Design, synthesis, and in vitro cancer cell growth inhibition evaluation and antimalarial testing of trioxanes installed in cyclic 2-enoate substructures.
A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC₅₀ = 0.5 μM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI₅₀ = 1.0 μM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 Å) leads to their physical contact. The UV-vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin-trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV-vis spectroscopy.
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Md Imran
MI
Hossain
Marta
M
Świtalska
Wei
W
Peng
Mariko
M
Takashima
Ning
N
Wang
Marcel
M
Kaiser
Joanna
J
Wietrzyk
Shingo
S
Dan
Takao
T
Yamori
Tsutomu
T
Inokuchi
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D041702:BALB 3T3 Cells; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011714:Pyrans / Q000737:chemistry*; D013329:Structure-Activity Relationship
C503429:1,2,4-trioxane; D000962:Antimalarials; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006571:Heterocyclic Compounds; D010545:Peroxides; D011714:Pyrans
1,2,4-Trioxanes; Anticancer agents; Antimalarial; COMPARE study; Endoperoxides