Cytotoxic responses to aromatic ring and configurational variations in α-conidendrin, podophyllotoxin, and sikkimotoxin derivatives

被引:15
作者
Dantzig, A
LaLonde, RT [1 ]
Ramdayal, F
Shepard, RL
Yanai, K
Zhang, MJ
机构
[1] SUNY Coll Environm Sci & Forestry, Dept Chem, Syracuse, NY 13210 USA
[2] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
关键词
D O I
10.1021/jm990563p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Derivatives of alpha -conidendrin, podophyllotoxin, and sikkimotoxin were prepared to evaluate the cytotoxic contributions of C-4 configuration and pendant and fused arene substitutions. Dimethyl-alpha -conidendryl alcohol (5), 9-deoxypodophyllol (6), and 9-deoxysikkimol (17) were dehydrated to their respective oxolane derivatives 4, 3, and 9. Diols 5 and 6 were converted via oxabicyclo[3.2.1] octanols 10 and 14 to target oxolanes 8 and 7 where C-4 had been inverted relative to that in 3 and 4. Cytotoxicities of the five oxolanes were determined in two drug-sensitive human leukemia and two multidrug-resistant cell lines expressing P-glycoprotein or multidrug-resistance associated protein (MRP). Changing the pendant arene configuration or replacing a m-methoxy by hydrogen resulted in a 100-fold cytotoxicity loss. Replacing a methylenedioxy group in the fused arene by two methoxy substituents reduced cytotoxicity by 10-fold. Drug-resistant cell lines were equally resistant to compounds 3, 4, 8, and 9 indicating that these four compounds do not serve as substrates of the transport proteins P-glycoprotein and MRP.
引用
收藏
页码:180 / 185
页数:6
相关论文
共 16 条
[1]  
BECK WT, 1979, CANCER RES, V39, P2070
[2]   Podophyllotoxin [J].
Canel, C ;
Moraes, RM ;
Dayan, FE ;
Ferreira, D .
PHYTOCHEMISTRY, 2000, 54 (02) :115-120
[3]   The asymmetric synthesis of aryltetralin lignans: (-)-isolariciresinol dimethyl ether and (-)-deoxysikkimotoxin [J].
Coltart, DM ;
Charlton, JL .
CANADIAN JOURNAL OF CHEMISTRY-REVUE CANADIENNE DE CHIMIE, 1996, 74 (01) :88-94
[4]  
Dantzig AH, 1996, CANCER RES, V56, P4171
[5]   RAPID COLORIMETRIC ASSAY FOR CELL-GROWTH AND SURVIVAL - MODIFICATIONS TO THE TETRAZOLIUM DYE PROCEDURE GIVING IMPROVED SENSITIVITY AND RELIABILITY [J].
DENIZOT, F ;
LANG, R .
JOURNAL OF IMMUNOLOGICAL METHODS, 1986, 89 (02) :271-277
[6]   NON-ENOLIZABLE PODOPHYLLOTOXIN DERIVATIVES [J].
GENSLER, WJ ;
MURTHY, CD ;
TRAMMELL, MH .
JOURNAL OF MEDICINAL CHEMISTRY, 1977, 20 (05) :635-644
[7]  
HARTWELL J L, 1958, Fortschr Chem Org Naturst, V15, P83
[8]   THE NATURALLY OCCURRING LIGNANS [J].
HEARON, WM ;
MACGREGOR, WS .
CHEMICAL REVIEWS, 1955, 55 (05) :957-1068
[9]  
HERRICK FW, 1977, RECENT ADV PHOTOCHEM, P443
[10]   In vitro propagation of Podophyllum peltatum [J].
Moraes-Cerdeira, RM ;
Burandt, CL ;
Bastos, JK ;
Nanayakkara, NPD ;
McChesney, JD .
PLANTA MEDICA, 1998, 64 (01) :42-45