title: Synthetic and biological studies of tubulin targeting c2-substituted 7-deazahypoxanthines derived from marine alkaloid rigidins.
abstract: C2-aryl- and C2-alkyl-7-deazahypoxanthines as analogues of marine alkaloid rigidins were prepared utilizing novel synthetic methods developed for the construction of the pyrrolo[2,3-d]pyrimidine ring system. The new compounds exhibited sub-micromolar to nanomolar antiproliferative potencies against a panel of cell lines including in vitro models for drug-resistant tumors, such as glioblastoma, melanoma and non-small-cell lung cancer. A selected representative C2-methyl-7-deazahypoxanthine was found to inhibit microtubule dynamics in cancer cells, lending evidence for tubulin targeting as a mode of action for these compounds in cancer cells. The results of the docking studies utilizing the colchicine site on β-tubulin were consistent with the observed structure-activity relationship data, including an important finding that derivatization at C2 with linear alkyl groups leads to the retention of activity, thus permitting the attachment of a biotin-containing linker for the subsequent proteomics assays. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, the reported antitubulin rigidin analogues have significant potential as new anticancer agents.
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Scott
authors.affiliation: Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA.
authors.forename: Menuka
authors.initials: M
authors.lastname: Karki
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
authors.forename: Mary R
authors.initials: MR
authors.lastname: Reisenauer
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rodrigues
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Dasari
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: W Ross
authors.initials: WR
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pelly
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Willem A L
authors.initials: WAL
authors.lastname: van Otterlo
authors.affiliation: Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shuster
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
authors.forename: Snezna
authors.initials: S
authors.lastname: Rogelj
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Magedov
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
authors.forename: Liliya V
authors.initials: LV
authors.lastname: Frolova
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornienko
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007042:Hypoxanthines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D061986:MCF-7 Cells; D018715:Microscopy, Video; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000470:Alkaloids; D007042:Hypoxanthines; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D014404:Tubulin; D050257:Tubulin Modulators
keywords: 7-deazapurines; alkaloids; drug discovery; privileged structures; pyrrolo[2,3-d]pyrimidines