title: Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues with aromatic side chains attached at C-17.
abstract: Two new analogues of the steroid hormone 1α,25-dihydroxyvitamin D3 with aromatic side chains attached at C-17 were designed to investigate their effects on VDR, HL-60 cell differentiation and tumor cell proliferation. These analogues were prepared by the classical photochemical ring opening approach. After the protection of both the 1α- and 3β-hydroxyl in 1α-hydroxydehydroepiandrosterone with TBS groups, followed by bromination with NBS and debromination in the presence of γ-collidine, the diene intermediate was obtained. Hydrazone formation followed by iodine oxidation gave a vinyl iodide. The aromatic side chain at C-17 was introduced via the Negishi coupling of the resulting intermediate with an in situ generated zinc reagent with the substituted aryl bromide (CD-side chain) in the presence of catalytic amount of Pd(PPh3)4. After the removal of the TBDMS and MOM protective groups, followed by UV irradiation and the subsequent thermal reaction, the 1α,25-(OH)2-D3 analogues with a substituted phenyl ring attached at C-17 to replace the C-20 and C-21 were prepared. In the VDR competitive binding assay, compounds 2 and 3 almost lost their binding ability, and were only 0.01% and 0.015% as potent as the 1α,25-dihydroxyvitamin D3. However, compounds 2 and 3 were as potent as 1α,25-(OH)2-D3 in inducing HL-60 cell differentiation at concentrations of 30, 100, 300, 1000 nM, respectively. Moreover, compounds 2 and 3 exhibited similar or better antiproliferative potency against MCF-7 human breast cancer cells, the IC50 values for analogues 2, 3 and the natural hormone were 7.08, 7.56, and 12.5 μM, respectively.
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Zhao
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, PR China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Sanuki, Kagawa 769-2193, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suenaga
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Sanuki, Kagawa 769-2193, Japan.
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
authors.forename: Cheng-Mei
authors.initials: CM
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China. Electronic address: liuzhaop@sdu.edu.cn.
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C118756:dihydroxy-vitamin D3; D014807:Vitamin D
keywords: Antiproliferative; HL-60 cell differentiation; Vitamin D; Vitamin D analogues; Vitamin D receptor