Synthesis and anticancer activity of some pyrido[2,3-d]pyrimidine derivatives as apoptosis inducers and cyclin-dependent kinase inhibitors

Aim: Due to emergence of resistance to available anticancer agents, there is a need to search for new cytotoxic agents. Methods: Pyrido[2,3- d]pyrimidines (4–6) and their tricyclic derivatives (7–13) were prepared and screened for their cytotoxicity against breast MCF-7, prostate PC-3 and lung A-549 cancer cell lines as well as normal fibroblasts WI-38. Results: The most active compounds were 6b, 6e and 8d compared with doxorubicin. Moreover, compounds 6b and 8d induced apoptosis in PC-3 and MCF-7, respectively via activation of CASP3 (in PC-3 only), Bax, p53 and down regulation of Bcl2 in addition to CDK4/6 inhibition. Conclusion: Pyrido[2,3- d]pyrimidine represents an important core for discovery of new potent cytotoxic agents acting on the cell cycle via apoptosis induction through either intrinsic or extrinsic pathways.

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PGV-0 AND PGV-1 INCREASED APOPTOSIS INDUCTION OF DOXORUBICIN ON MCF-7 BREAST CANCER CELLS

Pharmacon Jurnal Farmasi Indonesia ◽

10.23917/pharmacon.v12i2.32 ◽

2015 ◽

Vol 12 (2) ◽

pp. 55-59

Author(s):

Edy Meiyanto

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Chemotherapeutic Agent ◽

Apoptosis Induction ◽

Single Treatment ◽

Cell Cycle Modulation ◽

Induced Apoptosis ◽

Mcf 7

As chemotherapeutic backbone for breast cancer therapy, doxorubicin showed various side effects and induced resistancy of breast cancer cells. Development of targeted therapy on breast cancer focused on combinatorial therapy of doxorubicin and molecular targeted agents. PGV-0 and PGV-1, a curcumin analogue showed potency as co-chemotherapeutic agent with doxorubicin. Our previous study of PGV-0 and PGV-1 showed cytotoxic activity in T47D cells. Therefore, the aim of this research is to examine the synergistic effect of PGV-0, PGV-1 on the cytotoxic activity of doxorubicin through cell cycle modulation and apoptotic induction on MCF-7 breast cancer cell lines. The cytotoxic assay of PGV-0, PGV-1, doxorubicin, and their combination were carried out by using MTT assay. Cell cycle distribution and apoptosis were determined by flowcytometer FACS-Calibur and the flowcytometry data was analyzed using Cell Quest program. Single treatment of PGV-0, PGV-1 and doxorubicin showed cytotoxic effect on MCF-7 with cell viability IC50 value 50 µM, 6 µM and 350 nM respectively. Single treatment of Doxorubicin 175 nM induced G2/M arrest. Single treatment of PGV-0 5 µM induced G2/M arrest while in higher dose 12.5 µM, PGV-0 induced apoptosis. Combination of doxorubicin 175 nM and PGV-0 5 µM induced apoptosis. Combination of doxorubicin 175 nM and PGV-0 12.5 µM also increased apoptosis induction. Single treatment of PGV-1 0.6 µM induced G1 arrest while in higher dose 1.5 µM, PGV-1 induced apoptosis. Combination of doxorubicin 175 nM and PGV-1 0.6 µM induced apoptosis. Combination of doxorubicin 175 nM and PGV-0 1.5 µM also increased apoptosis induction. PGV-0 and PGV-1 are potential to be delevoped as co-chemotherapeutic agent for breast cancer by inducing apoptosis and cell cycle modulation, but the molecular mechanism need to be explored detail. Key words: PGV-0, PGV-1, doxorubicin, co-chemotherapy, breast cancer, cell cycle arrest, apoptosis

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Anti-proliferation Effect on Human Breast Cancer Cells via Inhibition of pRb Phosphorylation by Taiwanin E Isolated from Eleutherococcus trifoliatus

