Acta Pharm. 67 (2017) 557-567

full paper

Original research paper

A study on blocking store-operated Ca²⁺ entry in pulmonary arterial smooth muscle cells with xyloketals from marine fungi

JIE-BIN ZHOU, YING-YING SUN, YING-LIN ZHENG, CHU-QIN YU, HUA-QING LIN, JI-YAN PANG and JI-YAN PANG

cespjy@mail.sysu.edu.cn; huaqing_@vip.tom.com (H-Q.L.)

¹ Department of Guangdong Key Laboratory for New Pharmaceutical Dosage Forms, GuangDong Pharmaceutical University, Guangzhou, 510006, P. R. China

² School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China

Accepted June 22, 2017

Published online August 25, 2017

In this study, the effect of four xyloketal compounds 1-4 on store-operated calcium entry (SOCE) was investigated in primary distal pulmonary arterial smooth muscle cells (PASMCs) isolated from mice. The results showed that xyloketal A (1), an unusual ketal compound with C-3 symmetry, exhibited strong SOCE blocking activity. Secretion of interleukin-8 (IL-8) was also inhibited by xyloketal A. The parallel artificial membrane permeability assay (PAMPA) of 1-4 suggested that these xyloketals were easily penetrable through the cell membrane. Moreover, the molecular docking study of xyloketal A with activation region of the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1 (STIM1-ORAI1) protein complex, the key domain of SOCE, revealed that xyloketal A exibited non-covalent interaction with the key residue lysine 363 (LYS363) in the identified cytosolic regions in STIM1-C. These findings provided useful information for xyloketal A as SOCE inhibitor for further evaluation.

Keywords: xyloketal A, store-operated calcium entry, molecular docking, IL-8, parallel artificial membrane permeability assay