Taxane Anticancer Agents

343

INDEX

Downloaded by KAOHSIUNG MEDICAL UNIV on June 10, 2018 | https://pubs.acs.org Publication Date: December 7, 1994 | doi: 10.1021/bk-1995-0583.ix002

State University of New YorkBuffalo, 111 State University of New YorkStony Brook, 262 The Hebrew University, 154 The Scripps Research Institute, 302 The University of Texas M. D. Anderson Cancer Center, 31 U.S. Department of Agriculture Forest Service, 58

Uniformed Services University of the Health Sciences, 162 Université di Torino, 262 University of California-San Diego, 302 University of CaUfornia-Santa Barbara, 138 University of Kansas, 217 University of Tennessee, 173 Virginia Polytechnic Institute and State University, 203 Washington State University, 72

Subject Index A Α-ring contracted taxoids from 10-deacetylbaccatin III, synthesis, 193-194 A ring of paclitaxel, synthesis, 304/305 ABC ring of paclitaxel, synthesis, 306-307 20-Acetoxy-4-deacetyl-5-epi-20, 0-secotaxol, 88 Acetoxyoxetane, synthesis, 294-296 13-Acetyl-9(#)-dihydrobaccatin III, chemistry, 276-280 Activity, biological, See Biological activity Af-Acyl paclitaxel analogues, convergent synthetic method, 220-223 Adrenal cell effect intermediate filaments, 178-179 microfilaments, 176-178 microtubules, 179,180r Agronomics, biological production of paclitaxel, 4-5 Aliphatic Af-acyl and Af-oxycarbonyl paclitaxel analogues, convergent synthetic method, 222-223 3'-Alkyl and 3'-alkenyl analogues of docetaxel, 271-273 Anticancer agents, critical objectives in western medicine, 81 Antimitotic activity, docetaxel, 234-235,242-243 Antimitotic drugs, inhibition of microtubule dynamics, 142-143

Antitumor activity 3'-alky 1 and 3'-alkenyl analogues of docetaxel, 273 9(#)-dihydrotaxanes, 276-286 docetaxel, 46 in vivo, cyclohexyl analogues of docetaxel and paclitaxel, 271 paclitaxel, 25i,l 11-120 Apoptotic cell death, induction by paclitaxel, 150 Aromatic N-acyl paclitaxel analogues, convergent synthetic method, 220-222 2-Aroyl-2-benzoyltaxol analogue, synthesis, 211-213 3'-Aryl paclitaxel analogues, biology, 219-220 Assays, chemical production of paclitaxel, 8-9 3 '-(p-Azidobenzamido)taxol competition with paclitaxel for microtubule binding sites, 155,157/ microtubule assembly effect, 155,156/ molecular structure, 155,156/ specific labeling of β-tubulin, 155,158/ 3'-(p-Azidobenzamido)taxol-photolabeled β-tubulin, formic acid digestion products, 155,159-161

Β Β-16 melanoma, activity of paclitaxel, 25,27

Georg et al.; Taxane Anticancer Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1994.


344

TAXANE ANTICANCER AGENTS

Baccatin III structure, 203,233,247-248 synthesis of paclitaxel, 83 use in total synthesis of paclitaxel, 294 Baccatin ΙΠ ester functionalities, selective hydrolysis methods, 225-226 Bacterial polysaccharide use as chemotherapeutic agent, 162 See also Lipopolysaccharide Bioactive metabolites of endophytic fungi of Pacific yew, 81-96 Biological activity paclitaxel, 23,25i taxoid(s), 242-243 taxoid drug metabolites, 107 Biological production of paclitaxel agronomics, 4-5 biosynthesis, 3-4 chemical ecology, 7 genetics and genetic engineering, 3-4 strain selection and improvements, 6-7 Biological studies of future generation drugs, paclitaxel binding site, 9-11 Biosynthesis biological production of paclitaxel, 3-4 paclitaxel from baccatin III, 72-73 importance of pathway elucidation, 72 olefin precursor, 74-76 taxadiene cyclase, 75,77 taxadiene oxygenase, 77-79 Breast cancer docetaxel clinical trials, 47 paclitaxel clinical trials, 37—41

