New Approaches for the Synthesis of 2,3,5,6-Tetrahydrobenzo[d]thiazole Derivatives and their Anti- proliferative , c-Met Enzymatic Activity and Tyrosine Kinases Inhibitions

2021 ◽  
Vol 22 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Maher H. E. Helal ◽  
Sara S. Mohamed ◽  
Amira E. M. Abdallah
Keyword(s):  
Enzymatic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Heterocyclic Compounds ◽  
Cancer Cell Lines ◽  
Positive Control ◽  
Thiazole Derivatives ◽  
Active Compounds

Background: Many tetrahydrobenzo[d]thiazole derivatives were considered as the most important class of heterocyclic compounds due to their biological applications. There are many drugs known in the market containing the thiazole moiety which is responsible for the high drug activity. Objective: This work aimed to produce novel heterocyclic compounds such as pyrazole, isoxazole, thiophene, chromeno[7,8-d]thiazole, and thiazolo[4,5-h]quinoline derivatives. The newly synthesized heterocyclic compounds were evaluated against anticancer cell lines followed by c-Met enzymatic activity and tyrosine kinases inhibition for the most active compounds. Methods: In this work, the 3-phenyl-2-thioxo-2,3,5,6-tetrahydrobenzo[d]thiazol-7(4H)-one (3) was synthesized through the reaction of cyclohexane-1,3-dione with phenyl isothiocyanate and elemental sulfur. Compound 3 showed interesting activity toward some chemical reagents producing new heterocyclic compounds that can’t be obtained through another way. The newly synthesized compounds were evaluated towards the six cancer cell lines. The most active compounds were selected and tested toward c-Met enzyme by taking foretinib as the positive control. Also, the inhibitions toward the PC-3 cell line using the reference SGI-1776 were measured. Finally, the inhibitions towards the five tyrosine kinases were also tested. Results: The synthesized quinoline and chromene derivatives were evaluated toward c-Met enzyme using foretinib as the positive control the obtained results showed that twelve compounds exhibited IC50 values less than 1.30 nM. On the other hand, sixteen compounds showed higher inhibitions than the reference SGI-1776 (IC50 4.86 nM) toward the PC-3 cell line. Conclusion: Novel, heterocyclic compounds were synthesized with a high impact of biological activities. All synthesized compounds were screened for their anti-proliferative effect and most of them revealed high potent effects. In addition, the c-Met and prostate cancer cell line PC-3 inhibitions for the most active compounds showed that these compounds exhibited high inhibitions. Anti-proliferative activity of selected compounds toward cancer cell lines classified according to the disease showed that most compounds exhibited high inhibitions.

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 Heterocyclic Compounds Corporating benzo[d]imidazole as Anticancer Agents, Tyrosine, Pim-1 Kinases Inhibitions and their PAINS Evaluations

2020 ◽  
Vol 20 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Yara R. Milad ◽  
Bahaa M. Mostafa ◽  
Reem A. El-Ansary
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Heterocyclic Compounds ◽  
Cancer Cell Lines ◽  
Biologically Active ◽  
Strong Impact ◽  
Target Molecules

