Structure –activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents

AbstractDiterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the generaAconitum,Delphinium, andGarrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents ofAconitum andDelphinium 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 of1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further developmen...
Source: Journal of Natural Medicines - Category: Drugs & Pharmacology Source Type: research