C C ring of paclitaxel, synthesis, 305/,306 C-l alcohol introduction, pinene path to taxanes, 334-335 C-l hydroxyl group reactivity, taxoids with modified skeletons, 200-201 C-2 and C-4 modified taxoids, chemistry and structure-activity relationships, 197-200

C-2 stereochemistry, pinene path to taxanes, 334-335 C-2' and C-7 paclitaxel esters, watersoluble paclitaxel prodrugs, 125-126 C-2' and C-7 paclitaxel phosphates, 127 C-3 ' side chain analogues of 9(/?)-dihydrotaxanes, 280-281 C-4 acetate group of paclitaxel, effect on bioactivity, 208-210 C-7 hydroxyl group of paclitaxel, effect on bioactivity, 206-207 C-7 oxygenation, convergent route to taxane design, 322-324 C-7-C-9 analogues of 9(/?)-dihydrotaxanes, synthesis, 281-282 C-10 acetoxy group of paclitaxel, effect on bioactivity, 204,206 C-l l-C-12 double-bond reduction, taxoids with modified skeletons, 191-193 C-13 chain-modified paclitaxel analogues, synthesis, 217-218 C-26 murine colon tumor, inhibition by liposome-based formulations of paclitaxel, 117-118 Camphor, use in total synthesis of paclitaxel, 288 Cancer incidence, 81 See also Breast cancer, Gastrointestinal tract cancers, Head and neck cancer, Lung cancer, Non-small-cell lung cancer, Ovarian cancer, Renal cell cancer, Small-cell lung cancer Carbamate analogues of docetaxel, biological activities, 242-243 Carbotricyclic core, steps in pinene path, 332-334 Cardiac toxic effects, clinical problems of paclitaxel, 32 Cell death, apoptotic, induction by paclitaxel, 150 Cephalomannine, synthesis of side chain of paclitaxel, 204-205 Chemical developments of paclitaxel, total synthesis, 28-29


345


INDEX

Chemical ecology, biological production of paclitaxel, 7 Chemical production of paclitaxel, 8-9 Chemical studies of future generation drugs, 11-13 Chemistry 13-acetyl-9(/?)-dihydrobaccatin III, 277-280f 9(fl)-dihydrotaxanes, 276-286 3'-Af-modified taxoid synthesis, 241-242 paclitaxel, 217-228 protective group improvements, 239-241 stereoselective approaches to 3'-modified phenyl taxoids, 236-239 taxoids with modified skeletons, 189-201 Chemotherapy and paclitaxel, overview, 31 Clinical formulations, paclitaxel, 113-114 Clinical problems chemotherapy, 33 paclitaxel, 32-33 Clinical trials docetaxel, 47-51 paclitaxel, 37-45 Coley, William, cancer therapy, 162 Conformation, paclitaxel and analogues, 228-230 Convergent route to taxane design advance toward taxusin, 316-318 C-7 oxygenation, 322-324 expedient elaboration of taxane frameworks, 315-316 formulation of synthetic plan, 314-315 oxetane ring introduction, 321-322 ring-A oxygenation, 319-320 ring-B oxygenation level enhancement, 318-319 Convergent synthetic method, N-acyl paclitaxel analogues, 220-223 Core skeletal rearrangements, paclitaxel, 247-259 Cremophor EL action on steroid synthesis, 181,184/, 185 use with paclitaxel, 125 Crude paclitaxel, biological activity, 23,25i [4 + 4] cycloaddition strategy, transition metal catalyzed, 327-328

Cyclohexyl analogues of docetaxel and paclitaxel cytotoxicity, 270-271 syntheses, 268-270 3 '-Cyclohexyl and 2-cyclohexyl paclitaxel analogues, 223-224 Cytoskeletal system, schematic representation, 174/, 175 Cytoskeleton, role in steroidogenesis action of cremophor, 181-185 action of paclitaxel on steroid-secreting cells, 181-183/ intermediate filaments, 178-179 linkage of elements, 177 microfilaments, 176-178 microtubules, 179-181 reversibility of paclitaxel and cremophor effects, 185 Cytotoxicity 3'-alkyl and 3'-alkenyl analogues of docetaxel, 272-273 cyclohexyl analogues of docetaxel and paclitaxel, 270-271 9-deoxotaxol analogues, 285-286 docetaxel, 46 norsecotaxoids, 268 paclitaxel, 25t taxoids from 14P-hydroxy-10deacetylbaccatin III, 265-267

