated a pseudotyped HAdV-C5 presenting the HAdV-D49 fiber knob protein (HAdV-C5/D49K). This pseudotyped vector was efficient at infecting cells devoid of all known HAdV receptors, indicating HAdV-D49 uses an unidentified cellular receptor. Conversely, a pseudotyped vector presenting the fiber knob protein of the closely related HAdV-D30 (HAdV-C5/D30K), differing in four amino acids to HAdV-D49, failed to demonstrate the same tropism. These four amino acid changes resulted in a change in isoelectric point of the knob protein, with HAdV-D49K possessing a basic apical region compared to a more acidic region in HAdV-D30K. Structurally and biologically we demonstrate that HAdV-D49 knob protein is unable to engage CD46, while potential interaction with CAR is extremely limited by extension of the DG loop. HAdV-C5/49K efficiently transduced cancer cell lines of pancreatic, breast, lung, oesophageal and ovarian origin, indicating it may have potential for oncolytic virotherapy applications, especially for difficult to transduce tumor types. IMPORTANCE Adenoviruses are powerful tools experimentally and clinically. To maximize efficacy, the development of serotypes with low pre-existing levels of immunity in the population is desirable. Consequently, attention has focused on those derived from species D, which have proven robust vaccine platforms. This widespread usage is despite limited knowledge in their basic biology and cellular tropism. We investigated the tropism of HAdV-D49, demonstrating it uses a novel cell entry mechanism that bypasses all known HAdV receptors. We demonstrate, biologically, that a pseudotyped HAdV-C5/D49K vector efficiently transduces a wide range of cell lines, including those presenting no known adenovirus receptor. Structural investigation suggests that this broad tropism is the result of a highly basic electrostatic surface potential, since a homologous pseudotyped vector with a more acidic surface potential, HAdV-C5/D30K, does not display a similar pan-tropism. Therefore, HAdV-C5/D49K may form a powerful vector for therapeutic applications capable of infecting difficult to transduce cells.

scholarly journals The fiber knob protein of human adenovirus type 49 mediates highly efficient and promiscuous infection of cancer cell lines using a novel cell entry mechanism

2020 ◽  
Author(s):  
Alexander T. Baker ◽  
Gareth Marlow ◽  
James A. Davies ◽  
Elise Moses ◽  
Rosie M. Mundy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Surface Potential ◽  
Human Adenovirus ◽  
Cancer Cell Lines ◽  
Cell Entry ◽  
Therapeutic Applications ◽  
Wide Range ◽  
Pseudotyped Vector ◽  
Entry Mechanism

AbstractThe human adenovirus (HAdV) phylogenetic tree is diverse, divided across seven species and comprising over 100 individual types. Species D HAdV are rarely isolated with low rates of pre-existing immunity, making them appealing for therapeutic applications. Several species D vectors have been developed as vaccines against infectious diseases where they induce robust immunity in pre-clinical models and early phase clinical trials. However, many aspects of the basic virology of species D HAdV, including their basic receptor usage and means of cell entry, remain understudied.Here, we investigated HAdV-D49, which previously has been studied for vaccine and vascular gene transfer applications. We generated a pseudotyped HAdV-C5 presenting the HAdV-D49 fiber knob protein (HAdV-C5/D49K). This pseudotyped vector was efficient at infecting cells devoid of all known HAdV receptors, indicating HAdV-D49 uses an unidentified cellular receptor. Conversely, a pseudotyped vector presenting the fiber knob protein of the closely related HAdV-D30 (HAdV-C5/D30K), differing in four amino acids to HAdV-D49, failed to demonstrate the same tropism. These four amino acid changes resulted in a change in isoelectric point of the knob protein, with HAdV-D49K possessing a basic apical region compared to a more acidic region in HAdV-D30K. Structurally and biologically we demonstrate that HAdV-D49 knob protein is unable to engage CD46, whilst potential interaction with CAR is extremely limited by extension of the DG loop. HAdV-C5/49K efficiently transduced cancer cell lines of pancreatic, breast, lung, oesophageal and ovarian origin, indicating it may have potential for oncolytic virotherapy applications, especially for difficult to transduce tumour types.ImportanceAdenoviruses are powerful tools experimentally and clinically. To maximise efficacy, the development of serotypes with low pre-existing levels of immunity in the population is desirable. Consequently, attention has focussed on those derived from species D, which have proven robust vaccine platforms. This widespread usage is despite limited knowledge in their basic biology and cellular tropism.We investigated the tropism of HAdV-D49, demonstrating it uses a novel cell entry mechanism that bypasses all known HAdV receptors. We demonstrate, biologically, that a pseudotyped HAdV-C5/D49K vector efficiently transduces a wide range of cell lines, including those presenting no known adenovirus receptor. Structural investigation suggests that this broad tropism is the result of a highly basic electrostatic surface potential, since a homologous pseudotyped vector with a more acidic surface potential, HAdV-C5/D30K, does not display a similar pan-tropism. Therefore, HAdV-C5/D49K may form a powerful vector for therapeutic applications capable of infecting difficult to transduce cells.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

