Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Zhixin Ge; Meixi Hao; Meng Xu; Zhigui Su; Zisheng Kang; Lingjing Xue; Can Zhang

doi:10.1016/j.ejmech.2015.10.042

Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Eur J Med Chem. 2016 Jan 1:107:48-62. doi: 10.1016/j.ejmech.2015.10.042. Epub 2015 Nov 3.

Authors

Zhixin Ge¹, Meixi Hao¹, Meng Xu¹, Zhigui Su¹, Zisheng Kang¹, Lingjing Xue², Can Zhang³

Affiliations

¹ 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.
² 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.
³ 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.

PMID: 26562542
DOI: 10.1016/j.ejmech.2015.10.042

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.

Keywords: Anti-proliferation; Cancer therapy; Hypercalcemia; Nonsecosteroid; Phenyl-pyrrolyl pentane skeleton; VDR; Vitamin D(3)-agonistic activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Caco-2 Cells / drug effects
Calcitriol / adverse effects
Calcium / blood
Cell Proliferation / drug effects
Hep G2 Cells / drug effects
Humans
Hypercalcemia / chemically induced
Inhibitory Concentration 50
Ligands
MCF-7 Cells / drug effects
Mice, Inbred ICR
Molecular Docking Simulation
Pentanes / chemistry
Rats
Receptors, Calcitriol / agonists*
Receptors, Calcitriol / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Ligands
Pentanes
Receptors, Calcitriol
pentane
Calcitriol
Calcium