D ring of paclitaxel, synthesis, 308,309/ 4-Deacetyl-10-acetyltaxotere, synthesis and biology, 226 10-Deacetylbaccatin III regenerable source, 217 structure, 203,217,218/233,247-248 synthesis Α-ring contracted taxoids, 193-194 docetaxel, 234 paclitaxel, 3-13,83 10-Deacetylhomotaxol, synthesis and biology, 224-225 Deacetyloxytaxol, synthesis and biology, 226-228



346


4-Deacetyltaxol, synthesis and biology, 226 9-Deoxotaxol analogues, synthesis and cytotoxicity, 284-286 Deoxygenation at C-2, C-7, and C-10 methods, 209-211 structure-activity relationships of paclitaxel, 247-254 3 '-Dephenyl-3 '-benzyldocetaxel, synthesis, 238-239 9(/?)-Dihydrotaxanes, chemistry and antitumor activity, 276-286 9(/?)-Dihydrotaxol, synthesis, 279 9-Dihydrotaxotere, synthesis and biology, 226-228 gem-Dimethyl-y-hydroxybutyric acid linker, use in paclitaxel pro-prodrug synthesis, 130-131 Docetaxel 3'-alkyl and 3'-alkenyl analogues, 271-273 anticancer activities, 98-99,112 antimitotic activity, 234-235,242-243 antitumor activity, 4 biological activities, 107 cell cycle effects, 45-46 clinical trials, 31-56,102-103,124-125 cyclohexyl analogues, 268-271 cytotoxicity, 46 development and synthesis, 45 formulation and systemic administration problems, 125 in vivo preclinical studies, 100,102 large-scale production, 190-191 mechanism of action, 45,189,234 metabolic pathway, 104,106 pharmacokinetics, 99 phase I trials, 46-47 phase II trials, 47—48 preclinical studies, 99-100,105-106/ safety profile, 49-51 semisynthesis, 233-243 side effects, 262 structural determination, 103 structure, 98,124,189,233,247-248 structure-activity relationships, 234 synthesis, 104-105 use in cancer chemotherapy, 262

Doxorubicin trials in breast cancer, combination trials with paclitaxel, 39-41 Drug resistance, clinical problems of chemotherapy, 33 Drug supply, clinical problems of paclitaxel, 32-33

Ε Endophytic fungi of Pacific yew, source of paclitaxel, 81-96 Extraction, paclitaxel, 19-22

F Federal lands, bark harvest of Pacific yew, 61 Fluorination at C-7, structure-activity relationships of paclitaxel, 254-257 Flux, description, 139 Formic acid digestion products, 3 '-(p-azidobenzamido)taxolphotolabeled β-tubulin, 155,159-161 Formulations of paclitaxel, liposomebased, 112-120 Fragmentation cascade approach, design of phosphatase-activated paclitaxel prodrugs, 128 Fungi, endophytic, of Pacific yew, source of paclitaxel, 81-96 Future generation drugs biological studies, 9-11 chemical studies, 11-13

G Gastrointestinal tract cancers docetaxel clinical trials, 48-49 paclitaxel clinical trials, 44 Gene induction in murine macrophages, paclitaxel and lipopolysaccharides, 164-165


347

INDEX

Genetic engineering, biological production of paclitaxel, 3-4 Gibberellins, microbial source for paclitaxel, 84


H Head and neck cancer docetaxel clinical trials, 49 paclitaxel clinical trials, 44 Hematologic toxic effects, docetaxel, 49 Heteroaromatic N-acyl paclitaxel analogues, convergent synthetic method, 220-222 3 '-Heteroaromatic paclitaxel analogues, 219-220 Homotaxotere, biology and synthesis, 224-225 Hydrolysis methods, selective, baccatin III ester functionalities, 225 14P-Hydroxy- 10-deacetylbaccatin III, syntheses of new taxoids, 262-266 o-(Hydroxymethyl)benzoic acid linker, use in paclitaxel pro-prodrug synthesis, 131-133 o-Hydroxyphenylacetic acid linker, use in paclitaxel pro-prodrug synthesis, 130-132 Hypersensitivity reactions, clinical problems of paclitaxel, 32

