Design and synthesis of a cephalosporin-retinoic acid prodrug activated by a monoclonal antibody–β-lactamase conjugate
| Autor: | Sheng-Fa Yu, Azra Rabbani Chadegani, Mohsen Nemat Gorgani, Mohammad N. Soltani, Ali Khalafi-Nezhad, Maryam Zakerinia, Gholam H. Hakimelahi, Tai Wei Ly, Ali Akbar Moosavi-Movahedi |
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| Rok vydání: | 2001 |
| Předmět: |
Magnetic Resonance Spectroscopy
Cell Survival medicine.drug_class Clinical Biochemistry Cephalosporin Retinoic acid Pharmaceutical Science Antineoplastic Agents Tretinoin Tritium Biochemistry beta-Lactamases Mice chemistry.chemical_compound Drug Stability Drug Discovery Tumor Cells Cultured medicine Animals Humans Prodrugs Retinoid Molecular Biology chemistry.chemical_classification Metaplasia Cephem Hydrolysis Organic Chemistry Antibodies Monoclonal Water Esters Prodrug In vitro Cephalosporins Rats Kinetics Enzyme Solubility chemistry Cell culture Drug Design Keratins Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 9:2139-2147 |
| ISSN: | 0968-0896 |
| Popis: | Two novel series of all- trans -β-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 -β-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 =3.91×10 −11 M in the presence of a β-lactamase from Staphylococcus aureus 95. A tumor targeting fusion protein (dsFv3–β-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–β-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 β-retinoic acid for antitumor therapy. |
| Databáze: | OpenAIRE |
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