New approaches for the uses of cyclohexan-1,4-dione for the synthesis of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridine derivatives used as potential anti-prostate cancer agents and pim-1 Kinase inhibitors

Mohareb R.M.; Abdo N.Y.M.; El-Sharkawy K.A.

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New approaches for the uses of cyclohexan-1,4-dione for the synthesis of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridine derivatives used as potential anti-prostate cancer agents and pim-1 Kinase inhibitors

Mohareb R.M.; Abdo N.Y.M.; El-Sharkawy K.A.

Full Text link: https://t.ly/2dX8k

Date issued: 2018

Doi: https://doi.org/10.2174/1871520618666180604091358 PubMedID29866019

Publisher: Bentham Science Publishers B.V.

Series Info: Anti-Cancer Agents in Medicinal Chemistry
18

Type: Article

Keywords: Kinase inhibitor , Pyran , Pyridine , Thiazole , Thienopyridine , Thiophene , 2 amino 3 benzoyl 4 5 dihydrobenzo[b]thiophen 6(7h) one , 2 amino 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3b]pyridine 3 carbonitrile , 2 amino 7 oxo 4 phenyl 8 (2 phenylhydrazono) 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine 3 carbonitrile , 2 amino 7 oxo 4 phenyl 8 2 amino 8 (2 (4 chlorophenyl)hydrazono) 7 oxo 4 phenyl 5 67 8 tetrahydrobenzo [4 5]thieno[2 3 b]pyridine 3 carbonitrile , 2 amino 8 (2 (4 methoxyphenyl)hydrazono) 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo [4 5]thieno[2 3 b]pyridine 3 carbonitrile , 2 hydroxy 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine 3 carbonitrile , 2 hydroxy 7 oxo 4 phenyl 8 (2 phenylhydrazono) 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine 3 carbonitrile , 2 hydroxy 8 (2 (4 methoxyphenyl)hydrazono) 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine 3 carbonitrile , 3 9 diamino 1 (4 bromophenyl) 7 phenyl 1 4 5 6 tetrahydropyrido[3 2 :4 5]thieno[2 3 f]quinoline 2 8 dicarbonitrile , 3 9 diamino 1 (4 bromophenyl) 7 phenyl 5 6 dihydro 1hchromeno[6 5 :4 5]thieno[2 3 b]pyridine 2 8 dicarbonitrile , 3 9 diamino 1 (4 chlorophenyl) 7 phenyl 1 4 5 6 tetrahydropyrido[3 2 :4 5]thieno[2 3 f]quinoline 2 8 dicarbonitrile , 3 9 diamino 1 (4 chlorophenyl) 7 phenyl 5 6 dihydro 1hchromeno[6 5 :4 5]thieno[2 3 b]pyridine 2 8 dicarbonitrile , 3 9 diamino 1 7 diphenyl 1 4 5 6 tetrahydropyrido[3 2 :4 5]thieno[2 3 f]quinoline 2 8 dicarbonitrile , 3 amino 1 (4 bromophenyl) 9 hydroxy 7 phenyl 5 6 dihydro 1hchromeno[6 5 :4 5] thieno[2 3 b]pyridine 2 8 dicarbonitrile , 3 amino 1 (4 chlorophenyl) 9 hydroxy 7 phenyl 5 6 dihydro 1hchromeno[6 5 :4 5] thieno[2 3 b]pyridine 2 8 dicarbonitrile , 3 amino 9 hydroxy 1 7 diphenyl 1 4 5 6 tetrahydropyrido[2 :4 5]thieno[2 3 f]quinoline 2 8 dicarbonitrile , 3 amino 9 hydroxy 1 7 diphenyl 5 6 dihydro 1h chromeno[6 5 :4 5]thieno[2 3 b]pyridine 2 8 dicarbonitrile , 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine , 5 6 dihydro 1h chromeno[6 5 :4 5]thieno[2 3 b]pyridine , 8 (2 (4 chlorophenyl)hydrazono) 2 hydroxy 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo [4 5]thieno[2 3 b]pyridine 3 carbonitrile , 8 (2 2 hydroxy 8 (2 (4 methoxyphenyl)hydrazono) 7 oxo 4 phenyl 5 6 7 8 tetrahydrobenzo[4 5]thieno[2 3 b]pyridine 3 carbonitrile , androgen receptor , antineoplastic agent , cclohexane 1 4 dione , protein kinase Pim 1 , protein tyrosine kinase , scatter factor receptor , tetrahydrobenzothienopyridine , thienopyridine derivative , unclassified drug , unindexed drug , antineoplastic agent , cyclohexanone derivative , protein kinase inhibitor , protein kinase Pim 1 , pyridine derivative , antineoplastic activity , antiproliferative activity , Article , cancer cell line , cell growth , cell proliferation , colon cancer , controlled study , drug synthesis , elemental analysis , enzyme activity , enzyme substrate , GI50 , human , human cell , IC50 , infrared spectroscopy , lung cancer , MTT assay , non small cell lung cancer , prostate cancer , protein expression , radiosensitivity , stomach cancer , antagonists and inhibitors , chemical structure , chemistry , dose response , drug effect , drug screening , metabolism , structure activity relation , synthesis , tumor cell line , Antineoplastic Agents , Cell Line, Tumor , Cell Proliferation , Cyclohexanones , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-pim-1 , Pyridines , Structure-Activity Relationship

Abstract:

Background: Among the wide range of heterocycles, tetrahydrobenzothienopyridine derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the thiophene nucleus were known in the market. Method: A series of tetrahydrobenzothienopyridine derivatives were synthesized from the reaction of 2-amino- 3-benzoyl-4,5-dihydrobenzo[b]thiophen-6(7H)-one, synthesized and used for further heterocyclization reactions through reaction with different reagents. Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. Conclusion: The inhibition of the newly synthesized compounds towards c-Met kinase, the five c-Metdependent cancer cell lines (A549, HT-29, MKN-45, U87MG, and SMMC-7721) and one c-Met-independent cancer cell line (H460) were investigated using foretinib as a standard drug. The results showed that compounds 6b, 7e, 9b, 9e, 16c and 20d were more active than foretinib. Furthermore, compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity, where compounds 16b and 16c were of high potencies with IC50 values of 0.28 and 0.32 ?M, while compounds 6b and 13b were less effective (IC50 > 10 ?M). � 2018 Bentham Science Publishers.