Isolation, paclitaxel, 19-22

L Leukemia, P388, inhibition by liposome-based formulations of paclitaxel, 116-117 Lipopolysaccharide functions, 163 gene induction on murine macrophages, 164-164 induction of tumor regression, 162-163 tyrosine phosphorylation induction in murine macrophages, 164-165 Lipopolysaccharide analogues, blockage of lipopolysaccharide mimetic effects of paclitaxel, 167-168 Liposome-based formulations of paclitaxel activity against intraperitoneal P388 leukemia, 116-117 activity against subcutaneous C-26 murine colon tumor, 117-118 description, 115 empirical development, 119-120 in vitro and in vivo activity of prototype liposomes, 115-116 molecular basis of stability, 120 pharmaceutical properties, 118-119 Lung cancer clinical trials with paclitaxel, 42-43 incidence and types, 41-42 M

Macrophages, induction of tumor necrosis ΙΡΝ-γ-primed C3H/OuJ macrophages, factor by paclitaxel, 163-164 paclitaxel as trigger, 168-169 Masked lactone approach Immunoassay techniques, paclitaxel production by Taxomyces andreanae, 87design of phosphatase-activated paclitaxel prodrugs, 128 Indirect competitive inhibition enzyme synthesis of paclitaxel prodrugs, 129-133 immunoassay, paclitaxel production by Mass spectral analysis, paclitaxel Taxomyces andreanae, 88-91 production by Taxomyces andreanae, 87 "Interim Guide" team, Pacific yew Medicinal chemistry, paclitaxel, 217-230 environmental impact statement, 62 Melanoma, clinical trials with Intermediate filaments, role in steroid docetaxel, 49 secretion, 178-179



348


Metabolism of taxoid drugs, 98-109 biological activities of metabolites, 107 clinical trials, 102-103 in vitro preclinical studies, 99-101/,105-106 in vivo preclinical studies, 100,102 metabolic pathway, 104,106 pharmacokinetics, 99 structural determinations, 103-104 synthesis, 104-105 4-Methoxyphenyloxazolidine, side-chain protection, 240-241 Microbial source for paclitaxel chemical analysis of fungal extract, 85 endophytic fungi, 81 gibberellins, 84 reasons for interest, 83-84 search for microorganism, 85 Taxomyces andreanae, 85-93 unrelated bioactive compounds, 94-95 Microfilaments, role in steroid secretion, 177-178 in adrenal cells, 176-178 in ovarian cells, 178 in testicular cells, 178 Microtubule(s), role in steroid secretion, 179-181 binding site of paclitaxel, 154-155 characteristics of dynamics, 139,141/ dynamic instability, 139,142 in adrenal cells, 179,180i in ovarian cells, 179,180/,181 in testicular cells, 179,180r induction by paclitaxel, 145-150 inhibition of treadmilling and dynamic instability by paclitaxel, 143-145 paclitaxel binding, 143 stabilization by paclitaxel, 143 structure, 139,140/ treadmilling, 139,142 Microtubule binding activity, dissociation of liposaccharide mimetic activity, 165-167 Microtubule disassembly inhibitory activity 3'-alkyl and 3'-alkenyl analogues of docetaxel, 272-273

Microtubule disassembly inhibitory activity—Continued cyclohexyl analogues of docetaxel and paclitaxel, 270 taxoids from 14P-hydroxy- 10deacetylbaccatin ΙΠ, 265-267 Microtubule polymerization dynamics, inhibition by paclitaxel, 138-151 Mitotic block, induction by paclitaxel, 145-150 Mitotic spindle, description, 145 Murine macrophages, gene induction and tyrosine phosphorylation induction by liposaccharides and paclitaxel, 164-165

