Design and synthesis of a cephalosporin-retinoic acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate.
Two novel series of all-trans-beta-retinoic acid derivatives were synthesized and found to possess anticancer activity. The first series, cephalosporin 3'-retinoic esters 6 and 7 were, respectively, obtained by the condensation of all-trans-beta-retinoic acid (2) with cephalosporins 4 and 5. The second series, 7-(retinamido)cephalosporins 11 and 12, were synthesized, respectively, by the condensation of 2 with cephalosporins 9 and 10. These four heretofore undescribed compounds 6, 7, 11, and 12 showed inhibitory activity against murine leukemias (L1210 and P388), sarcoma 180, breast carcinoma (MCF7), and human T-lymphocytes (Molt4/C8 and CEM/0). They also inhibited squamous metaplasia and keratinization in tracheal organ cultures derived from vitamin-A-deficient hamsters. Moreover, cephalosporin 3'-retinoic ester 7 exhibited enhanced activity against keratinization with ED(50)=3.91 x 10(-11) M in the presence of a beta-lactamase from Staphylococcus aureus 95. A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based retinoid 7 and the potency of 7 toward L1210, P388, and MCF7 was found to approach that of the free retinoic acid (2). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to retinoid 7 than normal human embryonic lung cells. These notions provide a new approach to the use of beta-retinoic acid for antitumor therapy.
Hakimelahi
G H
GH
Institute of Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China. hosein@chem.sinica.edu.tw
Ly
T W
TW
Yu
S F
SF
Zakerinia
M
M
Khalafi-Nezhad
A
A
Soltani
M N
MN
Gorgani
M N
MN
Chadegani
A R
AR
Moosavi-Movahedi
A A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002511:Cephalosporins / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D006868:Hydrolysis; D007633:Keratins / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008679:Metaplasia / Q000517:prevention & control; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D012995:Solubility; D014212:Tretinoin / Q000737:chemistry / Q000633:toxicity; D014316:Tritium; D014407:Tumor Cells, Cultured; D014867:Water / Q000737:chemistry; D001618:beta-Lactamases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002511:Cephalosporins; D004952:Esters; D011355:Prodrugs; D014867:Water; D014316:Tritium; D014212:Tretinoin; D007633:Keratins; D001618:beta-Lactamases