Natural Product Communications ◽

10.1177/1934578x1400900921 ◽

2014 ◽

Vol 9 (9) ◽

pp. 1934578X1400900

Author(s):

Hui-Chun Wang ◽

Yen-Hsueh Tseng ◽

Hui-Rong Wu ◽

Fang-Hua Chu ◽

Yueh-Hsiung Kuo ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Inhibitors ◽

Folk Medicine ◽

Breast Adenocarcinoma ◽

Cyclin D ◽

Dependent Manner ◽

Cyclin Dependent Kinase ◽

Human Breast ◽

Mcf 7

Eleutherococcus trifoliatus has been used as a folk medicine since ancient times, especially as refreshing qi medicines. In our current study, taiwanin E, which possesses strong cytotoxicity, was isolated from the branches of E. trifoliatus by using a bioactivity guided fractionation procedure. Taiwanin E presented a potent anti-proliferation activity on the growth of a human breast adenocarcinoma cell line (MCF-7), with an IC50 value for cytotoxicity of 1.47 μM. Cell cycle analysis revealed that the proportion of cells in the G0/G1 phase increased in a dose-dependent manner (from 79.4% to 90.2%) after 48 h exposure to taiwanin E at a dosage range from 0.5 to 4μM. After treatment with taiwanin E, phosphorylation of retinoblastoma protein (pRb) in MCF-7 cells was inhibited, accompanied by a decrease in the levels of cyclin D1, cyclin D3 and cyclin-dependent kinase 4 (cdk4) and cdk6; in addition, there was an increase in the expression of cyclin-dependent kinase inhibitors p21WAF-1/Cip1 and p27Kip1. The results suggest that taiwanin E inhibits cell cycle progression of MCF-7 at the G0/G1 transition.

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In Vitro Anticancer Evaluation of Some Synthesized 2H-Quinolinone and Halogenated 2H-Quinolinone Derivatives as Therapeutic Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200811122753 ◽

2020 ◽

Vol 20 (18) ◽

pp. 2304-2315

Author(s):

Rahma M. Abd El-Aziz ◽

Islam Zaki ◽

Ibrahim M. El-Deen ◽

Marwa S. Abd-Rahman ◽

Faten Z. Mohammed

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Cancer Cell Lines ◽

Normal Breast ◽

Cytotoxic Agents ◽

Dna Flow Cytometry ◽

Induced Apoptosis ◽

Mcf 7

Background: Searching for new cytotoxic agents with apoptosis induction may represent a viable strategy for cancer treatment to overcome the increased resistance to available anticancer agents. Objective: The purpose of the current study was aimed at preparation and anticancer evaluation of two new series of 2H-quinolinone and halogenated 2H-quinolinone derivatives against two cancer cell lines. Methods: Two new series of 2H-quinolinone and halogenated 2H-quinolinone derivatives were prepared and screened for their cytotoxicity against breast MCF-7 and liver HepG-2 cancer cell lines as well as normal breast MCF-10a. Results: The tested molecules revealed good cytotoxicity and selectivity toward cancer cell lines relative to normal cells. These compounds were analyzed by DNA flow cytometry on MCF-7 cells. They were found to cause G2/M phase arrest and induced apoptosis at the pre-G1 phase. In addition, increased caspase 3/7 activity and decreased osteopontin expression verified the apoptotic activity. Conclusion: The potent compounds discovered in this study can be a hit for the discovery of new cytotoxic agents and are worthy of further investigation.

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Zn(ii), Cd(ii) and Hg(ii) saccharinate complexes with 2,6-bis(2-benzimidazolyl)pyridine as promising anticancer agents in breast and lung cancer cell lines via ROS-induced apoptosis

Dalton Transactions ◽

10.1039/d0dt01535k ◽

2020 ◽

Vol 49 (23) ◽

pp. 7842-7851

Author(s):

Ceyda Icsel ◽

Veysel T. Yilmaz ◽

Seyma Aydinlik ◽

Muhittin Aygun

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Lines ◽

Anticancer Agents ◽

Ros Generation ◽

Lung Cancer Cell ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest ◽

Induced Apoptosis ◽

Mcf 7

Highly cytotoxic Zn(ii) and Hg(ii) saccharinate complexes with 2,6-bis(2-benzimidazolyl)pyridine cause G0/G1 cell cycle arrest, excessive ROS generation, and mitochondrial and DNA damage in A549 and MCF-7 cell lines, respectively.

