Aconitase Carboxymethylation Of, 4 3-Fluorocitrate As Substrate For, 33

Index

Aconitase Amino acids (Cont.) carboxymethylation of, 4 biosynthesis (Cont.) 3-fluorocitrate as substrate for, 33 valine, 263-265 inhibition by 2-fluorocitrate, 9-10, 11-12 halogenated analogues, in peptide and toxicity of 2-fluorocitrate, 9-10, 12 synthesis, 307-309 Adenosine monophosphofluoridate, 178 metabolism, 265-278 Adenosine receptors, halogenated agonists transport, 296 for, 163 -y-Aminobutyric acid S-Adenosylmethionine as neurotransmitter, 294 and catechol O-methylation, 345 transaminase in 5'-deoxy-5'-methylthioadenosine halogenated irreversible inhibitors, biosynthesis, 176 294-295 Alanine inhibitors, as anticonvulsants, 294 iJ-chioro, 279, 281-285, 287-188 Amphetamine, 322 enzyme inhibition by, 279, 281-285 4-bromo, 322 incorporation into peptides, 287-288 4-chloro (peA) iJ,iJ-dichloro, enzyme inhibition by, 285 inhibition of amine uptake by, 322 iJ,iJ-difluoro, enzyme inhibition by, and serotonin depletion, 336-337 285-286 toxicity, 322 iJ-fluoro iJ,iJ-difluoro, 322, 323 inhibition of alanine racemase by, iJ-fluoro, 322, 323 280-284 4-fluoro, 322 synthesis, 280 l-iJ-D-Arabinofuranosyladenine, 162 trifluoro, enzyme inhibition by, 285-287 l-iJ-D-Arabinofuranosylcytosine, 144-145, iJ-Alanine, a-fluoro, as fluorouracil metab• 162 olite, 129, 130 l-iJ-D-Arabinofuranosyl-2-fluoroadenine, Amino acids 161, 162-163 analogues, as irreversible enzyme inhibi• antitumor activity, 163 tors, 278-295 metabolism, 163 biosynthesis, 255-265 toxicity, mechanism of, 163 histidine, 263 l-iJ-D-Arabinofuranosyl-5-fluorouracil, isoleucine, 263-265 143-144, 170 leucine, 263-265 antitumor activity, 144 phenylalanine, 257-259, 260 antiviral activity, 170 tryptophan, 257, 259-262 Arachidonic acid tyrosine, 257-259 the "arachidonic acid cascade," 105, 106

353 354 Index

Arachidonic acid (Cont.) 5-Bromo-2'-deoxyuridine (Cont.) fluorinated analogues, 119-123 antiviral activity (Cont.) formation of fluoro-HETE analogues mutagenicity, 156 from, 120, 122 teratogenicity, 156-157 as potential precursors of fluorinated history, 150-151 PGI2 and TXA2 analogues, 119 incorporation into DNA, 153-158 structures, 119, 120, 122 as radiosensitizer, 157-158 Arginine, 256, 261, 293 Bromopyruvic acid a-difluoromethyl, 293 as affinity label, 22-26 as polyamine precursor, 293 as cross-linking agent, 26-27 Asparagine, 3-fluoro, 276, 304-305 (E)-5-Bromovinyl-2/-deoxyuridine antitumor activity, 304 antiviral activity, 160 incorporation into mammalian protein, diphosphate sugar, inhibition of protein 304-305 glycosylation by, 238 Asparagine-linked oligosaccharides: see Glycoproteins, asparagine-linked Catechol O-methyltransferase Aspartic acid, 275-276 biological function, 345 decarboxylase, 279 ring-fluorinated catechols as substrates 3-fluoro, 276, 304-305 for, 272, 345-346 metabolism, 275-276 Chloral hydrate, 59-60 in nucleoside biosynthesis, 275-276 Chloroacetaldehyde ATP citrate lyase, 31-33 reaction with DNA, 45, 46 3/-Azido-3/-deoxythymidine (AZT), 159, reaction with nucleic acid components, 160-161 41-44 5-substituted analogs, anti-HIV activity historical, 