title: Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors.
abstract: A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50of 36nM and showed a submicromolar mean GI50value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Ju-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Shin
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Nakcheol
authors.initials: N
authors.lastname: Jeong
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Chan-Wha
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: eunice@kist.re.kr.
authors.forename: Eunice EunKyeong
authors.initials: EE
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: gkeum@kist.re.kr.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620851:5-benzyl-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo(2,3-d)pyrimidin-2-amine; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011743:Pyrimidines; D011758:Pyrroles
keywords: Antiproliferative; Cancer; Hsp90; Pyrrolo[2,3-d]pyrimidines; Structure-based design