Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Abstract

Sesquiterpene lactones (STLs) are a class of plant secondary metabolites widely found in nature with potent antitumor activities. In this work, two isolated STLs 1β-hydroxy alantolactone (1) and ivangustin (2) were derivatized through diversity-oriented strategy, and in vitro cytotoxic activity assessments were conducted against six cell lines including HeLa, PC-3, HEp-2, HepG2, CHO and HUVEC. The cytotoxic structure-activity relationship showed that the double bond between C5 and C6 was beneficial to improve activity; C1-OH oxidized derivatives showed a slight stronger activity, comparable to the positive drug etoposide (VP-16). Yet, C1-OH esterified derivatives decreased the potency which were different from those of 1-O-acetylbritannilactone (ABL) reported previously by us, and C13-methylene reductive and spiro derivatives resulted in almost complete ablation of cytotoxic activity. Mechanistic basis of cytotoxicity of the representative compound 1i was assayed to relate with apoptosis and cell cycle arrest. Furthermore, 1i inhibited TNF-α-induced canonical NF-κB signaling in PC-3 cells. Molecular modeling studies exhibited additional hydrogen bond interaction between 1i and the residue Lys37 of p65, indicating that 1i could form covalent protein adducts with Cys38 on p65.

Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70

“…Previously, docking experiments were conducted to predict the formation of covalent protein adducts of parthenolide and semi-synthetic SL derivatives with Cys38 located in the p65 subunit of NF-κB [20,53]. Another recent docking study showed that parthenolide and its derivatives interact with critical amino acid residues of inhibitor of NF-κB kinase subunit β (IKKβ) in a non-covalent fashion [54].…”

“…Likewise, several semi-synthetic parthenolide derivatives have been developed for their anti-leukemic activity [13,14]. In addition, synthetic modifications of SLs, including oxidation and esterification of the hydroxyl group, amination, reduction, and coupling of the α-methylene-γ-lactone moiety have resulted in variations in the anticancer activity of these compounds [13,14,15,16,17,18,19,20].…”

Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells

“…Even though, all agents are used in chemotherapy. Moreover, better understanding of the mechanism endothelial injury caused by chemotherapy, might lead to better prevention from the damage [96,[100][101][102]. The results on non-cancer cell line suggested that selected compounds were more toxic towards HT-29 colorectal cancer cells than normal cells-EA.hy926 cell line.…”

Anticancer efficiency of cycloartane triterpenoid derivatives isolated from <em>Cimicifuga yunnanensis</em> Hsiao on triple-negative breast cancer cells

“…As the secondary metabolic agents preserved through natural selection in the process of the biological evolution during millions of years, natural products have chemical and biological diverse features 34,35. With the characteristics of biological activity or chemical–structural diversity, natural product not only provides us with novel antitumor drugs but also inspires us in terms of chemical synthesis and structural modification, which can be identified as the precursor of semisynthesis 36,37.…”