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tetramethyl Nordihydroguaiaretic acid (TMNDGA) is a synthetic derivative of NDGA, a non-selective lipoxygenase inhibitor. It inhibits Sp1 transcription factor binding at the HIV long terminal repeat promoter and at the α-ICP4 promoter, a gene essential for HSV replication, with IC50 values of 11 and 43.5 µM respectively1,2 TMNDGA induces growth arrest and apoptosis by suppressing Sp1-dependent Cdc2 and survivin gene expression giving rise to its antitumorigenic activity.3 The in vivo growth of xenografts in numerous human tumor types was suppressed upon treatment with TMNDGA.4 It also inhibits the growth of mouse and human melanomas and human colon cancer in vivo without causing other tissue toxicity.5 TMNDGA is currently in Phase I & II clinical trials for treatment of high grade glioma brain tumors.
1
Hwu, J.R., Tseng, W.N., Gnabre, J., et al. Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of tat-regulated HIV transactivation. J Med Chem412994-3000(1998).
2
Chen, H., Teng, L., Li, J., et al. Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA. J Med Chem413001-3007(1998).
3
Chang, C., Heller, J.D., Kuo, J., et al. Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci USA101(36)13239-13244(2004).
4
Park, R., Chang, C., Liang, Y., et al. Systemic treatment with tetra-O-methyl nordihydroguaiaretic acid suppresses the growth of human xenograft tumors. Clin Cancer Res11(12)4601-4609(2005).
5
Lambert, J.D., Meyers, R.O., Timmermann, B.N., et al. Tetra-O-methylnordihydroguaiaretic acid inhibits melanoma in vivo. Cancer Lett17147-56(2001).
Chen, H., Teng, L., Li, J., et al. Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA. J Med Chem413001-3007(1998).
Lambert, J.D., Meyers, R.O., Timmermann, B.N., et al. Tetra-O-methylnordihydroguaiaretic acid inhibits melanoma in vivo. Cancer Lett17147-56(2001).
Park, R., Chang, C., Liang, Y., et al. Systemic treatment with tetra-O-methyl nordihydroguaiaretic acid suppresses the growth of human xenograft tumors. Clin Cancer Res11(12)4601-4609(2005).
Chang, C., Heller, J.D., Kuo, J., et al. Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci USA101(36)13239-13244(2004).
Hwu, J.R., Tseng, W.N., Gnabre, J., et al. Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of tat-regulated HIV transactivation. J Med Chem412994-3000(1998).