Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues

Abstract

Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.

Biodegradable, Drug‐Loaded Nanovectors via Direct Hydration as a New Platform for Cancer Therapeutics

“…To further characterize the physical properties of the nanovector formulation we conducted experiments to determine particle stability, PTL release profile and copolymer stability in PBS and human serum (HS). Standard dosimetry in vivo requires multiple doses of PTL due to its short half‐life (in the order of hours), which means that particle stability should be evaluated over hours and days. Consistent correlation DLS data of unfiltered samples showed that particles were stable over the course of 6 d in PBS at 37 °C (Figure S7, Supporting Information), which was supported by AF4 (Figure S8, Supporting Information).…”

Costunolide—A Bioactive Sesquiterpene Lactone with Diverse Therapeutic Potential

“…Germacranolides are key precursors of other sesquiterpene lactones with various polycyclic skeletons, such as guaianolides, eudesmanolides, etc. [4]. Costunolide, a colorless crystalline powder with a molecular formula of C 15 H 20 O 2 and a molecular weight of 232.318 g/mol, is a well-known sesquiterpene lactone in the germacranolides series.…”

Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

“…A lot of effort has been made to overcome its instability in both acidic and basic conditions and improve its solubility and bioavailability [191][192][193][194][195][196][197][198][199]. Several new water-soluble PN derivatives have been designed, synthesized and their activity has been evaluated in vitro and in vivo [43,47,[193][194][195][196][197][198][199][200][201][202]. Better solubility and higher anticancer activity have been recently obtained with PN derivatives prepared through the aza-Michael addition of nitrogen-containing anticancer drugs such as cytarabine and melphalan [200].…”