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In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190930143856 ◽

2020 ◽

Vol 19 (16) ◽

pp. 2010-2018

Author(s):

Youstina W. Rizzk ◽

Ibrahim M. El-Deen ◽

Faten Z. Mohammed ◽

Moustafa S. Abdelhamid ◽

Amgad I.M. Khedr

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Topoisomerase Ii ◽

Cancer Cell Lines ◽

Bax Protein ◽

Hybrid Molecules ◽

Mcf 7

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

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In Vitro Evaluation of Chitosan Induced Cytotoxicity against Cancerous Cell lines: MCF-7, Saos-2 and HeLa

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190507113949 ◽

2019 ◽

Vol 19 ◽

Author(s):

Zeinab Abedian ◽

Niloofar Jenabian ◽

Ali Akbar Moghadamnia ◽

Ebrahim Zabihi ◽

Roghayeh Pourbagher ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Lines ◽

Anticancer Agents ◽

Fibroblast Cells ◽

Apoptosis Induction ◽

Cytotoxic Effects ◽

Cancerous Cell ◽

Significant Concentration ◽

Mcf 7

Objective/ Background: Cancer is still the most common cause of morbidity in world and new powerful anticancer agents without severe side effects from natural sources is important. Methods: The evaluation of cytotoxicity and apoptosis induction was carried out in MCF-7,HeLa and Saos-2 as cancerous cell lines with different histological origin and human fibroblast served as control normal cell. The cells were treated with different concentrations of chitosan and the cytotoxicity was determined using MTT assay after 24, 48 and 72 h .The mode of death was evaluated by flow cytometry . Results: While both types of chitosan showed significant concentration-dependently cytotoxic effects against the three cancerous cell lines, fibroblast cells showed somehow more compatibility with chitosan. On the other hand, there were no significant differences between LMWC and HMWC cytotoxicity in all cell lines. The flow cytometry results showed the apoptosis pattern of death more in Saos-2 and HeLa while necrosis was more observable with MCF7. Also higher viability with both types of chitosan was seen in fibroblast as normal cells Conclusion: Chitosan shows anticancerous effect against 3 cancerous cell lines, while it is compatible with normal diploid fibroblast cells. Furthermore, it seems that the molecular weight of chitosan does not affect its anticancerous property.

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Hybridized Quinoline Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and Molecular Docking

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666181112121058 ◽

2019 ◽

Vol 19 (4) ◽

pp. 439-452 ◽

Cited By ~ 3

Author(s):

Mohamed R. Selim ◽

Medhat A. Zahran ◽

Amany Belal ◽

Moustafa S. Abusaif ◽

Said A. Shedid ◽

...

Keyword(s):

Cell Cycle ◽

Anticancer Agents ◽

Caspase 3 ◽

Biological Evaluation ◽

Tubulin Polymerization ◽

Design Synthesis ◽

Chemical Structures ◽

M Phase ◽

Induced Apoptosis ◽

Derivatives Of

Objective: Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer active agents. Methods: Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline 7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13-15 and thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin polymerization inhibition and cell cycle analysis were evaluated. Results: Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds 3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis. Conclusion: Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation and optimization.

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Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽

10.3390/cancers13081790 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1790

Author(s):

Katarzyna Malarz ◽

Jacek Mularski ◽

Michał Kuczak ◽

Anna Mrozek-Wilczkiewicz ◽

Robert Musiol

Keyword(s):

Cell Cycle ◽

Anticancer Activity ◽

Cell Cycle Arrest ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

P53 Protein ◽

Structural Similarity ◽

M Cell ◽

Cycle Arrest ◽

Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

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