scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

scholarly journals Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3041
Author(s):  
Xiaohan Hu ◽  
Sheng Tang ◽  
Feiyi Yang ◽  
Pengwu Zheng ◽  
Shan Xu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Design Synthesis ◽  
Structure Activity ◽  
Excellent Activity ◽  
Ic50 Values ◽  
Mcf 7

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.

scholarly journals Synthesis of Lapachol-Based Glycosides and Glycosyl Triazoles with Antiproliferative Activity Against Several Cancer Cell Lines

2021 ◽  
Author(s):  
Flaviano Melo Ottoni ◽  
Lucas Bonfim Marques ◽  
Juliana Martins Ribeiro ◽  
Lucas Lopardi Franco ◽  
José Dias Souza Filho ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Effects ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Biological Activities ◽  
Cancer Cell Lines ◽  
Tumor Cell Lines

Abstract Lapachol (1), a natural naphthoquinone, presents several biological activities including antitumor activity, used as anticancer coadjuvant whose use was abandoned because of adverse effects. Herein, we reported the synthesis and cytotoxicity evaluation against cancer cell lines of a series of Oglycosides and glycosyl triazoles derived from lapachol. In addition to the determination of IC50, the DNA fragmentation and clonogenicity were also evaluated. The glycoside derived from D-glucose (5) was far more active than lapachol (1) and more active in tumor cell lines HL60, Jurkat, THP-1 and MDA-MB-231 than to the non-tumoral PBMC cell line, indicating an improvement in activity and selectivity as compared with lapachol (1). Compound 5 and the glycosides derived from D-galactose (14), D-N-acetylglucosamine (15) and L-fucose (16) showed good results in the DNA fragmentation and clonogenicity assays in the studies of subdiploid DNA content, indicating a pro-apoptotic potential and a good antiproliferative activity of these glycosides.

scholarly journals Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0246197
Author(s):  
Jorge Marquez ◽  
Jianping Dong ◽  
Chun Dong ◽  
Changsheng Tian ◽  
Ginette Serrero
Keyword(s):  
Flow Cytometry ◽  
Western Blot ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Negative Regulator ◽  
Target Validation ◽  
Antibody Drug

Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for hematopoietic and lymphoid tumors. However, there is need to identify new targets for ADCs, particularly for solid tumors and cancers with unmet needs. From a hybridoma library developed against cancer cells, we selected the mouse monoclonal antibody 33B7, which was able to bind to, and internalize, cancer cell lines. This antibody was used for identification of the target by immunoprecipitation and mass spectrometric analysis, followed by target validation. After target validation, 33B7 binding and target positivity were tested by flow cytometry and western blot analysis in several cancer cell lines. The ability of 33B7 conjugated to saporin to inhibit in vitro proliferation of PTFRN positive cell lines was investigated, as well as the 33B7 ADC in vivo effect on tumor growth in athymic mice. All flow cytometry and in vitro internalization assays were analyzed for statistical significance using a Welsh’s T-test. Animal studies were analyzed using Two-Way Analysis of Variance (ANOVA) utilizing post-hoc Bonferroni analysis, and/or Mixed Effects analysis. The 33B7 cell surface target was identified as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was confirmed by showing that PTGFRN-expressing cells bound and internalized 33B7, compared to PTGFRN negative cells. Cells able to bind 33B7 were PTGFRN-positive by Western blot analysis. In vitro treatment PTGFRN-positive cancer cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers.

