title: Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy.
abstract: A series of nonsecosteroidal vitamin D3 receptor (VDR) ligands with phenyl-pyrrolyl pentane skeleton were synthesized for cancer therapy. In contrast to 1α,25-dihydroxyvitamin D3 (Calcitriol), these VDR ligands exhibited anti-proliferative activity without inducing hypercalcemia. These compounds were evaluated for vitamin D3-agonistic ability and anti-proliferative activity in vitro. Among them, compounds 5k and 5i exhibited equivalent vitamin D3-agonistic activity compared with Calcitriol. Meanwhile, compound 5k displayed promising inhibiting profile against MCF-7, HepG-2 and Caco-2 with IC50 values of 0.00586 μM, 0.176 μM, and 1.01 μM (Calcitriol: 5.58 μM, 80.83 μM and 4.46 μM) respectively. Compound 5i inhibited proliferation of PC-3 with IC50 value of 0.00798 μM (Calcitriol: 17.25 μM). Additionally, neither of these compounds significantly elevated serum calcium in rats.
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
authors.forename: Meixi
authors.initials: M
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
authors.forename: Zisheng
authors.initials: Z
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address: xuelingjing65@163.com.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Nature Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address: zhangcan@cpu.edu.cn.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects; D002117:Calcitriol / Q000009:adverse effects; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D020128:Inhibitory Concentration 50; D008024:Ligands; D061986:MCF-7 Cells / Q000187:drug effects; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D010420:Pentanes / Q000737:chemistry; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010420:Pentanes; D018167:Receptors, Calcitriol; C033353:pentane; D002117:Calcitriol; D002118:Calcium
keywords: Anti-proliferation; Cancer therapy; Hypercalcemia; Nonsecosteroid; Phenyl-pyrrolyl pentane skeleton; VDR; Vitamin D(3)-agonistic activity