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.
Hakimelahi
Gholam Hossein
GH
Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan, Republic of China. hosein@tai-genbiotech.com.tw
Shia
Kak-Shan
KS
Pasdar
Manijeh
M
Hakimelahi
Shahram
S
Khalafi-Nezhad
Ali
A
Soltani
Mohammad N
MN
Mei
Nai-Wen
NW
Mei
Hui-Ching
HC
Saboury
Ali A
AA
Rezaei-Tavirani
Mostafa
M
Moosavi-Movahedi
Ali A
AA
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