ABSTRACT
The preparation of C-7 paclitaxel ethers is described. Various substituted ethers were prepared via activation of the corresponding methylthiomethyl ether followed by alcohol addition. Variation of the C-7 ether group as well the 3' side chain position led to the discovery of a novel taxane, BMS-184476 (4), with preclinical antitumor activity superior to paclitaxel.
Subject(s)
Antineoplastic Agents/chemical synthesis , Paclitaxel/analogs & derivatives , Paclitaxel/chemical synthesis , Taxoids , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Ethers , Humans , Magnetic Resonance Spectroscopy , Paclitaxel/chemistry , Paclitaxel/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
The stereospecific syntheses of the metabolically blocked 6-alpha-F, Cl, Br paclitaxel, and 6-alpha-F-10-acetyldocetaxel are described and in vitro and in vivo activity is presented.
Subject(s)
Paclitaxel/chemical synthesis , Taxoids , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Drug Stability , Humans , Inhibitory Concentration 50 , Paclitaxel/analogs & derivatives , Paclitaxel/chemistry , Paclitaxel/metabolism , Paclitaxel/pharmacology , Tumor Cells, CulturedABSTRACT
The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Chlorambucil/chemistry , Chlorambucil/pharmacology , Disease Models, Animal , Female , Humans , Inhibitory Concentration 50 , Mice , Neoplasm Transplantation , Ovarian Neoplasms/drug therapy , Paclitaxel/chemistry , Paclitaxel/pharmacology , Sarcoma/drug therapy , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The sphericity and wall-thickness uniformity requirements of direct-drive inertial-fusion targets are of the order of less than 1%. These shells display self-interference patterns (SIP's) when irradiated with a spatially incoherent, narrow-bandwidth light source and viewed with a compound microscope. These patterns are distinct concentric fringes when the target is uniform, whereas faint, distorted, or discontinuous fringes indicate a nonuniform target. We determined the wall thickness to within +/-0.5 microm by counting the number of fringes in the SIP, independent of the outside diameter. Thickness uniformity is verified to an accuracy better than 0.05 microm. The wall thickness of gas-filled targets can be determined to this accuracy without knowledge of the type of gas or its pressure. The SIP fringe technique is used to select polymer shells typically of 800- to 1000-microm diameter and 5- to 12-microm wall thickness. The fringe locations have been modeled by use of ray tracing and agree well with actual measurements of well-characterized shells. Details of the formation of the SIP fringes, a theoretical model, and the method used for quantitative measurement of the shell-wall thickness with the SIP are presented with validation examples.
