Induction of G2/M arrest, caspase activation and apoptosis by α-santonin derivatives in HL-60 cells

Abstract

Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2 μM, respectively)]. However, after 48 h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents.

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

“…In the fight against cancer, search for new chemical entities (NCEs) with chemotherapeutic properties is really worthy and numerous methods have been utilized to acquire compounds, including isolation from plants and animals and the use of synthetic and combinatorial chemistry and molecular modeling [19,[28][29][30][31].…”

Novel platensimycin derivatives with herbicidal activity

“…NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (Varian, Palo Alto, CA). The solvent employed was deuterated chloroform, and the signal of the hydrogen of CHCl 3 was used as the reference ( δ = 7.22) in the H NMR. The signal of the carbon of CDCl 3 was used as the reference ( δ = 77) in the 13 C NMR.…”

“…[1,3]cyclopropa [1,2] benzen-6-yl}-propanamide (11) 95). [1,3]cyclopropa [1,2]benzen-6-yl}-propanamide (12) [1,3]cyclopropa [1,2]benzen-6-yl}-propanamide (13) (ppm): 0.92 (t, 3H, J = 9 Hz, NCH 2 CH 2 CH 3 ); 1.09 (s, 3H, H14); 1.16 (d, 3H, J = 6 Hz, H3 ′ ); 1.21 (s, 3H, H15); 1.51 (sext, 2H, J = 6 Hz, NCH 2 CH 2 ); 1.58-1.88 (m, 5H, H4, H4 ′ , H5, H5 ′ , H6); 2.51-2.63 (m, 1H, H2 ′ ); 3.21-3.33 (quint., 2H, NCH 2 ); 3.67 (d, 1H, J = 9 Hz, H7); 5.78 (t, 1H, J = 6 Hz, NH); 5.91 (d, 1H, J = 6 Hz, H2); 7.83 (d, 1H, J = 6 Hz, H1). 13 C NMR (75 MHz, CDCl 3 ) (ppm): 7.9 (C15); 11.6 (NCH 2 CH 2 CH 3 ); 13.5 (C13); 17.7 (C14); 23.0 (NCH 2 CH 2 ); 23.1 (C5); 31.6 (C4); 40.4 (NCH 2 ); 41.5 (C3a); 42.1 (C2 ′ ); 45.3 (C6); 47.1 (C3b); 52.2 (C8); 68.7 (C7); 129.6 (C2); 163.0 (C1); 176.9 (C1 ′ ); 209.0 (C3).…”

“…Bioactive secondary metabolites are natural products that have not been efficiently explored for discovery of new pesticides. Natural products provide inspiration for the development of new products, and sesquiterpene lactones should be cited for their wide biological activity as anti‐inflammatory, antigerminative, phytotoxic and anticancer agents . Sesquiterpenes are biosynthesised mainly by plants of the family Asteraceae but are also isolated from the fungus Biscogniauxia nummularia , representing a new promising class of biological agent.…”

“…Dehydrocostuslactone (1), costunolide (2) and -santonin (3) are examples of natural sesquiterpene lactones, and -methylene--santonin (4), lumisantonin (5), -methylene-lumisantonin (6), O-acetylisophotosantonin (7), -methylene-O-acetylisophotosantonin (8) and photosantonic acid (9) are only a few examples of synthetic derivatives that exhibit some kind of biological activity ( Fig. 1).…”