Background: Benzo[d]imidazoles are highly biologically active, in addition, they are considered as a class of heterocyclic compounds with many pharmaceutical applications. 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 the benzo[d]imidazole derivatives followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The 1-(1H-benzo[d]imidazol-2-yl)propan-2-one (3) and the ethyl 2-(1H-benzo[d]imidazol-2-yl)acetate (16) were used as the key starting material which reacted with salicylaldehyde to give the corresponding benzo[4,5]imidazo[1,2-a]quinoline derivatives. On the other hand, both of them were reacted with different reagents to give thiophene, pyran and benzo[4,5]imidazo[1,2-c]pyrimidine derivatives. The synthesized compounds were evaluated against the six cancer cell lines A549, HT-29, MKN-45, U87MG, and SMMC7721 and H460 together with inhibitions toward tyrosine kinases, c-Met kinase and prostate cancer cell line PC-3 were recorded using the standard MTT assay in vitro, with foretinib as the positive control. Results: Most of the synthesized compounds exhibited high inhibitions toward the tested cancer cell lines. In addition, tyrosine and Pim1 kinases inhibitions were performed for the most active compounds where variation of substituent through the aryl ring and heterocyclic ring afforded compounds with high activities. Our analysis showed that there is a strong correlation between structure of compound and substituents of target molecules. Conclusion: Our present research proved that the synthesized heterocyclic compounds with varieties of substituents has a strong impact through the activity of compounds. The evaluations through different cell lines and tyrosine kinases indicated that the compounds were excellent candidates as anticancer agents. This could encourage doing further research within this field for the building of compounds with high inhibitions.

The Uses of Dimedone for the Synthesis of Thiophene, Thiazole and Annulated Derivatives with Antitumor, Pim-1 Kinase Inhibitions, PAINS Evaluations and Molecular Docking

2021 ◽  
Vol 21 ◽  
Author(s):  
Wagnat W. Wardakhan ◽  
Amira M. Elmetwally ◽  
Abeer A. Mohamed ◽  
Rafat M. Mohareb
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Heterocyclic Compounds ◽  
Cancer Cell Lines ◽  
Strong Impact ◽  
Structure Activity ◽  
Anti Cancer ◽  
Target Molecules

Background: Dimedone is considered as one of the most important class of compounds belonging to cyclohexan-1,3-dione. Such group of compounds were considered as precursors for many pharmaceutically active heterocyclic compounds. Objective: The target molecules through this work were synthesized from arylhydrazones of dimedone with different substituent’s enhancing study of their structure activity relationship. Methods: Arylhydrazones of dimedones were subjected to a series of heterocyclization reactions affording annulated compounds. The antiproliferative activities of the synthesized molecules were evaluated against six cancer cell lines. In addition, inhibitions toward tyrosine kinases, Pim-1 kinases and PAINS of the most active compounds were also studied. c-Met enzymatic inhibitions and molecular docking studied were carried for three compounds. Results: Anti-cancer evaluations together with tyrosine and Pim-1 kinases of most of the synthesized compounds were carried out through this work. The study revealed that changing of substituent had a strong impact on the activity of themolecule. Conclusion: Many of the synthesized compounds exhibited high inhibitions toward the six cancer cell lines and this will encourage further work through the synthesis of target molecule with the same ring systems. The three compounds 7b, 8c and 12b that revealed excellent inhibitions were tested against c-Met kinase and their molecular modelling was expressed.

scholarly journals Multi-component Reactions of Cyclohexan-1,3-diketones to Produce Fused Pyran Derivatives with Antiproliferative Activities and Tyrosine Kinases and Pim-1 Kinase Inhibitions

2021 ◽  
Vol 68 (1) ◽  
pp. 51-64
Author(s):  
Rafat Milad Mohareb ◽  
Rehab Ali Ibrahim ◽  
Ensaf Sultan Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Ethyl Cyanoacetate ◽  
Cancer Cell Lines ◽  
The Other ◽  
Thiazole Derivatives ◽  
Dione Derivative ◽  
Cytotoxic Compounds ◽  
Antiproliferative Activities