Ν 3'-N-modified taxoid, synthesis, 241-242 National Cancer Institute's stimulation approach, paclitaxel research, 2-3 National Environmental Policy Act of 1969, Pacific yew environmental impact statement, 62-63 Natural compounds, structural and property diversity, 18 Nonhematologic toxic effects, docetaxel, 50-51 Non-small-cell lung cancer clinical trials with docetaxel, 48 paclitaxel trials in lung cancer, 42^13 Norsecotaxoids, syntheses, 267-268 Northern hemisphere of paclitaxel C-7 hydroxyl group, 206-207 C-10 acetoxy group, 204,206 Ο Olefin precursor of paclitaxel, characterization, 74-76 Opened oxetane analogues of taxoids, synthesis and chemical reactivity, 195-197 Ovarian cancer docetaxel clinical trials, 48 paclitaxel clinical trials, 34-37


349


INDEX

Ovarian cells, steroidogenesis Paclitaxel—Continued antimitotic mechanism, 247 intermediate filaments, 179 antitumor activity, 25ί,111-120,168-169 microfilaments, 178 apoptotic cell death, 150 microtubules, 179-181 binding site on microtubule, 154-155 Oxazoline synthetic route, side-chain binding to microtubules, 143 chemistry of paclitaxel, 204-205 biological activity, 107 Oxetane analogues of taxoids, synthesis biosynthesis, 72-79 and chemical reactivity, 195-197 blockage of lipopolysaccharide mimetic Oxetane ring effects, 167-168 convergent route to taxane design, cancer trials 321-322 breast cancer, 37-41 paclitaxel, effect on bioactivity, 207-208 GI tract cancer, 44-45 N-Oxycarbonyl paclitaxel analogues, head and neck cancer, 43^4 convergent synthetic method, 222-223 lung cancer, 42-43 ovarian cancer, 35-36 Ρ chemical developments, 28-29 chemistry, 203-214,217-228 chemotherapeutic potential, 326 P388 leukemia, inhibition by liposomechronology of development, 27-28 based formulations of paclitaxel, clinical development, 18-28,302 116-117 clinical formulations, 113-114 Pacific yew clinical trials, 31-56,102-103,124-125, bark harvest on Federal lands, 61 bioactive metabolites of endophytic 173,175,328 fungi, 81-96 competition with 3 '-(p-azidobenzamido)ecological role, 58,60/61 taxol, 155,157/ geographical range, 58,59/ conformation, 228-230 growth rate, 58 cyclohexyl analogues, 268-271 cytotoxicity, 25t, 154 importance and potential uses, 70-71 de novo construction, 313 paclitaxel content, 58 Pacific yew environmental impact statement discovery, 19 extraction, 19-22 alternatives, 64,66-67/ formulation alternatives, 114-120 analysis, 64-65,68-69* formulation problems, 112-114,125 authors, 63 functions, 154 implementation, 65,70 "Interim Guide" team, 62 gene induction in murine macrophages, 164-165 National Environmental Policy Act of in vivo preclinical studies, 100,102 1969, 62-63 inhibition of treadmilling and dynamic preferred alternatives, 65 instability of microtubules, 143-145 proposed action and need, 63 isolation, 19-22 record of decision, 65 large-scale production, 190-191 Yew Act of 1992, 62 limitations of current formulations, 114 Paclitaxel mechanism of action, 138-139,189,234 action on steroid synthesis, 181-183/ metabolic pathway, 104 activity in B-16 melanoma, 25,27 microbial source, 83-85 anticancer activity, 81-82,98-99,111,173



