Bilobalide and PC12 cells: A structure activity relationship study

Toyonobu Usuki; Yukiko Yoshimoto; Makiko Sato; Tae Takenaka; Ryota Takezawa; Yusuke Yoshida; Masayuki Satake; Noriyuki Suzuki; Daisuke Hashizume; Sergei V Dzyuba

doi:10.1016/j.bmc.2019.115251

Bilobalide and PC12 cells: A structure activity relationship study

Bioorg Med Chem. 2020 Jan 15;28(2):115251. doi: 10.1016/j.bmc.2019.115251. Epub 2019 Dec 9.

Authors

Affiliations

¹ Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan. Electronic address: t-usuki@sophia.ac.jp.
² Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan.
³ Adjusted Cell Experiment Laboratory Inc, 5-4-30 Nishi-Hashimoto, Midori-ku, Sagamihara-shi, Kanagawa 252-0131, Japan.
⁴ Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁵ Materials Characterization Support Unit, RIKEN Center for Emergent Matter Science (CEMS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁶ Department of Chemistry and Biochemistry, Texas Christian University, Fort Worth, TX 76129, USA.

PMID: 31848115
DOI: 10.1016/j.bmc.2019.115251

Abstract

Ginkgo biloba extracts have been postulated to beneficial for improving cognitive function and as such they have been used as a potential treatment of Alzheimer's disease. The main active ingredients of the extract are terpene trilactones (TTLs), such as bilobalide (BB) and ginkgolides. Several structure-activity relationship (SAR) studies using ginkgolide scaffolds produced more biologically potent species by modification of the lactone moieties. However, modifications of BB scaffold have been limited, and no SAR studies on BB have been accomplished to date. Thus, the aim of this study was to elucidate how the modification of the lactone moieties of BB would affect their biological activities in a number of assays, including proliferating cell activity, neuroprotective effects against Aβ (1-40) peptides, and neurite outgrowth effects in PC12 neuronal cells. It appeared that the derivatives containing lactone groups showed similar biological activity to native BB, while those that possessed no lactone moieties exhibited lower neurite outgrowth effects. Thus, the results suggested that the lactone moieties of BB played an important role in exerting neurite outgrowth effects in PC12 cells.

Keywords: Bilobalide; Derivatization; PC12; SAR; Terpene trilactone.

MeSH terms

Amyloid beta-Peptides / antagonists & inhibitors*
Animals
Cell Proliferation / drug effects
Cells, Cultured
Crystallography, X-Ray
Cyclopentanes / chemistry
Cyclopentanes / isolation & purification
Cyclopentanes / pharmacology*
Dose-Response Relationship, Drug
Furans / chemistry
Furans / isolation & purification
Furans / pharmacology*
Ginkgolides / chemistry
Ginkgolides / isolation & purification
Ginkgolides / pharmacology*
Models, Molecular
Molecular Structure
Neurons / drug effects
Neuroprotective Agents / chemistry
Neuroprotective Agents / isolation & purification
Neuroprotective Agents / pharmacology*
PC12 Cells
Peptide Fragments / antagonists & inhibitors*
Rats
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Cyclopentanes
Furans
Ginkgolides
Neuroprotective Agents
Peptide Fragments
amyloid beta-protein (1-40)
bilobalide