2020 ◽  
Vol 20 (10) ◽  
pp. 1209-1220
Author(s):  
Rafat M. Mohareb ◽  
Ensaf S. Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Proliferative Activity ◽  
Cancer Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Cytotoxic Compounds ◽  
Triazine Derivatives ◽  
Target Molecules

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

New Approaches for the Synthesis of Fused Thiophene, Pyrazole , Pyran and Pyridine Derivatives with Anti-Proliferative Together with c-Met Kinase and Prostate Cancer Cell Inhibitions

2020 ◽  
Vol 20 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Yara R. Milad ◽  
Reem A. El-Ansary
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Aromatic Aldehydes ◽  
Cancer Cell Lines ◽  
Enzymatic Activities ◽  
Pyridine Derivatives ◽  
Wide Range ◽  
Target Molecules

Background:: Recently multi-component reactions producing pyran and pyridine derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus were known. Objective:: We are aiming in this work to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione followed by its heterocyclization reactions to produce anticancer target molecules. Methods:: This work demonstrated multi-component reactions of cyclohexan-1,3-dione with aromatic aldehydes and diethylmalonate using triethylamine as a catalyst to give the 7,8-dihydro-4H-chromen-5(6H)-one derivatives 4a-c. The reaction of compounds 4a-c with either of hydrazine hydrate of phenylhydrazine gave the chromeno[2,3-c]pyrazole derivatives 5a-f, respectively. In addition, further heterocyclization reactions were adopted to give the chromeno[3,2-d]isoxazole, chromene-3-carboxamide derivatives. Moreover, the multi-component reaction of cyclohexan-1,3-dione (1) with either of aromatic aldehydes and diethylmalonate using a catalytic amount of ammonium acetate gave the 1,4,5,6,7,8-hexahydroquinoline derivatives 13a-c. The anti-proliferative activities of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 were studied. In addition the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. Results:: Anti-proliferative evaluations, c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured and the results obtained in most cases, indicated that the presence of electronegative Cl group through the molecule favour the inhibitions. Conclusion:: The compounds with high anti-proliferative activity towards the cancer cell lines were 4a, 4b, 6d, 6e, 6f, 10e, 10f, 12c, 14e, 14f, 15c, 16d, 16e, 16f, 19c and 20c. Compounds 4b, 6c, 6d, 8b, 10c, 10d, 12b, 13b, 14c, 14d, 15b, 16c, 16d, 17b, 17c, 19b, 20b and 20c exhibited high potency against c-Met kinase and compounds 4a, 4b, 6b, 6c, 6d, 6f, 8b, 8c, 10c, 10d, 10e, 12b, 12c, 13a, 13b, 13c, 14c, 14d, 14e, 14f, 15b, 15c, 16b, 16c, 16d, 17b, 17c, 19c, 19d, 20a, 20b and 20c displayed high inhibitions toward PC-3 cell line.

scholarly journals Recombinant deoxyribonucleoside kinase from Drosophila melanogaster can improve gemcitabine based combined gene/chemotherapy for targeting cancer cells

