ABSTRACT
Six novel docetaxel analogues that possess a N-(7-nitrobenz-2-oxa-1,3-diazo-4-yl)amido-6-caproyl chain in position 7 or 3' (11 and 16a), a N-(7-nitrobenz-2-oxa-1,3-diazo-4-yl)amido-3-propanoyl group at 3' (16b) and a 5'-biotinyl amido-6-caproyl chain in position 7, 10 or 3', respectively, have been synthesized. These compounds exhibit activity against microtubule disassembly similar to that of docetaxel but show discrepant activities on living cells. Although addition of microtubules to 11, 16a and b enhance their fluorescence, no shift of the emission maxima was observed. The fluorescent docetaxel derivatives show a specific labeling of microtubules in living cells, demonstrating that the microtubule cytoskeleton constitutes their main subcellular localization.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Paclitaxel/analogs & derivatives , Taxoids , Animals , Antineoplastic Agents, Phytogenic/chemistry , Avidin/chemistry , Biotin/chemistry , Brain Chemistry , Cattle , Cells, Cultured , Docetaxel , Fluorescent Dyes/chemical synthesis , Macropodidae , Magnetic Resonance Spectroscopy , Microtubules/drug effects , Microtubules/metabolism , Paclitaxel/chemical synthesis , Paclitaxel/chemistry , Tubulin/metabolismABSTRACT
A variety of synthetic analogues of taxol, a naturally occurring antitumor diterpene, were examined for their potency to inhibit microtubule disassembly. For some of the compounds, the in vitro cytotoxic properties showed a good correlation with the tubulin assay. This structure-activity relationship study shows that inhibition of microtubule disassembly is quite sensitive to the configuration at C-2' and C-3'. A correlation between the conformation of the side chain at C-13 and the activity is suggested. Of all the compounds examined, one of the most potent in inhibiting microtubule disassembly and in inhibiting murine P388 leukemic cells, N-debenzoyl-N-tert-(butoxycarbonyl)-10-deacetyltaxol, named taxotere, was selected for evaluation as a potential anticancer agent.
Subject(s)
Alkaloids/chemistry , Antineoplastic Agents/chemistry , Alkaloids/pharmacology , Animals , Antineoplastic Agents/pharmacology , Brain/ultrastructure , Cell Division/drug effects , Chemical Phenomena , Chemistry , Leukemia P388/pathology , Mice , Microtubules/drug effects , Microtubules/metabolism , Molecular Conformation , Molecular Structure , Paclitaxel , Stereoisomerism , Structure-Activity Relationship , Swine , Tubulin/metabolismABSTRACT
Inactivated, nonadjuvanted tissue culture-origin rabies vaccine was tested in 168 dogs for its ability to provide protection against challenge of immunity 1 year after vaccination. Several laboratory methods were used concurrently to measure the potency of the vaccine. When used at full strength, the vaccine protected 70% of dogs after either a 1- or 2-dose vaccination schedule. When vaccine was diluted to contain less antigenic mass, the 1-dose schedule was not as effective as 2 doses. High serum-neutralizing antibody titers developed by 7 days after vaccination, but the titers declined rapidly thereafter. The US reference vaccine protected 28 of 30 dogs.