In this work the multi-component reactions of either of the arylhydrazocyclohexan-1,3-dione derivatives 3a–c with either of benzaldehyde (4a), 4-chlorobenzaldehyde (4b) or 4-methoxybenzaldehyde (4c) and either malononitrile (5a) or ethyl cyanoacetate (5b) giving the 5,6,7,8-tetrahydro-4H-chromene derivatives 6a–r, respectively, are presented. The reaction of two equivalents of cyclohexan-1,3-dione with benzaldehyde gave the hexahydro-1H-xanthene-1,8(2H)-dione derivative 7. On the other hand, the multi-component reactions of compound 1 with dimedone and benzaldehyde gave 13. Both of 7 and 13 underwent heterocyclization reactions to produce fused thiophene, pyran and thiazole derivatives. Selected compounds among the synthesized compounds were tested against six cancer cell lines where most of them gave high inhibitions; especially compounds 3b, 3c, 6b, 6c, 6d, 6f, 6i, 6m, 6n, 8b, 14a, 15 and 16 being the most cytotoxic compounds. Further tests against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 6c, 6d, 6f, 6n, 14a and 15 were the most potent of the tested compounds toward the five tyrosine kinases and compounds 3c, 6c, 6d, 6n and 15 displayed the highest inhibitions toward Pim-1 kinase.

scholarly journals New Approaches for the Synthesis of Heterocyclic Compounds Derived from Cyclohexan-1,3-dione with Anti-proliferative Activities

2021 ◽  
Vol 68 (1) ◽  
pp. 72-87
Author(s):  
Rafat Milad Mohareb ◽  
Yara Raafat Milad ◽  
Ayat Ali Masoud
Keyword(s):  
Hydrazine Hydrate ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Heterocyclic Compounds ◽  
Elemental Sulfur ◽  
Hydroxylamine Hydrochloride ◽  
Phenyl Isothiocyanate ◽  
Thiazole Derivatives ◽  
Oxime Derivatives

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a–d and 6a–d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a–d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.

Uses of Cyclohexan-1,3-dione for the Synthesis of Thiazole, Pyrazole, Thiophene, Isoxazole and Pyran Derivatives with Antitumor Activities

2020 ◽  
Vol 17 (5) ◽  
pp. 597-609
Author(s):  
Rafat Milad Mohareb ◽  
Nadia Youssef Megally Abdo ◽  
Waleed Nabeel Al-darkazali
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Cancer Cell Lines ◽  
Structural Features ◽  
Active Compounds ◽  
Wide Range ◽  
Heterocyclic Derivatives ◽  
Therapeutic Activities ◽  
High Inhibition

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market. Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Synthesis of Thiazole, Thiophene, Pyran and Pyridine Derivatives Derived from 3-phenyl-1H-pyrazol-5(4H)-one with Anti-proliferative, Tyrosine Kinase and PIM-1 Kinase Inhibitions

2020 ◽  
Vol 17 (4) ◽  
pp. 485-501
Author(s):  
Rafat Milad Mohareb ◽  
Ibram Refat Mikhail
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Cancer Cell Lines ◽  
Structural Features ◽  
Pyrazole Derivatives ◽  
Active Compounds ◽  
Starting Compound ◽  
Wide Range ◽  
Therapeutic Activities

Background: A wide range of pyrazole derivatives gained special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the pyrazole nucleus are known in the market. Methods: The 3-phenyl-1H-pyrazol-5(4H)-one was the key starting compound for many heterocyclic reactions to produce substituted and fused pyrazole derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460 were measured through which compounds showed high inhibitions. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty-nine pyrazole derivatives were synthesized. Nine of them 8b, 9, 12b, 12d, 14b, 15b, 18d, 18f, 19b, and 21d were the most active compounds toward the selected cancer cell lines. Compounds 12b, 14b, 18d, 18f, and 21d showed high inhibitions toward the tyrosine kinases, whereas compounds 14b, 18d, and 18f were the most potent inhibitors of Pim-1.