2019 ◽  
Author(s):  
Mahak Fatima ◽  
M. Mubasshar Iqbal Ahmed ◽  
Faiza Batool ◽  
Anjum Riaz ◽  
Moazzam Ali ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Nucleoside Analogs ◽  
Cancer Cell Lines ◽  
Control Group ◽  
Wide Range

A recombinant deoxyribonucleoside kinase from Drosophila melanogaster with a deletion of the last 20 amino acid residues (named DmdNKΔC20) was hypothesized as a potential therapeutic tool for gene therapy due to its broad substrate specificity and better catalytic efficiency towards nucleosides and nucleoside analogs. This study was designed to evaluate the effect of DmdNKΔC20 for sensitizing human cancer cell lines towards gemcitabine and to further investigate its role in reversal of acquired drug resistance in gemcitabine-resistant cancer cell line. The DmdNKΔC20 gene was delivered to three different cancer cell lines, including breast, colon and liver cancer cells, using lipid-mediated transfection reagent. After transfection, gene expression of DmdNKΔC20 was confirmed by reverse transcription quantitative PCR (qRT-PCR) and the combined effect of DmdNKΔC20 and gemcitabine based cytotoxicity was observed by cell viability assay. We further evolved a gemcitabine-resistant breast cancer cell line (named MCF7-R) through directed evolution in the laboratory, which showed 375-fold more resistance compared to parental MCF7 cells. Upon transfection with DmdNKΔC20 gene, MCF7-R cells showed 83-fold higher sensitivity to gemcitabine compared to the control group of MCF7-R cells. Moreover, we observed 79% higher expression of p21 protein in transfected MCF7-R cells, which may indicate induction of apoptosis. Our findings highlight the importance and therapeutic potential of DmdNKΔC20 in combined gene/chemotherapy approach to target a wide range of cancers, particularly gemcitabine-resistant cancers.

scholarly journals Antiproliferative and Apoptosis Induction Potential of the Methanolic Leaf Extract ofHolarrhena floribunda(G. Don)

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
J. A. Badmus ◽  
O. E. Ekpo ◽  
A. A. Hussein ◽  
M. Meyer ◽  
D. C. Hiss
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Molecular Probe ◽  
Blue Dye ◽  
Apoptosis Induction ◽  
Cycle Arrest ◽  
Wide Range

Natural plant products with potent growth inhibition and apoptosis induction properties are extensively being investigated for their cancer chemopreventive potential.Holarrhena floribunda(HF) is used in a wide range of traditional medicine practices. The present study investigated the antiproliferative and apoptosis induction potential of methanolic leaf extracts of HF against breast (MCF-7), colorectal (HT-29), and cervical (HeLa) cancer cells relative to normal KMST-6 fibroblasts. The MTT assay in conjunction with the trypan blue dye exclusion and clonogenic assays were used to determine the effects of the extracts on the cells. Caspase activities were assayed with Caspase-Glo 3/7 and Caspase-9 kits. Apoptosis induction was monitored by flow cytometry using the APOPercentage and Annexin V-FITC kits. Reactive oxygen species (ROS) was measured using the fluorogenic molecular probe 5-(and-6)-chloromethyl-2′,7′-dichlorofluorescein diacetate acetyl ester and cell cycle arrest was detected with propidium iodide. Dose-response analyses of the extract showed greater sensitivity in cancer cell lines than in fibroblast controls. Induction of apoptosis, ROS, and cell cycle arrest were time- and dose-dependent for the cancer cell lines studied. These findings provide a basis for further studies on the isolation, characterization, and mechanistic evaluation of the bioactive compounds responsible for the antiproliferative activity of the plant extract.

scholarly journals Optimization of Microwave-Assisted Extraction Process of Callicarpa candicans (Burm. f.) Hochr Essential Oil and Its Inhibitory Properties against Some Bacteria and Cancer Cell Lines

Processes ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 173 ◽  
Author(s):  
Quoc Toan Tran ◽  
Thu Le Vu Thi ◽  
Tien Lam Do ◽  
Hong Minh Pham Thi ◽  
Bich Hoang Thi ◽  
...  
Keyword(s):  
Essential Oil ◽  
Cell Lines ◽  
Cancer Cell ◽  
Microwave Power ◽  
Cancer Cell Lines ◽  
Extraction Process ◽  
Raw Material ◽  
Extraction Time ◽  
Microwave Assisted ◽  
Wide Range