350


Paclitaxel—Continued microtubule bundling, 145-150 microtubule stabilization, 138 mitotic block, 145-150 northern hemisphere chemistry, 204-207 numbering scheme, 302,304/ occurrence in Pacific yew, 58 pharmaceutical development problems, 111-112 pharmacology, 111-120 pharmacokinetics, 99 phosphatase-activated prodrugs, 124-135 physical and chemical properties, 2If pinene path, 328-338 preclinical and clinical problems, 31-33 preclinical studies, 99-100,101/ production, 3-9 production by Taxomyces andreanae, 86-93 properties, physical and chemical, 211 research overview, 1-16 side-chain chemistry, 203-205 side effects, 262 solubility in cosolvents and nonaqueous media, 112-113 southern hemisphere chemistry, 207 stabilization of microtubules, 143 structural determination, 21-26/103 structure, 1-2,19,20/74,98,112,124,189, 203,217,218/233,247-248,302, 304/313,326 structure-activity relationships, 203-215,217-228,234-236 supply dilemma, 82-83 supply from Pacific yew bark, 61-70 synthesis, 104-105,288-300,302-309 total synthesis, 288-299,302-309 toxicity mechanisms, 114 transition metal catalyzed [4 + 4] cycloaddition strategy, 327-328 tubulin binding, 27 tumor necrosis factor induction in macrophages, 163-164 tyrosine phosphorylation induction in murine macrophages, 164-165

Paclitaxel analogues conformation, 228-230 lipopolysaccharide mimetics, 165 3'-phenyl, biology, 219-221 Patchino, use in total synthesis of paclitaxel, 288-293 Patient tolerance, clinical problems of chemotherapy, 33 Pharmacokinetics, metabolism of taxoid drugs, 99 Pharmacology, paclitaxel formulations, 111-120 3 '-Phenyl analogues of docetaxel, biological activities, 242-243 3'-Phenyl analogues of paclitaxel, biology, 219-221 3 '-Phenyltaxoids, stereoselective approaches, 236-239 3-Phenylisoserine preparation using Staudinger reaction, 237-239 synthesis, 217-219 Phosphatase-activated prodrugs of paclitaxel, 124-136 C-2' and C-7 paclitaxel phosphates, 127 design strategies, 127-128 effect of linker on water solubility, 134-135 in vitro evaluation, 133-134 in vivo evaluation, 134-135 protaxols, 126 synthesis using masked lactone approach, 129-133 water-soluble prodrugs, 125-126 Pinene path to taxanes C-ring elaboration through aldol closure, 337-338 C-ring studies, 335-336 C-l alcohol introduction, 334-335 C-2 stereochemistry, 334-335 connectivity analysis, 329-330 emergence, 328-332 feasibility, 332-338 methoxyaryl C-ring precursors, 336 nonaromatic C-ring precursors, 336-337


351


INDEX

Pinene path to taxanes—Continued pathway, 330-332 steps to carbotricyclic core, 332-334 strategic considerations, 329-330 Preclinical studies, taxoid drugs, 99-101,105-106 Primed macrophages, description, 168 Procurement, initial, paclitaxel, 19 Prodrugs of paclitaxel, phosphatase activated, See Phosphatase-activated prodrugs of paclitaxel Production of paclitaxel biological, 3-7 chemical, 8-9 Properties, physical and chemical, paclitaxel, 21r Protaxols, properties, 126 Purified paclitaxel, biological activity, 23,25i

Semisynthesis chemical production of paclitaxel, 8 docetaxel, 233-243 Side-chain analogues of docetaxel, semisynthesis, 233-243 Side-chain chemistry of paclitaxel oxazoline synthetic route, 204-205 structure-activity relationship, 214 synthesis via cephalomannine, 204-205 Side chain of paclitaxel, synthesis, 28 Small-cell lung cancer clinical trials with docetaxel, 48 paclitaxel trials in lung cancer, 43 Solubility of paclitaxel in cosolvents and nonaqueous media, 112-113 Southern hemisphere of paclitaxel 2-aroyl-2-benzoyltaxol analogue synthesis, 211-213 C-4 acetate group, 208-210 deoxygenation at C-2, 209-211 oxetane ring, 207-208 Specific monoclonal antibodies, R development for paclitaxel production by Taxomyces andreanae, 87-88 Radioisotopic labeling studies, paclitaxel Stereoselective approaches, 3 '-modified production by Taxomyces andreanae, 91 Regioselective oxetane ring opening, phenyl taxoids, 236-239 Steroidogenesis structure-activity relationships of paclitaxel, 257-259 action of cremophor, 181-185 Renal cell cancer, clinical trials with action of paclitaxel on steroid-secreting docetaxel, 49 cells, 181-183/ Ring A oxygenation, convergent route to cytoskeleton involvement, 175-181 taxane design, 319-320 general mechanisms, 175 Ring Β oxygenation level enhancement, Strain selection and improvements for biological production of paclitaxel, 6-7 convergent route to taxane design, Structural determination 318-319 paclitaxel, 21-24/26/ Ring Β rearrangement, 9(#)-dihydrotaxane analogues, 282-283 taxoid drugs, 103-104 Route selection for total synthesis of Structure-activity relationships chemical developments in paclitaxel paclitaxel, 303-305 research, 28 description, 214,217-228,234-236 docetaxel, 234 S paclitaxel, 247-259 taxoids, 189-201,263-273 Sarcomas, clinical trials with docetaxel, 49 7-Succinylbaccatin ΙΠ, structure, 88 Secondary metabolites of natural Supply dilemma, paclitaxel, 82-83 compounds, therapeutic potential, 18



