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CRM1 inhibitory and antiproliferative activities of novel 4′-alkyl substituted klavuzon derivatives
[Display omitted] •Syntheses of nine novel 4′-alkyl substituted klavuzon derivatives were performed.•Roles of substituents over potency and selectivity cytotoxicity were shown.•Effects of the substituents over CRM1 inhibition property were presented.•Induction of apoptosis, cell cycle arrests in MIA...
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Published in: | Bioorganic & medicinal chemistry 2017-08, Vol.25 (16), p.4444-4451 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | [Display omitted]
•Syntheses of nine novel 4′-alkyl substituted klavuzon derivatives were performed.•Roles of substituents over potency and selectivity cytotoxicity were shown.•Effects of the substituents over CRM1 inhibition property were presented.•Induction of apoptosis, cell cycle arrests in MIA PaCa-2 cells were shown.•Time and concentration dependent disruptions of 3D spheroids were also presented.
Klavuzons are 6-(naphthalen-1-yl) substituted 5,6-dihydro-2H-pyran-2-one derivatives showing promising antiproliferative activities in variety of cancer cell lines. In this work, racemic syntheses of nine novel 4′-alkyl substituted klavuzon derivatives were completed in eight steps and anticancer properties of these compounds were evaluated. It is found that size of the substituent has dramatic effect over the potency and selectivity of the cytotoxic activity in cancerous and healthy pancreatic cell lines. The size of the substituent can also effect the CRM1 inhibitory properties of klavuzon derivatives. Strong cytotoxic activity and CRM1 inhibition can be observed only when a small substituent present at 4′-position of naphthalen-1-yl group. However, these substituents makes the molecule more cytotoxic in healthy pancreatic cells rather than cancerous pancreatic cells. Among the tested compounds 1,2,3,4-tetrahydrophenanthren-9-yl substituted lactone was the most cytotoxic compound and its antiproliferative activity was also tested in 3D spheroids generated from HuH-7 cell lines. |
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ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2017.06.030 |