Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Handle URI:
http://hdl.handle.net/10754/625233
Title:
Synthesis and evaluation of modified chalcone based p53 stabilizing agents
Authors:
Iftikhar, Sunniya; Khan, Sardraz; Bilal, Aishah; Manzoor, Safia; Abdullah, Muhammad; Emwas, Abdul-Hamid M.; Sioud, Salim; Gao, Xin ( 0000-0002-7108-3574 ) ; Chotana, Ghayoor Abbas; Faisal, Amir; Saleem, Rahman Shah Zaib
Abstract:
Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (Cal-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI50 values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI50 of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-hour post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.
KAUST Department:
King Abdullah University of Science and Technology, Thawal, Saudi Arabia
Citation:
Iftikhar S, Khan S, Bilal A, Manzoor S, Abdullah M, et al. (2017) Synthesis and evaluation of modified chalcone based p53 stabilizing agents. Bioorganic & Medicinal Chemistry Letters. Available: http://dx.doi.org/10.1016/j.bmcl.2017.07.042.
Publisher:
Elsevier BV
Journal:
Bioorganic & Medicinal Chemistry Letters
Issue Date:
15-Jul-2017
DOI:
10.1016/j.bmcl.2017.07.042
Type:
Article
ISSN:
0960-894X
Sponsors:
Authors acknowledge the support by LUMS in the form of faculty initiative fund to enable this research work and extend our acknowledgement to KAUST for NMR and HRMS analysis.
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0960894X17307382
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Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorIftikhar, Sunniyaen
dc.contributor.authorKhan, Sardrazen
dc.contributor.authorBilal, Aishahen
dc.contributor.authorManzoor, Safiaen
dc.contributor.authorAbdullah, Muhammaden
dc.contributor.authorEmwas, Abdul-Hamid M.en
dc.contributor.authorSioud, Salimen
dc.contributor.authorGao, Xinen
dc.contributor.authorChotana, Ghayoor Abbasen
dc.contributor.authorFaisal, Amiren
dc.contributor.authorSaleem, Rahman Shah Zaiben
dc.date.accessioned2017-07-19T10:45:05Z-
dc.date.available2017-07-19T10:45:05Z-
dc.date.issued2017-07-15en
dc.identifier.citationIftikhar S, Khan S, Bilal A, Manzoor S, Abdullah M, et al. (2017) Synthesis and evaluation of modified chalcone based p53 stabilizing agents. Bioorganic & Medicinal Chemistry Letters. Available: http://dx.doi.org/10.1016/j.bmcl.2017.07.042.en
dc.identifier.issn0960-894Xen
dc.identifier.doi10.1016/j.bmcl.2017.07.042en
dc.identifier.urihttp://hdl.handle.net/10754/625233-
dc.description.abstractTumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (Cal-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI50 values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI50 of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-hour post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.en
dc.description.sponsorshipAuthors acknowledge the support by LUMS in the form of faculty initiative fund to enable this research work and extend our acknowledgement to KAUST for NMR and HRMS analysis.en
dc.publisherElsevier BVen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0960894X17307382en
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic & Medicinal Chemistry Letters, 15 July 2017. DOI: 10.1016/j.bmcl.2017.07.042. © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectChalconesen
dc.subjectAntitumoren
dc.subjectDrug discoveryen
dc.titleSynthesis and evaluation of modified chalcone based p53 stabilizing agentsen
dc.typeArticleen
dc.contributor.departmentKing Abdullah University of Science and Technology, Thawal, Saudi Arabiaen
dc.identifier.journalBioorganic & Medicinal Chemistry Lettersen
dc.eprint.versionPost-printen
dc.contributor.institutionDepartment of Chemistry, SBASSE, Lahore University of Management Sciences, Lahore 54792, Pakistanen
dc.contributor.institutionDepartment of Biology, SBASSE, Lahore University of Management Sciences, Lahore 54792, Pakistanen
kaust.authorEmwas, Abdul-Hamid M.en
kaust.authorSioud, Salimen
kaust.authorGao, Xinen
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