Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins: Exploration of the N3 and N9 Positions and Interaction with Multi-Drug Resistance Proteins

Simple item page
dc.contributor.authorDasari, Ramesh
dc.contributor.authorBlauz, Andrzej
dc.contributor.authorMedellin, Derek C.
dc.contributor.authorKassim, Roaa M.
dc.contributor.authorViera, Carlos
dc.contributor.authorSantarosa, Maximo
dc.contributor.authorTurner, Danielle
dc.contributor.authorvan der Westhuyzen, Alet E.
dc.contributor.authorvan Otterlo, Willem
dc.contributor.authorOlivas, Taryn
dc.contributor.authorYildiz, Tugba
dc.contributor.authorBetancourt, Tania
dc.contributor.authorShuster, Charles B.
dc.contributor.authorRogelj, Snezna
dc.contributor.authorRychlik, Blazej
dc.contributor.authorHudnall, Todd W.
dc.contributor.authorFrolova, Liliya V.
dc.contributor.authorKornienko, Alexander
dc.date.accessioned2020-03-13T14:32:40Z
dc.date.available2020-03-13T14:32:40Z
dc.date.issued2019-02-05
dc.description.abstractOur laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.
dc.description.departmentChemistry and Biochemistry
dc.description.versionThis is the accepted manuscript version of an article published in ChemMedChem.
dc.formatText
dc.format.extent25 pages
dc.format.medium1 file (.pdf)
dc.identifier.citationDasari, R., Blauz, A., Medellin, D. C., Kassim, R. M., Viera, C., Santarosa, M., Turner, D., van der Westhuyzen, A. E., van Otterlo, W. A. L., Olivas, T., Yildiz, T., Betancourt, T., Shuster, C. B., Rogelj, S., Rychlik, B., Hudnall, T., Frolova, L. V., Kornienko, A. (2019). Microtubule-targeting 7-deazahypoxanthines derived from marine alkaloid rigidins: Exploration of the N3 and N9 positions and interaction with multidrug-resistance proteins. ChemMedChem, 14(3), pp. 322–333.
dc.identifier.doihttps://doi.org/10.1002/cmdc.201800658
dc.identifier.issn1860-7187
dc.identifier.urihttps://hdl.handle.net/10877/9442
dc.language.isoen
dc.publisherJohn Wiley and Sons Ltd.
dc.sourceChemMedChem, 2019, Vol. 14, No. 3, pp. 322–333.
dc.subjectalkaloids
dc.subjectantitumor agents
dc.subjectdrug discovery
dc.subjectpyrrolo[2,3-d]pyrimidines
dc.subject7-deazapurines
dc.subjectChemistry and Biochemistry
dc.titleMicrotubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins: Exploration of the N3 and N9 Positions and Interaction with Multi-Drug Resistance Proteins
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
nihms-1020680.pdf
Size:
885.87 KB
Format:
Adobe Portable Document Format
Description:
Download

License bundle

Now showing 1 - 2 of 2
No Thumbnail Available
Name:
license.txt
Size:
2.54 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
No Thumbnail Available
Name:
PERMISSION-ChemMedChem.pdf
Size:
119.23 KB
Format:
Adobe Portable Document Format
Description:
Download

Collections

College of Science and Engineering