CHEMOTHERAPEUTIC POTENTIAL OF NOVEL XANTHONE SOURCED FROM SWERTIA CHIRATA AGAINST SKIN CARCINOGENESIS

2020 ◽  
pp. 84-88
Author(s):  
ATISH BARUA ◽  
PRITHA CHOUDHURY ◽  
CHINMAY KUMAR PANDA ◽  
PROSENJIT SAHA
Keyword(s):  
Skin Cancer ◽  
Antitumor Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Self Renewal ◽  
Qrt Pcr ◽  
Swertia Chirata

Objective: Swertia chirata forms a rich source of bio-active compounds, among which xanthones form an important part. Among the xanthones present in it, 1,5,8 Tri-hydroxy-3-methoxy xanthone (TMX) was found to be the most active. The present study aims to evaluate the chemotherapeutic potential of it against metastatic skin cancer cell lines. Methods: In this study, the antitumor activity of TMX (the active component of chirata plant) was evaluated in A431, SKMEL-5, and A375 cell line by using in-vitro assays such as cell viability assay, cell cycle analysis, caspase 3 activity assay, intracellular reactive oxygen species (ROS) level determination by dichlorofluorescein diacetate, and quantitative real-time polymerase chain reaction (qRT-PCR). Results: In vitro studies showed that TMX from S. chirata exhibited significant antitumor activity by inducing apoptosis and restricting proliferation in both melanoma and non-melanoma skin cancer cell lines, but no such activity was seen in normal skin cancer cell line WS1. The qRT-PCR analysis revealed that in both the melanoma ad non-melanoma cell lines, TMX could exert its antitumor activity by downregulating c-Myc, cyclin-D1, and β-catenin and up-regulating Wnt antagonist gsk-3β, thereby suppressing wnt self-renewal pathway, but such regulation was absent in normal cell line. Conclusions: TMX from chirata could effectively inhibit the proliferation of metastatic skin cancer (both melanoma and non-melanoma) cell lines while being non-toxic to normal cell lines. The chemotherapeutic potential of TMX against metastatic skin cancer cell lines was achieved by downregulating several key regulatory genes enabling the suppression of the self-renewal pathway, the chief reason behind the invasiveness of cancer cells.

Novel N-bridged pyrazole-1-carbothioamides with potential antiproliferative activity: design, synthesis, in vitro and in silico studies

2021 ◽  
Vol 13 (20) ◽  
pp. 1743-1766
Author(s):  
Islam H El Azab ◽  
Essa M Saied ◽  
Alaa A Osman ◽  
Amir E Mehana ◽  
Hosam A Saad ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
In Silico ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Molecular Docking Study ◽  
In Silico Studies

Thiazole-substituted pyrazole is an important structural feature of many bioactive compounds, including antiviral, antitubercular, analgesic and anticancer agents. Herein we describe an efficient and facile approach for the synthesis of two series of 36 novel N-bridged pyrazole-1-phenylthiazoles. The antiproliferative activity of a set of representative compounds was evaluated in vitro against different human cancer cell lines. Among the identified compounds, compound 18 showed potent anticancer activity against the examined cancer cell lines. The in silico molecular docking study revealed that compound 18 possesses high binding affinity toward both SK1 and CDK2. Overall, these results indicate that compound 18 is a promising lead anticancer compound which may be exploited for development of antiproliferative drugs.

scholarly journals Synthesis and Antiproliferative activity in vitro of Amidino Substituted 2-phenylbenzazoles

2019 ◽  
Vol 92 (2) ◽  
pp. 181-189 ◽  
Author(s):  
Livio Racané ◽  
Kristina Butković ◽  
Irena Martin-Kleiner ◽  
Marijeta Kralj ◽  
Grace Karminski-Zamola ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Cancer Cell Lines ◽  
Benzimidazole Derivatives ◽  
Antiproliferative Agents ◽  
Benzothiazole Derivatives

Within this work we describe the synthesis of versatile substituted 2-phenyl benzothiazole 3–10 and 2-phenylbenzimidazole 12–19 derivatives bearing amidino groups. Furthermore, the synthesized compounds were explored for their antiproliferative activity in vitro on three cancer cell lines. Tested compounds showed moderate to strong antiproliferative activity. Furthermore, the type of the attached amidino group on benzazole nuclei has the significant impact on the antiproliferative activity only within benzimidazole derivatives with 2-imidazolinyl substituted derivatives being more active in comparison to amidino substituted analogues. All obtained results revealed that this type of benzothiazole derivatives have a great potential for further optimization and development of more efficient potential antiproliferative agents.

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