Design, Synthesis, and Biological Evaluation of a Cephalosporin– Monohydroguaiaretic Acid Prodrug Activated by a Monoclonal Antibody–-Lactamase Conjugate Gholam Hossein Hakimelahi, a, * Kak-Shan Shia, a Manijeh Pasdar, b Shahram Hakimelahi, b Ali Khalafi-Nezhad, c Mohammad N. Soltani, c Nai-Wen Mei, d Hui-Ching Mei, e Ali A. Saboury, f Mostafa Rezaei-Tavirani f and Ali A. Moosavi-Movahedi f, * a Institute of Chemistry, Academia Sinica, Taipei, Taiwan 115, Republic of China b Department of Cell Biology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 c Department of Chemistry, Faculty of Science, Shiraz University, Shiraz, Iran d Co-Wealth Medical Science & Biotechnology Inc., Taipei 106, Taiwan e Department of Medical Technology, China Medical College, Taichung 404, Taiwan f Institute of Biochemistry-Biophysics, Tehran University, Tehran, Iran Received 13 March 2002; accepted 22 April 2002 Abstract—A novel cephalosporin derivative of monohydroguaiaretic acid (cephem-M 3 N, 7) was synthesized and found to possess anticancer activity against human leukemia (K562), breast carcinoma (MCF7), human lung cancer (A549), human colon cancer (Colo205) and pancreatic cancer cells (Capan2 and MiaPaCa2). A tumor targeting fusion protein (dsFv3–b-lactamase) was also used in conjunction with cephem-based M 3 N 7 and its potency toward K562, MCF7, A549, Colo205, Capan2, and MiaPaCa2 was found to approach that of the free M 3 N(4). In the presence of dsFv3–b-lactamase, tumor cells were found to be much more sus- ceptible to conjugate 7 than normal human embryonic lung (HEL) cells and normal fibroblasts (Hef522). These notions provide a new approach to the use of nordihydroguaiaretic acid (NDGA) and its derivatives for antitumor therapy. # 2002 Elsevier Science Ltd. All rights reserved. Introduction Nordihydroguaiaretic acid (NDGA, 5) is a versatile molecule which has an antitumor capability probably related with the inhibition of the lipoxygenases (LOX) activity. 1,2 This antioxidant 3 molecule possesses a wide range of pharmacological activities, including the inhi- bition of the human papillomavirus, 4 herpes simplex, 5 human immunodeficiency virus, 6 and protects against TPA-induced tumor promotion in mouse skin, 7 TPA- caused induction of ornithine decarboxylase 8 and pro- tein kinase C, 9 as well as having hyperglycemic activ- ity. 10,11 NDGA (5) inhibits various kinds of injuries, neoplasm, 12 progestron production, 13 StAR protein expression, 13 and fos–jun–DNA complex formation. 14 Disruption of transcription factor action, fos-jun dimerization, has been shown to impair the transcrip- tional activation and cell transformation regulated by these proteins. 14 The mechanism of NDGA in cell differentiation and apoptosis is one of the most important topics under investigation in biology. 15 It was reported 16 that 5-LOX and 12-LOX are upregulated in human pancreatic can- cer cells and that blockade of these enzymes by NDGA abolishes the cancer cell growth and induces apopto- sis. 17 No specific cell phase arrest following treatment with LOX inhibitor 5 was observed, suggesting that inhibition of pancreatic cancer cell proliferation occur- red in all phases of the cell cycle. 16 This is consistent with the effects of LOX metabolites in lung cancer cells. 18 On the other hand, apoptosis induced by LOX inhibitors in breast carcinoma cells was found to be 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(02)00140-2 Bioorganic & Medicinal Chemistry 101 (2002) 2927–2932 *Corresponding author at present address: TaiGen Biotechnology, 7F, 138 Hsin Ming Rd., Neihu Dist., Taipei, Taiwan 114, ROC. Tel.: +886-2-27901861; fax: +886-2-27963606; e-mail: hosein@ tai- genbiotech.com.tw