11‐Aza‐artemisinin Derivatives Exhibit Anticancer Activities by Targeting the Fatty Acid Binding Protein 6 (FABP6)

Abstract

Artemisinin (Qinghaosu), a sesquiterpene lactone isolated from the Chinese medicinal herb Artemisia annua, is famous as the first‐line antimalarial drug, and reported to also possess anticancer properties. Though many studies have proceeded focusing on artemisinin and bioactive derivatives in clinic or laboratory, their cellular targets and mechanism of actions have still remained obscure. Here, two new 11‐aza‐artemisinin derivatives AAD1 and AAD2, which displayed cytotoxity against multiple cancer cell lines, were synthesized and applied as the probes for target identification and anticancer mechanism research. Using T7 phage display screen method, fatty acid binding protein 6 (FABP6) was identified and verified as one of the potential targets. Further studies showed FABP6 is a direct binding protein of AAD1 and AAD2, and mediated the corresponding anticancer activities of these artemisinin derivatives.

Phage display technology for target determination of small-molecule therapeutics: an update

“…Examples include a plant-derived natural product oxymatrine to treat chronic hepatitis B (CHB) [66], a lipocyclodepsipeptide MA026 that shows anti-hepatitis C virus (HCV) activity [67]. Off-target for conventional anti-cancer compounds, such as α-SQMG, camptothecin (CPT), etoposide (Etp), or doxorubicin [68][69][70][71], as well as for anti-tumor compounds with unique mechanism (CBP501, daptomycin, 11-aza-artemisinin, estradiol or Ridaifens) were identified [72][73][74][75][76][77]. Furthermore, following bioactive compounds were used for phage display biopanning as bait; tumor hypoxia-targeting LW6 [78], antiangiogenic methylsynephrine or PFOS [79,80], simvastatin and fluvastatin used to treat cardiovascular disease [81], flavonoid analogues [82], an inhibitor for plant hormone biosynthesis (Brz2001) [83], or the rice blast fungus differentiation (roxithromycin) or appressorium formation (chloramphenicol) [84,85], neuroprotective agents (neoechinulin A) [86], and central nervous system stimulants [87].…”

Two-Component versus Three-Component Condensations in the Race between Hydrazide, Triketone, and Hydrogen Peroxide-How do All Six Reactive Centers Cooperate to Incorporate the Most Diverse Set of Heteroatomic Bridges in a Tricyclic Frame?

“…The introduction of a nitrogen atom into a peroxide molecule can significantly affect its bioactivity, e.g., due to the additional opportunities for the formation of N-hydrogen bonds with biomolecules. 18 For example, 11-aza-artemisinin and 6-azaartemisinin (Scheme 1A) are more potent than artemisinin. 19− 21 The literature approaches to the synthesis of aminoperoxides are relatively limited and include ozonolysis of O-methylated dioximes; 22−24 ozonolysis of alkenes in the presence of primary amines; 25 ozonolysis of vinyl ethers in the presence of imines; 26,27 condensation of highly reactive aldehydes and ketones with hydrogen peroxide and ammonia or primary amines; 28−31 and opening/recyclization of pentaoxa-and heptaoxaspiroalkanes in the presence of nitrogen sources; 32,33 the Curtius rearrangement of acyl azides derived from peroxysubstituted carboxylic acids.…”

“…Synthetic peroxides exhibit activity against α-coronavirus NL63 and β-coronaviruses OC43 and SARS-CoV-2. – Because molecular complexity drives chemical innovation in the pharmaceutical industry, , there is growing interest to the synthesis of highly complex cyclic peroxides from readily available and simple reactants. The introduction of a nitrogen atom into a peroxide molecule can significantly affect its bioactivity, e.g., due to the additional opportunities for the formation of N -hydrogen bonds with biomolecules . For example, 11-aza-artemisinin and 6-aza-artemisinin (Scheme A) are more potent than artemisinin. – …”