Callicarpa candicans (Burm. f.) Hochr. (Callicarpa cana L.) is a medicinal plant that is distributed mainly in the tropics and subtropics of Asia and finds a wide range of uses in traditional medicine. In this study, we attempted and optimized the microwave-assisted hydro-distillation (MAHD) process to obtain essential oil from the leaves of C. candicans. In addition, the obtained oil was analyzed for volatile composition by gas chromatography–mass spectrometry (GC-MS) and assayed for bioactivity against several bacteria and cancer cell lines. To optimize the extraction process, response surface methodology (RSM) in combination with central composite design (CCD) was adopted. Experimental design and optimization were carried out with respect to three experimental factors including the ratio of water to raw material, extraction time, and microwave power. The optimal extraction conditions were obtained as follows: water to raw material ratio of 6/1 (v/w), extraction time 42 min, and microwave power 440 W. Composition determination of the obtained C. candicans essential oil indicated the presence of predominant components including caryophyllene <b-> (10.45%), cadinene <d-> (10.28%), gurjunene <a-> (8.95%), muurolene <g-> (8.92%), selinene <a-> (7.06%), selinene <b-> (5.59%), and copaene <a-> (5.40%). In comparison with the essential oils obtained via traditional hydro-distillation method, the essential oil extracted by MAHD exhibited superior anti-proliferative activity on all tested cancer cell lines. Current results imply that the MAHD is capable of recovering biologically-active natural products of greater quantity than that recovered by the conventional distillation.

Anti-Cancer and Kinases Inhibitor Activities of Synthesized Heterocyclic Substituted Thiophene Fused with Cyclohexane Derivatives

2017 ◽  
Vol 14 (1) ◽  
pp. 768-774 ◽  
Author(s):  
Abd El-Galil E Amr ◽  
Hassan Z Ghanem ◽  
Mohamed A Al-Omar ◽  
Mohamed M Abdalla ◽  
Mohamed G Assy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Mechanism Of Action ◽  
Sphingosine Kinase ◽  
Cancer Cell Lines ◽  
Anticancer Activities ◽  
Kinase Inhibition ◽  
Wide Range ◽  
Anti Cancer

We herein report the anti-cancer and kinases inhibitor activities of some synthesized heterocyclic substituted thiophene fused with cyclohexane derivatives (Fig. 1) were synthesized before. Sixteen of these compounds were conveniently screened for their in vitro cytotoxicity against a wide range of cell lines, and showed potent activities against lung and leukemic cancer cell lines. The in vivo antilung and antileukemic cancers of the most active in vitro compounds was estimated and founded highly potent and compared to the standard drugs Bevacizumab and Etoposide. In search for the mechanism of action of anticancer activities it was found that these compounds exert its action via sphingosine kinase inhibition and inhibition of p53 ubiquitination.

scholarly journals Iranian propolis efficiently inhibits growth of oral streptococci and cancer cell lines

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Fariba Asgharpour ◽  
Ali Akbar Moghadamnia ◽  
Ebrahim Zabihi ◽  
Sohrab Kazemi ◽  
Amirmorteza Ebrahimzadeh Namvar ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Cell Lines ◽  
Cancer Cell ◽  
Biofilm Formation ◽  
Cytotoxic Effect ◽  
Cancer Cell Lines ◽  
Oral Streptococci ◽  
Cariogenic Bacteria ◽  
Wide Range ◽  
The Impact