41-43 of, 161 mechanism of etheno-adduct forma• tion, 42-43 reaction with nucleotides and dinucieo• Bacterial citrate lyase, 33 tides, 43-44 Bromoacetaldehyde reaction with oligo- and polynucieotides, reaction with DNA, 45-56 44 reaction with nucleic acid components, reaction with RNA, 44-45 41-44 5-Chloro-5'-deoxycytidine, as radiosensi- historical,41-43 tizer, 158 mechanism of etheno-adduct forma• 5-Chloro-5'-deoxyuridine, 150-151 tion, 42-43 2-Chlorocitric acid, as anorectic agent, 34 reaction with RNA, 44-45 5-(2-Chloroethyl)-2/-deoxyuridine, 159, 160 Bromoacetic acid 2-Chloroisocaproic acid, biological as carboxymethylating agent, 3-4 properties, 8-9 glyceraldehyde-3-phosphate dehydro• I'3-Chlorophenethylamines genase inhibition by, 2-3 as a-adrenergic blocking agents, 329 and lactate formation, 2 ethyleneiminium ions from, 329 toxicity, 1-2 I'3-Chloropyruvic acid, from 5-Bromo-2'-deoxycytidine, as radio- l'3-chloroalanine, 287 sensitizer, 158 Cholesterol 5-Bromo-2'-deoxyuridine, 150-157 radioiodinated analogues as adrenal antiviral activity, 151-153 imaging agents, 72 carbocyclic analogs, 159-160 in steroid hormone biosynthesis, 65, 66 and cell function, 153-157 Chymotrypsin and cell-cycle kinetics, 155 inhibition by haloketones, 47, 49 effect on cell differentiation, 154-155 reaction mechanism, 47, 48 Index 355

Citrate synthase, 11, 15,31 1-(2' ,3' -Dideoxy-2'-fluoro-/3-D• fluoroacetate as substrate, 11 arabinofuranosyl)-adenine, 171 3-fluorocitrate as substrate, 31 1-(2' ,6'-Dideoxy-6' -fluoro-/3-D• fluorooxaloacetate as substrate, 11 ribofuranosyl)-5-iodouracil, 177 stereochemistry of reaction, 11, 15 19,19-Difluoroandrost-4-ene-3,17 -dione, Clonidine, 323 aromatase inhibition by, 80 Cortocosteroids, halogenated, 67-70 Dimethylallyl pyrophosphate 9a-halo-ll/3-hydroxycorticosterone fluorinated analogues, 96-98 biological properties, 67-68 as isopentenyl pyrophosphate isomerase mechanism of halogen effects, 68-69 inhibitors, 97 Cycloserine, 279 and prenyl transferase mechanism, Cytidine-deoxycytidine deaminase, 141-143, 97-98 149-150 role in terpene biosynthesis, 93-94 Dopamine Deoxycytidine kinase, 141-143, 149, 158 biological functions, 319-321 6'-Deoxy-6-fluoroaristeromycin, 177 biosynthesis, 270, 320 3-Deoxy-3-fluorocitric acid, as substrate for [18Fl-6-fluoro, in positron emission tomo- citrate processing enzymes, 31, 33 graphy, 270-273, 346, 347 2' -fluorocytidine, antiviral activity, 165 a-fluoromethyl, 290, 291 5'-Deoxy-2-fluoro-5'-iodoadenosine, 176-177 receptors and schizophrenia, 331 2'-Deoxy-2'-fluorouridine monophosphate, ring-fluorinated analogues, 330 165 2'-Deoxy-2-haloadenosines, antitumor activ• Ecdysone, 78-79 ity, 163 receptor, labelling with 1-(2'-Deoxy-2' -halo-/3-D-arabinofuranosyl)-5- 26-iodoponasterone, 78 substituted cytosines, antiviral prop• Eicosanoids: see Arachidonic acid; Leuko• erties, 168-171 trienes; Prostaglandins 1-(2'-Deoxy-2' -halo-/3-D-arabinofuranosyl)-5- Epinephrine substituted uracils, antiviral proper• biological functions, 319-321 ties, 168-171 biosynthesis, 320 2'-Deoxy-2'-halogenated nuc1eosides, ring-fluorinated analogues, adrenergic 164-167; see also 