Design, synthesis, and biological evaluation of a cephalosporin-monohydroguaiaretic acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate.
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-beta-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-beta-lactamase, tumor cells were found to be much more susceptible 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.
Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan, Republic of China. hosein@tai-genbiotech.com.tw
Gholam Hossein
GH
Hakimelahi
Kak-Shan
KS
Shia
Manijeh
M
Pasdar
Shahram
S
Hakimelahi
Ali
A
Khalafi-Nezhad
Mohammad N
MN
Soltani
Nai-Wen
NW
Mei
Hui-Ching
HC
Mei
Ali A
AA
Saboury
Mostafa
M
Rezaei-Tavirani
Ali A
AA
Moosavi-Movahedi
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002511:Cephalosporins; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology*; D009637:Masoprocol; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001618:beta-Lactamases / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D002511:Cephalosporins; D018796:Immunoconjugates; D011355:Prodrugs; D009637:Masoprocol; D001618:beta-Lactamases