352


Taxoid drug(s), metabolism, 98-107 Taxoid drug metabolites, biological activity, 107 Taxol, See Paclitaxel Taxomyces andreanae confirmation of paclitaxel production, 86-93 isolation, 85-86 Taxotere, See Docetaxel Taxus brevifolia, See Pacific yew Taxusin, synthesis, 313-324 Testicular cells, steroidogenesis intermediate filaments, 179 microfilaments, 178 microtubules, 179,180i Tissue culture, biological production of T paclitaxel, 4 Taxadiene cyclase, role in biosynthesis of Total synthesis of paclitaxel, 8,28-29, 288-299,304-309 paclitaxel, 75,77 Taxadiene oxygenase, role in biosynthesis Toxicity mechanisms, paclitaxel, 114 Transition metal catalyzed [4 + 4] of paclitaxel, 77-79 cycloaddition strategy, paclitaxel, Taxanes 327-328 bioactive metabolites of endophytic Treadmilling, description, 139 fungi, 81-96 2-(Trichloromethyl)oxazolidine, sidedesign, convergent route, 313-324 chain protection, 239-240 pinene path, 332-338 Trimethyl lock linker, use in paclitaxel Taxoids pro-prodrug synthesis, 129-130 biological activity, 242-243 β-Tubulin, specific labeling with chemistry, 236-242 discovery, 189 3'-(/?-azidobenzamido)taxol, 155,158/ Tubulin binding, paclitaxel, 27 from 14P-hydroxy-10-deacetylTumor necrosis factor baccatin ΠΙ, 265-267 identification, 162-163 3'-N-modified, synthesis, 241-242 induction in macrophages by paclitaxel, new, syntheses, 262-266 163-164 structure-activity relationships, Tyrosine phosphorylation induction in 234-236,263-273 murine macrophages, paclitaxel and syntheses, 262-273 lipopoly saccharides, 164-165 with modified skeletons Α-ring contracted taxoids from 10-deacetylbaccatin ΙΠ, 193-194 C-l hydroxyl group reactivity, 200-201 C-2 and C-4 modified taxoids, 197-200 V C-l l-C-12 double bond reduction, Vinblastine, inhibition of microtubule 191-193 dynamics, 142-143 opened oxetane analogues, 195-197

Synthesis 3'-alkyl and 3'-alkenyl analogues of docetaxel, 271-272 cyclohexyl analogues of docetaxel and paclitaxel, 268-270 9-deoxotaxol analogues, 284-286 9(/?)-dihydrotaxane analogues, 280-282 norsecotaxoids, 267-268 paclitaxel, total, 8,28-29,288-299, 304-309 taxoid(s), 262-273 taxoid drugs, 104-105 taxusin, 313-324


353

INDEX

Y

Water-soluble paclitaxel prodrugs C-2'esters, 125-126 C-7 esters, 126

Yew, Pacific, See Pacific yew Yew Act of 1992, Pacific yew environmental impact statement, 62


W

Production: Charlotte McNaughton Indexing: Deborah H. Sterner Acquisition: Barbara Pralle Cover design: AlanKahan Printed and bound by Maple Press, York, PA


Taxane Anticancer Agents

Recommend Documents