2'-Deoxy-2'• selectivities, 324-327 fluorocytidine, 2'-Deoxy-2'• Erythritol, 2-deoxy-2-fluoro, 216, 217 fluorouridine 2' -substituent effect on biological proper• [18Fl-AcetyJcyc1ofoxy, in position emission ties, 164-167 tomography of opiate receptors, 346, 2'-substituent effect on conformation, 347 164, 165-166 Fluorinated dicarboxylic acids as mecha• 3'-Deoxy-3' -halonuc1eoside triphosphates, nistic probes, 28-30 and DNA polymerases, 174-175 Fluoroacetic acid, 9-14; see also Fluoroa- Dichloroacetic acid, 5-8 cetyl CoA glyoxalate formation, from 6 as acetyl CoA synthase substrate, 14 metabolic effects of, 5-8 in citric acid cycle, 9 oxalate formation from, 6, 7 and fluorocitrate biosynthesis, 9, 11-14; pyruvate dehydrogenase complex, stimu• see also 2-Fluorocitric acid lation by, 5-6 formation, from fluoroacetamido sugars, pyruvate dehydrogenase kinase, inhibition 230 by, 5-6 formation, from fluoroglycerol, 219 therapeutic potential of, 8 formation, from 29-fluorophytosterol, 2' ,3'-Dideoxy-3' ,5-difluorouridine, 174, 80-81 175-176 formation, from 5-fluorotryptophan, 270 356 Index

Fluoroacetic acid (Cont.) Fluoroglycerols, 217-220 fonnation, from 3-fluorotyrosine, 267, 3-phosphate, inhibition of 269-270 glycerol-3-phosphate dehydrogenase formation, from 5-fluorouracil, 149 by, 219-220 isolation, 9 as substrates for glycerol kinase, 217-218 toxicity, 9, 13-14 toxicity, 219 Fluoroacetyl CoA, 14-15 Fluoroketones, as enzyme inhibitors, 50-59 fonnation, from (-)-2-fluorocitrate, 31, 32 acetylcholinesterase inhibition, 51-52 reaction with glyoxylate, 15 carboxypeptidase inhibition, 52 2-Fluoroadenine, toxicity, 163 juvenile hormone esterase inhibition, 2-Fluoroadenosine, biological properties, 55-57 161-162 pepsin inhibition, 52 Fluoroalkylphosphonates, 178-182 phospholipase A2 inhibition, 54-55, 57 effect of fluorine on acidity, 179-180 renin inhibition, 52-54, 55, 56 nucleotide containing, 178-182 Fluorolactic acid, from fluoromethyl w-Fluorocarboxy1ic acids, metabolism, 28 glyoxal, 59 2-Fluorocitric acid, 11-14, 270 Fluoromalic acid, 15, 17-19,28-29 biosynthesis from fluoroacetate, 9, 11 Fluoromethyl glyoxal, as glyoxalase inhibi• fonnation, from 3-fluorotyrosine, 267, 270 tor, 58-59 mechanism of toxicity, 9-13 5-Fluoroorotic acid, 127, 128, 134 aconitase inhibition, 9-10, 11-12 3-Fluorooxaloacetic acid, 11, 17-18, 19, inhibition of citrate transport by, 12-13 28-29, 31 structure of toxic isomer, 11-12 from difluorofumarate, 29 toxicity, 9-10, 13-14 from 3-fluorophosphoenol pyruvic acid, 5-Fluorocytosine; see also 19 5-Fluoro-2' -deoxycytidine from 3-fluoropyruvate, 17-18 2,2'-anhydro-1-/1-D-arabinofuranosyl 3-Fluorophosphoenol pyruvic acid antitumor activity, 144-145 as substrate for enzyme I, 18-19 1-/1-D-arabinofuranosyl-5-fluorouracil as substrate for PEP carboxykinase, 19 from, 145 as substrate for pyruvate kinase, 18-19 1-/1-D-arabinofuranosyl-5-fluorocytosine 29-Fluorophytosterol, as pro-insecticide, from, 145 80-81 1-/1-D-arabinofuranosyl-, antitumor activ• 3-Fluoropropane-1,2-diol, propanediol de• ity, 143-145 hydrase inhibition by, 221-222 history, 127-128 3-Fluoropropionic acid, as enzyme 