Synthesis and Anti-Proliferative Evaluations of New Heterocyclic Derivatives using 5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one Derivatives Derived from Cyclohexa-1,4-dione

2020 ◽  
Vol 20 ◽  
Author(s):  
Mahmoud A.A. Mahmoud ◽  
Meshari A. Alsharif ◽  
Rafat M. Mohareb
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Mtt Assay ◽  
Cancer Cell Lines ◽  
Positive Control ◽  
Human Lung Cancer ◽  
Wide Range ◽  
Target Molecules

Background: Recentlty pyrazoloquinazoline 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 quinazoline 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 through the synthesis of a series of 5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 4a-i using the multicomponent reactions of cyclohexan-1,4-dione (1), the 5-amino-4-(2-arylhydrazono)-4H-pyrazol-3-ol derivatives 2a-c the aromatic aldehydes 3a-c, respectively. The synthesized compounds were evaluated against c-Met kinase, PC-3 cell line and different kinds of cancer cell lines together with normal cell line, tyrosine kinases and Pim-1 kinase. Methods: Muticomponent reactions were adopted using compound 1 to get different 5,6,8,9- tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives which underwent further heterocyclization reactions. The c-Met kinase activity of all compounds was evaluated using Homogeneous TimeResolved Fluorescence (HTRF) assay taking foretinib as the positive control. . The anti-proliferative activity of all target compounds against the human prostatic cancer PC-3 cell line were measured using MTT assay using SGI-1776 as the reference drug. All the synthesized compounds were assessed the inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer) and MKN-45 (human gastric cancer cancer) cancer cell lines together with foretinib as the positive control by a MTT assay. Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions were perform for 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 antiprolifeative activity were tested toward c-Met and the results showed that compounds 4e, 4f, 4g, 4i, 6i, 6k, 6l, 8f, 8i, 10d, 10e, 10f, 10h, 12e, 12f, 12g, 12h, 12i, 14f, 14g, 14h and 14i were the most potent compounds. Further selection of compounds for the Fused Quinazoline Derivatives as Anticancer Agents Pim-1 kinase inhibition activity showed that compounds 4f, 6i, 6l, 8h, 8i,8g, 10d, 12i and 14f were the most active compounds to inhibit Pim-1.

ANTITUMOR EFFECT OF SUNITINIB AND BORTEZOMIB ON BREAST CANCER CELL LINE IN VITRO

2017 ◽  
Vol 63 (1) ◽  
pp. 141-145
Author(s):  
Yuliya Khochenkova ◽  
Eliso Solomko ◽  
Oksana Ryabaya ◽  
Yevgeniya Stepanova ◽  
Dmitriy Khochenkov
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Antitumor Effect ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Actual Problem

The discovery for effective combinations of anticancer drugs for treatment for breast cancer is the actual problem in the experimental chemotherapy. In this paper we conducted a study of antitumor effect of the combination of sunitinib and bortezomib against MDA-MB-231 and SKBR-3 breast cancer cell lines in vitro. We found that bortezomib in non-toxic concentrations can potentiate the antitumor activity of sunitinib. MDA-MB-231 cell line has showed great sensitivity to the combination of bortezomib and sunitinib in vitro. Bortezomib and sunitinib caused reduced expression of receptor tyrosine kinases VEGFR1, VEGFR2, PDGFRa, PDGFRß and c-Kit on HER2- and HER2+ breast cancer cell lines

Synthesis and Characterization of Quinoline-3-Carboxamide Derivatives as Inhibitors of the ATM Kinase

2020 ◽  
Vol 20 (23) ◽  
pp. 2070-2079
Author(s):  
Srimadhavi Ravi ◽  
Sugata Barui ◽  
Sivapriya Kirubakaran ◽  
Parul Duhan ◽  
Kaushik Bhowmik
Keyword(s):  
Western Blot ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cancer Cell Lines ◽  
Atm Kinase ◽  
Cytotoxicity Studies

Background: The importance of inhibiting the kinases of the DDR pathway for radiosensitizing cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to the development of resistance towards DNA damaging therapeutics. Objective: In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported. Methods: Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and MDA-MB-231. Results: Three of the synthesized compounds showed promising cytotoxicity towards a selected set of cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line, MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least three times less toxic when compared with HCT116. Conclusion: In conclusion, these experiments will lay the groundwork for the evolution of potent and selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.

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