Synthesis and cytotoxic activity of alpha-santonin derivatives.
Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC(50) values in the range of 0.36-14.5 microM, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development.
Arantes
Francisco F P
FF
Department of Chemistry, Federal University of Viçosa, Av. P.H. Rolfs, S/N, CEP 36570-000 Viçosa, MG, Brazil.
Barbosa
Luiz C A
LC
Alvarenga
Elson S
ES
Demuner
Antônio J
AJ
Bezerra
Daniel P
DP
Ferreira
José R O
JR
Costa-Lotufo
Letícia V
LV
Pessoa
Cláudia
C
Moraes
Manoel O
MO
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D012500:Santonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D012500:Santonin