Abstract Background Propolis is a natural bee product with a wide range of biological activities that are related to its chemical composition. The present study investigated the quantification of quercetin (Q) in Ardabil ethanol extract of propolis (AEEP), and then compared its anti-bacterial, anti- biofilm and cytotoxic effects on cancer and normal cell lines. Method In the present study, the chemical composition of AEEP was determined through the high-performance liquid chromatography (HPLC). The AEEP and its main component, quercetin (Q), were evaluated in vitro against 57 oral streptococci by a broth micro-dilution method. The biofilm formation was assessed through the crystal violet staining and MTT assays. The impact of AEEP and Q anti-proliferative effect were evaluated on the fibroblast as normal and cancer cell lines (KB and A431). Results The Q concentration in the composition of AEEP was 6.9% of all its components. The findings indicated that the AEEP and Q were efficient against the cariogenic bacteria and were able to inhibit the S.mutans biofilm adherence at a sub-MIC concentration. Moreover, electron micrographs indicated the inhibition of biofilms compared to control biofilms. In addition, the AEEP and Q indicated a dose-dependent cytotoxic effect on A431 and KB cell lines. On the contrary, they had no cytotoxic effect on fibroblast cells. Conclusion The results indicated that the synergistic impact of main components of AEEP was related to the inhibition of the cancer cell proliferation, cariogenic bacteria and oral biofilm formation. It may play a promising role in the complementary medicine and, it is suggested to be used as food additives.

scholarly journals Therapeutic applications of three-dimensional organoid models in lung cancer

Organoid ◽  
2021 ◽  
Vol 1 ◽  
pp. e6
Author(s):  
Chang Dong Yeo ◽  
Young-Pil Yun ◽  
Dong Hyuck Ahn ◽  
Yongki Hwang ◽  
Seung Hee Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Research ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Three Dimensional ◽  
Cancer Cell Lines ◽  
Genomic Diversity ◽  
Therapeutic Applications ◽  
Cancer Models

Lung cancer, which remains a major cause of mortality worldwide, is a histologically diverse condition and demonstrates substantial phenotypic and genomic diversity among individual patients, manifesting as both intertumoral and intratumoral heterogeneity. This heterogeneity has made it difficult to develop lung cancer models. Two-dimensional (2D) cancer cell lines have been used to study genetic and molecular alterations in lung cancer. However, cancer cell lines have several disadvantages, including random genetic drift caused by long-term culture, a lack of annotated clinical data, and most importantly, the fact that only a subset of tumors shows 2D growth on plastic. Three-dimensional models of cancer have the potential to improve cancer research and drug development because they are more representative of cancer biology and its diverse pathophysiology. Herein, we present an integrated review of current information on preclinical lung cancer models and their limitations, including cancer cell line models, patient-derived xenografts, and lung cancer organoids, and discuss their possible therapeutic applications for drug discovery and screening to guide precision medicine in lung cancer research. Altogether, the success rate of generating lung cancer organoids must be improved, and a lung cancer organoid culture system is necessary to achieve the goal of designing an individualized therapeutic strategy for each lung cancer patient.

Multi-Component Reactions of Cyclohexan-1,3-dione: Synthesis of Fused Pyran, Pyridine, Thiophene and Pyrazole Derivatives with c-Met, AntiProliferative Activities

2021 ◽  
Vol 21 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Amira M. Elmetwally ◽  
Abeer A. Mohamed
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Heterocyclic Ring ◽  
Cancer Cell Lines ◽  
Wide Range ◽  
Target Molecules

Background: Recently products of multi-component reactions (MCR’s) acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR’s were known. Objective: We are aiming in this work to synthesize target molecules not only possess anti-tumour activities but also cMet and prostate cancer inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione through its multi-component reactions to produce anticancer target molecules. Methods: Cyclohexan-1,3-dione underwent different multi-component reactions to produce fused pyran, pyridine and thiophene derivatives. The anti-proliferative activity of the newly synthesized compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions toward c-Met kinase and prostate cancer cell line were studied. Antitumor evaluations toward seventeen cancer cell lines subpanel according the diseases, for certain compounds were also demonstrated. Pim-1 kinase inhibitions of the most active compounds were also measured. Results: Anti-proliferative evaluations, c-Met and Pim-1 kinase inhibitions were performed for most of the synthesized compounds where the varieties of substituent through the aryl ring and the heterocyclic ring afforded compounds with high activities. Conclusion: Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b and 25b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cell showed that the presence of the electronegative Cl group within the molecule was responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.

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