5-Fluoro-2'-deoxycytidine, 141-143 substrate, 16-17 incorporation into DNA, 143 3-Fluoropyruvic acid, 17-22,28 as prodrug for 5-fluorodeoxyuridine mo• from 3-fluorophosphoenol pyruvic acid, nophosphate, 141-143 18-19 tumor cell-selectivity, 141-143 as stereochemical probe for pyruvate ki• Fluoro-2'-deoxyuridine nase, 17 monophosphate, 129-133 as stereochemical probe in transcarboxy• formation from 5-fluorodeoxycytidine, lase reaction, 17 141-143 as substrate for pyruvate dehydrogenase, formation from 5-fluorouracil, 129-131 20-22 thymidylate synthase inhibition by, 5-Fluorouracil; see also 5-F1uorouridine; 129-133, 153, 158 5-Fluoro-2' -deoxyuridine triphosphate, incorporation into DNA, catabolism, 129 136-138 history, 127-129 and cytotoxicity, 137-138 mechanisms of antitumor activity, 129-140 effect on DNA structure, 138 prodrugs for, 140-141 Index 357

5-Fluorouridine Glucose (Cont.) 5'-deoxy-4'-fluoro, 140, 175-176 3-deoxy-3-fluoro (Cont.) 2',3'-dideoxy-3'-fluoro, 174, 175 and glucose transport, 203-206, 207 diphosphate sugars, 138, 236, 238; see incorporation into glycogen, also Glycoproteins, asparagine-linked 222, 223 triphosphate, incorporation into RNA, metabolism, 210-211, 214-215 133-136 6-phosphate, metabolism, 209-210 and antitumor activity of 5-fluorouracil, 4-deoxy-4-fluoro 133-136, 139-140 metabolism, 210-211 and mRNA function, 134-135 6-phosphate, metabolism, 209-210 and rRNA structure and function, 134 I-phosphate, from glycogen, 194-196 and snRNA, relation to cytotoxicity, 135 Glutamic acid, 276-278, 294 and tRNA function, 136 decarboxylase, 276-278, 294-295 Folic acid, 131-133, 139-140 -y-aminobutyric acid synthesis by, in thymidylate synthesis cycle, 131-133 276-278, 294-295 Fructose irreversible inhibition, by halogenated I-deoxy-l-fluoro, 206-207 analogues, 290 3-deoxy-3-fluoro, 209-210, 211, 215 3-fluoro, biological properties, 4-deoxy-4-fluoro, 209-210 277-278 4-fluoro, biological properties, 277-278 Galactose (R,S)-a-fluoromethyl, 289, 290 6-deoxy-6-fluoro, incorporation into gly• Glutamine, 276-277 coproteins, 234 Glycine, 3-halovinyl 2-deoxy-2-haloacetamido, antitumor alanine racemase inhibition by, 288 activity, 229-232 incorporation into peptides, 288 Glucose Glycogen biological transport metabolism, 194-199 fluorinated hexoses, as substrates for, phosphorylase, 194-196 203-206, 207 complex with glucose, 194-196 mechanism, 203-206 and fluorodeoxy glucose analogues, 2-deoxy 194-196 e 4 C]-labelIed, in autoradiography, 212 Glycolytic pathway, 208 metabolism, 212 Glycoproteins, asparagine-linked, 224-236, I-deoxy-l-fluoro, as glycosidase 238 substrates, 200-201 biosynthesis, 224-225 2-deoxy-2-fluoro classification, 225 eSFJ-IabelIed, in positron emission 6-deoxy-6-fluoromannose, as substrate tomography, 212 for GlcNAc-P-transferase, 235 formation of GDP and UDP deriva• fluorinated pyrimidine-containing tives, 226-228 diphosphate sugars, and synthesis, and glucose transport, 203-206 236, 238 glycosides, as glucosidase inhibitors, inhibition of glycosylation, 200, 202-203 by bromoconduritol, 236 as inhibitor of protein glycosylation, by 9-deoxy-9-fluoro-N• 225-229 acetylneuroaminic acid, 232-233 metabolism, 212-214 by deoxyhalo sugars, 225-238 6-phosphate, metabolism, 210, 212-214 6-fluorofucose, an incorporated 3-deoxy-3-fluoro inhibitor, 233-234 [lsFJ-IabelIed, in positron emission to• by haloacetamido sugars, 229-232 mography, 215 by halogenated hexosamines, 232 358 Index

Glycoproteins, O-linked, 236 Histidine (Cont.) biosynthesis, inhibition by fluorinated 4-fluoro, 262, 273, 274, 306, 308-309 acetamidogalactoses, 236, 237 histidine ammonia lyase inhibition by, Glycosidases 273 I-deoxy-l-fluorohexoses as substrates for, incorporation into peptides, 196-201 308-309 inhibition, by 2-deoxy-2-fluorogylcosides, 2-iodo, 262, 306 200, 202-203 4-iodo, 262, 306 reaction mechanism, 196-200 metabolism, 273-274 2-trifluoromethyl, 309

Haloacetol phosphates, 218-229 as inhibitors of aldolase, 218-219 Inositol, fluorinated, 237, 238 as inhibitors of glycerol-3-phosphate de• Immunoglobulins hydrogenase, 219-220 biological function, 239 as inhibitors of triosephosphate isome• Iga J539, 239-242 rase, 220-221 deoxyfluorogalactosides, as binding Haloaldehydes as transition state analogs, probes, 239-242 50-51 /3(1-6)-D-galactopyrans, as antigens, Haloketones 239-240 as affinity labels, 46-50; see also Fluoro- model for binding sites, 241-242 ketones Iga W3129, 242-244 chymotrypsin inhibition by, 47 binding site, for dextran, 244 receptor labelling by, 45-50 deoxyfluoroglucopyanosides as binding and trypsin inhibition, mechanism, 49 probes, 243-244 as transition state analogues, 50-59; see structure, 239-240 also Fluoroketones as enzyme inhibi• Iodoacetic acid tors as carboxymethylating agent, 3-4 /3-Halomalic acids; see also Fluoromalic glyceraldehyde-3-phosphate dehydroge• acid nase inhibition by, 2-3 from halofumarates, 28 and lactate formation, 2 as substrates for and inhibitors of toxicity, 2-4 /3-methylaspartase, 29-30 5-Iodo-5' -amino-2' ,5' -dideoxyuridine, Haloperidol, 331-332 antiviral properties, Histamine 158-159 biological functions, 337-338 5-Iodo-2' -deoxycytidine, as radio sensitizer , a-fluoromethyl, 290 158 ring-halogenated analogues, 338-339 5-Iodo-2' -deoxyuridine Histidine antiviral activity, 151-153, 157 2-bromo, 262, 306 carbocyclic analogues, 159-160 4-bromo, 262-266 and cell function, IS3-lS4, 156-lS7 effect of halogenated analogues on history, ISO-lSI biosynthesis of, 262-263 [ 125Ij-S-iodo-2'-deoxyuridine, 158 2-fluoro, 262-263, 273-274, 302, 305-307 incorporation into DNA, 153-154 A TP :phosphoribosyltransferase inhibi• as radiosensitizer, 157-158 tion by, 263 teratogenicity, 156-157 histidine ammonia lyase inhibition by, 12-Iodo-cis-9-octadecenoic acid, as lipoxyge• 273 nase inhibitor, 123 incorporation into protein, 302, (E)-5-Iodovinyl-2' -deoxyuridine, antiviral 305-306, 307 activity, 160 Index 359

Isopentenyl pyrophosphate Mevalonic acid fluorinated analogues, 96-98 fluorinated analogues, 94-96 and prenyl transfer mechanism, 97-98 effects on cholesterol biosynthesis, structures, 96 94-96 as substrates and inhibitors of isopen• effects on juvenile hormone bio• tenyl pyrophosphate isomerase, synthesis, 94-96 96-97 structures, 95 role in terpene biosynthesis, 93-94 role in terpene biosynthesis, 93-94 Isoproterenol Monoamine oxidases (MAO A and MAO 2,6-dichloro, 328 B) ring-halogenated analogues, 324-326 biological functions, 340 inhibitors, irreversible, 342-345 brain-selective, 344-345 Leucine 2-substituted-3-haloallylamines, biosynthesis, 263-265 343-345 5,5,5-trifluoro, 263-265 inhibitors, reversible, 341-342 leucine biosynthesis inhibition by, 264 The "NIH Shift," 265-268 repression of Ile-V al biosynthesis by, N ocloprost, 110-111 264-265 Norepinephrine toxicity, 263 biological functions, 319-320 Leucovorin, 140 biosynthesis, 320 Leukotrienes, biosynthesis, 121-122 ring-fluorinated analogues, 324-327 Lysine Nucleocidin, 175, 176 as cadaverine precursor, 293-294 a-difluoromethyl, 293-294 Oligo(2' -deoxy-2' -haloribonucleotides in DNA biosynthesis, 165-167 Malate dehydrogenase, 17-19,28-29 Ornithine Malate synthase, 15 a-chloromethyl, 291, 292 Maltosyl fluorides, as substrates for a-cyanomethyl, 291, 292 {3-amylases, 197-200 decarboxylase, inhibition, 291-293 D-Mannose a,a-difluoromethyl (DFMO), 291-292 2-deoxy-2-fluoro- ornithine decarboxylase inhibition by, from 2-deoxy-2-fluoroglucose, 214 291-192 formation of GDP and UDP in trypanosomiasis treatment, 292 derivatives, 226 (R,S)-a-fluoromethyl, 289-290 inhibition of protein glycosylation by, (E)-fluoromethyldehydro, 292-293 226-228 in polyamine biosynthesis, 291 4-deoxy-4-fluoro- Orotate (pyrimidine) phosphoribosyl• formation of GDP derivative, 228 transferase, 129, 130 inhibition of protein glycosylation by, 228 Pepstatin, 53 Melatonin {3-Phenethylamines; see also Amphetamine; biological functions, 334-335 Methamphetamine ring-substituted analogues, 335-336 halogenated analogs, 322-323 2-iodo, as high affinity ligand, 336 Phenylalanine in pituitary LH response, 335 biosynthesis, 255-260 Methamphetamine, 322 by bacteria, effect of halogenated ana• 4-bromo, toxicity, 322 logues, 258-259 4-chloro, toxicity, 322 4-bromo, 266 360 Index

Phenylalanine (Cont.) Prostaglandins (Cont.) 3-chloro, 266 halogenated clavulones: see Punaglandins 4-chloro, 259, 266-268, 269 structure, 108 dechlorination, by phenylalanine hy• Protease inhibitors; see Fluoroketones as droxylase, 266-268 enzyme inhibition tryptophan hydroxylase inhibition by, Protein biosynthesis, 296-307 269 amino acid selectivity in, 296-298 tyrosine hydroxylase inhibition by, 269 haloamino acids as substrates for, 298-307 a,a-difluoromethyl-3 ,4-dihydroxy, 298 Punaglandins, 111-113 Phenylalanine biological properties, 111-113 3,4-dihydroxy (DOPA), 270-273 halogenated clavulones, 112-113 fluorinated analogues, in positron emis• structures, 112 sion tomography, 271-273 Pyridoxal phosphate-linked enzymes metabolism, 270-272 inactivation by /3-halogenated 2-fluoro, 254, 258-259, 267 amino acids and amines, 3-fluoro, 254, 258-259, 261, 267 278-295 4-fluoro, 254, 258-259, 261, 265-266, mechanism of action, 280-281 303, 308 defluorination, by phenylalanine hy• droxylase, 265-266 Radiohalogenated androgens, 77-78 incorporation into bacterial protein, as androgen receptor imaging agent, 303 77-78 incorporation into mammalian protein, structures, 78 303 Radiohalogenated estrogen analogues, in peptide total synthesis, 308 72-75 a-fluoromethyl-3 ,4-dihydroxy, 289-290 as estrogen receptor imaging agents, Phenylephrine, ring fluorinated, 325, 326 73-75 Phosphoenol 3-bromopyruvic acid, 27 18F-labeled estrogen receptor ligands, I-Phosphoribose pyrophosphate (PRPP), 73-75 129, 130 structures, 74, 75 Prazosin, 329 Radiohalogenated Progestins, 75-77, Prostacyclin (PGI,) 79-80 biological properties, 113 as affinity label for progesterone biosynthesis, 106, 113, 114 receptor, 79-80 halogenated analogues, 113-117 as progesterone receptor imaging agents, effects of fluorine on potency and 75-77 selectivity, 113-114 and estrogen receptor concentration, structures, 115, 116 75 Prostaglandins; see also Prostacyclin; structures, 76, 77, 79 Thromboxane Radioisotopes of the halogens, 71-72 biological properties, 105, 107, III Retinal, 88; see also Rhodopsin, fluorinated biosynthesis, 105, 106 analogues chlorinated and fluorinated analogues of fluorinated analogues, 89-90 PGE and POD, 109-111 fluorinated rhodopsin formation from, as anti-ulcer agents, 111 89 fluorinated POF2a and POE analogues, structures, 90 107-110 Retinoic acid, fluorinated analogues effects of fluorine on metabolic deacti• biological properties, 93 vation, 107 structures, 93 effects of fluorine on potency, 107-108 Rhodopsin, 88-89; see also Retinals, structures, 109, 110 fluorinated analogues Index 361

Rhodopsin (Cont.) Sucrose (Cont.) fluorinated analogues, 89-93 1'-deoxy-l'-fluoro (Cont.) effects of fluorine on photoisomeriza• enzymatic synthesis, 206-207 tion of, 89-93 as substrate for sucrose transporter, formation, from fluorinated retinals, 206-207 89 Sweetness of sugars, 244-246 and NMR studies of the biochemistry effect of halogenation, 245-246 of vision, 89 mechanisms, 244-246 Ribonucleotide reductases, 171-173 inhibition by 2'-deoxy-2'• haloribonucleotides, 172-173 Tetrahydrouridine reaction mechanism, 172-173 and enhancement of radiosensitization, 158 in 5-fluoro-2'-deoxycytridine chemother• Schnakerz adduct, 282-284 apy, 141-143 Serotonin in 5-trifluoro-2'-deoxcytidine chemo• biological functions, 332-333 therapy, 149-150 7-chloro, 332, 333 Thromboxane (TXA:z) depletion, by 4-chloroamphetamine, 322, biosynthesis, 105, 106, 114 336-337 10,IO-difluoro-TXAz, 118 1-(2,5-dimethoxy-4-bromophenyl)-2- structure and reactivity, 118 aminopropane (DOB), as antagonist, Thymidine kinase 334 2'-deoxy-2'-fluorocytidine as substrate for, ring-fluorinated, 332, 333-334 165 detection, by electron energy-loss in 5-fluoro-2'-deoxyuridine monophos• spectroscopy, 334 phate formation, 129-130, 141-142 and serotonin transport, 333 gene, amplification by Spiroperidol, 331 5-bromo-2'-deoxyuridine, 154-155 eSFJ-labelled, in positron emission inhibition, by tomography of dopamine receptors, 5'-amino-2',5'-dideoxythymidine, 346 158 Statine, as proteinase inhibitor structural inhibition, by 5-bromo-2'-deoxyuridine, unit, 53-56 152 Steroid hormones inhibition, by 5-iodo-2'-deoxyuridine, biological properties, 67 152 biosynthesis, 65-66 phosphorylation of 5-trifluoromethyl-2'• Steroid sex hormones, halogenated deoxyuridine by, 146, 148 analogues, 70-80; see also. phosphorylation of 5-iodo-5'-amino-2'5'• Radiohalogenated estrogen dideoxythymidine by, 159 analogues; Radiohalogenated pro• role in chemotherapy, 148, 152, 158-159, gestins; Radiohalogenated 160, 169-170 androgens. Thymidylate synthase cyproterone acetate, 70-71 and anti-tumor activity of 5-fluoro-2'• defluoronorgestrel, 70-71 deoxycytidine, 141 flutamide,70-71 and anti-tumor activity of 5-fluorouracil, fluoxymestrone, 70-71 130-133, 139-140 Sucrose 1-{3-D-Arabinofuransoyl-5-fluorouracil-5'• analogues, as substrates for sucrose phosphate as substrate for, transporter, 206-207 143-144 biological transport, 206 1-{3-D-Arabinofuransoyl-5'-phosphate as 1'-deoxy-l'-fluoro substrate for, 143 362 Index

Thymidylate synthase (Cont.) Tryptophan (Cont.) dehalogenation of 5-bromo- and 5-iodo- 6-fluoro, 260, 261, 270 2'-deoxyuridine monophosphate by, inhibition of tryptophan hydroxylase, 152-153 270 2'-Deoxy-2'-fluorouridine mono phosphate Tyramine, halogenated analogs, 323-324 as substrate for, 165 Tyrosine inhibition, by 1-,8-D-arabinofuranosyl-5- biosynthesis, 257-259 fluorouracil-5'-phosphate, 170 effect of halogenated analogues, 259 inhibition, by 5-fluoro-2'-deoxyuridine• 3-chloro, 259, 261, 266-268 monophosphate, 131-133, 139-140 from 4-chlorophenylalanine, inhibition, by 5-fluoro-2',3'-dideoxy-3'• 266-268 fluorouridine monophosphate, 2-fluoro, 267 175-176 3-fluoro, 259, 261, 267, 269-270, inhibition, by 5-trifluoromethyl-2'• 299-302 deoxyuridine monophosphate, 146, incorporation into bacterial protein, 147, 148 299-302 reaction mechanism, 131-133 metabolism, 269-270 5-Trifluoromethyl-2'-deoxycytidine toxicity, 267, 269-270 antitumor activity, 149-150 a-fluoromethyl, 289-290 as prodrug for 5-trifluoromethyl- formation of, from 2'-deoxyuridine, 149-150 4-fluorophenylalanine, 265 5-Trifluoromethyl-2'-deoxyuridine, 3-iodo, 259, 261 antitumor activity, 146-148 antiviral activity, 148 metabolism, 146 Urocanic acid, fluorinated, 274 monophosphate biosynthesis, 146 inhibition of thymidylate synthase by, Valine, ),,),,),,),,),,),-hexafluoro, in peptides, 146, 147, 148 308 triphosphate Vitamin D3 DNA polymerase inhibition by, 148-150 biosynthesis, 82, 83 incorporation into DNA, 148-150 biological properties, 82-88 S-Trifluoromethylhomocysteine, biological Vitamin D3, fluorinated analogues, 82-84, properties, 275 88 Trimetoquinol, fluorinated analogues, as more potent vitamin D3 agonists, 327-328 85-87 Tryptophan by inhibition of metabolism, 86-87 biosynthesis, 257, 259-262 by introduction of trans-fluorohydrin effect of halogenated analogues on, into structure, 86 259-262 structures, 85, 86, 87 2,3-dihydro-5-fluoro, 262 as potential vitamin D3 antagonists, 4-fluoro, incorporation into bacterial pro• 82-84, 88 tein, 300-302 effects of fluorine on hydroxylative 5-fluoro, 260-262, 270, 301-302 activation of vitamin D3, 82-85 incorporation into bacterial protein, effects of fluorine on receptor binding, 301-302 88 inhibition of tryptophan hydroxylase, structures, 84, 88 270 metabolism, 270 as substrate for tryptophan synthase, ,8-D-Xylopyranosyl fluoride, as substrate 261-262 for ,8-xylosidase, 200-201