Open AccessStructure–activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents
Author(s) -
Koji Wada,
Masuo Goto,
Takahiro Shimizu,
Nami Kusanagi,
Megumi Mizukami,
Yuji Suzuki,
Kang-Po Li,
KuoHsiung Lee,
Hiroshi Yamashita
Publication year - 2019
Publication title -
natural medicines/journal of natural medicines
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.512
H-Index - 46
eISSN - 1861-0293
pISSN - 1340-3443
DOI - 10.1007/s11418-019-01331-6
Subject(s) - alkaloid , terpenoid , chemistry , stereochemistry , acylation , ranunculaceae , aconitum , delphinium , cancer cell lines , biochemistry , cancer cell , biology , cancer , botany , genetics , catalysis
Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents of Aconitum and Delphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6, 7, 13, 13a, 13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1, 31, 33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns-C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5-7) displayed more potency than 1,14-diacyldelcosine derivatives (5a-7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24 h. 1-Acylation of 1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents.