NO147953B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive antracyklinglukosider - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive antracyklinglukosider Download PDFInfo
- Publication number
- NO147953B NO147953B NO78781949A NO781949A NO147953B NO 147953 B NO147953 B NO 147953B NO 78781949 A NO78781949 A NO 78781949A NO 781949 A NO781949 A NO 781949A NO 147953 B NO147953 B NO 147953B
- Authority
- NO
- Norway
- Prior art keywords
- antibiotics
- acid
- preparation
- therapeutically active
- glososides
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 16
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 229930182470 glycoside Natural products 0.000 claims description 6
- 150000002338 glycosides Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 description 19
- 229940088710 antibiotic agent Drugs 0.000 description 17
- DNZPQXXGAMXDHH-FCNQEGBTSA-N aclacinomycin S zwitterion Chemical compound O([C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 DNZPQXXGAMXDHH-FCNQEGBTSA-N 0.000 description 13
- PXKJRTZJMGPOGS-YBVXKORNSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1[C@H](C[C@@H](OC1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 PXKJRTZJMGPOGS-YBVXKORNSA-N 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PITHJRRCEANNKJ-UHFFFAOYSA-N Aclacinomycin A Natural products C12=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 PITHJRRCEANNKJ-UHFFFAOYSA-N 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 6
- 229960004176 aclarubicin Drugs 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 241000192125 Firmicutes Species 0.000 description 5
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 5
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- STUJMJDONFVTGM-UHFFFAOYSA-N cinerubine A Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 STUJMJDONFVTGM-UHFFFAOYSA-N 0.000 description 4
- STUJMJDONFVTGM-CEPMKHARSA-N methyl (1r,2r,4s)-4-[4-(dimethylamino)-5-[4-hydroxy-6-methyl-5-(6-methyl-5-oxooxan-2-yl)oxyoxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)C(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 STUJMJDONFVTGM-CEPMKHARSA-N 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical group N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 4
- MDUVOMDREZPQPI-UHFFFAOYSA-N Aklavinone Natural products CCC1(O)CC(O)c2c(O)c3C(=O)C4C(C=CC=C4O)C(=O)c3cc2C1C(=O)OC MDUVOMDREZPQPI-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000006819 RNA synthesis Effects 0.000 description 3
- WGXOAYYFWFRVSV-UHFFFAOYSA-N Rhodirubin A Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(O)C(C)O1 WGXOAYYFWFRVSV-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- CPUWOKRFRYWIHK-YAPFQWMQSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-4-(dimethylamino)-5-[(2s,4s,5s,6s)-4-hydroxy-5-[(2s,5r,6s)-5-hydroxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7-trihydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CC[C@@H](O)[C@H](C)O1 CPUWOKRFRYWIHK-YAPFQWMQSA-N 0.000 description 3
- WGXOAYYFWFRVSV-JEGHDPRDSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-4-(dimethylamino)-5-[(2s,4s,5s,6s)-4-hydroxy-5-[(2s,5s,6s)-5-hydroxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CC[C@H](O)[C@H](C)O1 WGXOAYYFWFRVSV-JEGHDPRDSA-N 0.000 description 3
- STUJMJDONFVTGM-CWMGJFPWSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-4-(dimethylamino)-5-[(2s,4s,5s,6s)-4-hydroxy-6-methyl-5-[(2r,6r)-6-methyl-5-oxooxan-2-yl]oxyoxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@@H](C)O1 STUJMJDONFVTGM-CWMGJFPWSA-N 0.000 description 3
- DEGUCPPGAZTULS-UHFFFAOYSA-N methyl 4-[5-[5-(4,5-dihydroxy-6-methyloxan-2-yl)oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7-trihydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 DEGUCPPGAZTULS-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JWFRNGYBHLBCMB-HCWXCVPCSA-N (3s,4r,5s)-3,4,5-trihydroxyhexanal Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)CC=O JWFRNGYBHLBCMB-HCWXCVPCSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- FDWRIIDFYSUTDP-UHFFFAOYSA-N 102850-49-7 Natural products CC1OC(O)CC(O)C1O FDWRIIDFYSUTDP-UHFFFAOYSA-N 0.000 description 2
- WMUYJHSRMOORHK-BIIVOSGPSA-N C[C@H](O)[C@@H](O)[C@@H](N(C)C)CC=O Chemical compound C[C@H](O)[C@@H](O)[C@@H](N(C)C)CC=O WMUYJHSRMOORHK-BIIVOSGPSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZJBMQVPEJHVSQA-OCYVVMCSSA-N Pyrromycin Chemical compound O([C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 ZJBMQVPEJHVSQA-OCYVVMCSSA-N 0.000 description 2
- ZJBMQVPEJHVSQA-UHFFFAOYSA-N Rutilantin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC1CC(N(C)C)C(O)C(C)O1 ZJBMQVPEJHVSQA-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RACGRCLGVYXIAO-YOKWENHESA-N aklavinone Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RACGRCLGVYXIAO-YOKWENHESA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- WGXOAYYFWFRVSV-CNXUHMGHSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-4-(dimethylamino)-5-[(2s,4s,5s,6s)-4-hydroxy-5-[(2s,5r,6s)-5-hydroxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylate Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CC[C@@H](O)[C@H](C)O1 WGXOAYYFWFRVSV-CNXUHMGHSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- HJEZFVLKJYFNQW-PRFXOSGESA-N (13S)-13-dihydrodaunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)[C@H](C)O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 HJEZFVLKJYFNQW-PRFXOSGESA-N 0.000 description 1
- HWMJTJZEJBSVCG-GPDBLRFJSA-N (2s,3s,4r)-4-[(2s,3r,4r,5r,6s)-4,5-dihydroxy-3-methoxy-6-methyloxan-2-yl]oxy-2,5,7-trihydroxy-3,9-dimethoxy-2-methyl-3,4-dihydrotetracene-1,6,11-trione Chemical compound CO[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C(OC)C=C3C3=O)=C3C=C2C(=O)[C@@](C)(O)[C@H]1OC HWMJTJZEJBSVCG-GPDBLRFJSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- SMNNBONTPYNICF-UHFFFAOYSA-N Aclacinomycin B Natural products CCC1(O)CC(OC2CC(C(OC3CC(O)C(OC4CCC(=O)CO4)C(C)O3)C(C)O2)N(C)C)c5c(O)c6C(=O)c7ccccc7C(=O)c6cc5C1C(=O)OC SMNNBONTPYNICF-UHFFFAOYSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- LJZPVWKMAYDYAS-UHFFFAOYSA-N Aklavine Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC1CC(N(C)C)C(O)C(C)O1 LJZPVWKMAYDYAS-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZBDDFHXUDIPRSM-UHFFFAOYSA-N Cinerubin-B Natural products O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(O)=C1C(OC3OC(C)C(OC4OC(C)C5OC6OC(C)C(=O)CC6OC5C4)C(C3)N(C)C)CC(CC)(O)C(C(=O)OC)C1=C2 ZBDDFHXUDIPRSM-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- XXIHHRIZGBRENI-WDSKDSINSA-N L-rhodinose Chemical compound C[C@H](O)[C@@H](O)CCC=O XXIHHRIZGBRENI-WDSKDSINSA-N 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- -1 MA144-j Gl Chemical compound 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VHJWDTPKSIFZBV-UHFFFAOYSA-N Steffimycin Natural products COC1C(O)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C(OC)C=C3C3=O)=C3C=C2C(=O)C(C)(O)C1OC VHJWDTPKSIFZBV-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- LJZPVWKMAYDYAS-QKKPTTNWSA-N aclacinomycin T Chemical compound O([C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 LJZPVWKMAYDYAS-QKKPTTNWSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229950000950 daunorubicinol Drugs 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- ZBDDFHXUDIPRSM-DQCCILMQSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1 Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 ZBDDFHXUDIPRSM-DQCCILMQSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RQHZAASWYUEYCJ-JVWHUAOPSA-N siwenmycin Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-JVWHUAOPSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229950008413 steffimycin Drugs 0.000 description 1
- HUVMFXSDLOUNSJ-UHFFFAOYSA-N steffimycin Natural products COC1C(O)C(O)C(C)OC1OC2C(OC)C(C)(O)C(=O)c3cc4C(=O)c5cc(OC)ccc5C(=O)c4c(O)c23 HUVMFXSDLOUNSJ-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/56—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical directly bound to a condensed ring system having three or more carbocyclic rings, e.g. daunomycin, adriamycin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/465—Streptomyces
- C12R2001/48—Streptomyces antibioticus ; Actinomyces antibioticus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/886—Streptomyces
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/886—Streptomyces
- Y10S435/888—Streptomyces antibioticus
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte
ved fremstilling av nye terapeutisk aktive antracyklinglukosider med den generelle formel II som angitt i kravets ingress.
Forskjellige typer antracyklinglykosider er blitt funnet i vekstmedia for mikroorganismer, hvilket er beskrevet i litteraturen. Blant disse har daunomycin og adriamycin allerede funnet klinisk anvendelse ved behandling av kreft hos mennes-ker, og aclacinomycin A, carminomycin og rubidazone er under klinisk utprøvning og har vakt stor interesse innen feltet kreft-kjemoterapi.
Ved undersøkelse av kulturer av streptomyces med hensyn til metabolitter med antitumor-aktivitet er det funnet nye forbindelser, og etter rensning og karakterisering basert på
deres fysiokjemiske egenskaper er'det nå underbygget at de nye antibiotika som er betegnet MA 144-S1 og -S2 er nye forbindelser med potent antitumor-aktivitet og som utviser lav toksisitet.
Fremstilling av adriamycin ved kultivering av S. neuceticus
var caesius er vist i US-patent nr. 3.590.028. Kjemisk omdannelse av daunomycin til adriamycin er vist i US patent nr. 3.803.124.
Daunomycin (fremstilt ved dyrkning av S. peuceticus i U.K. 1.003.383) kan være den samme som Rhone-Poulenc<1>s 13.057 R.P.
(tidligere betegnet med rubidomycin og nå betegnet med daunori-bicin, (se de engelske patenter nr. 985.598, 1.188.262 og 1.241.750 og US-patent nr. 3.616.242) og er sannsynligvis identisk med Ciba's danubomycin som er vist i US-patent nr. 3.092.550 og UK-patent nr. 901.830. Se også US-patent nr. 3.686.163 vedrørende dihydrodaunomycin.
Antracyklin-antibiotika inneholdende aklavinon-aglykongrupper er åpenbart i (a) aclacinomycin A og B i US patent nr. 3.988.315 og Oki'et
al. i J, Antibiotics 28: 830 (1975).
(b) Aklavin i J. Bacteriol. 72:90 (1956).
Antracyklin-antibiotika med £-pyrromycinon-aglykongrupper er beskrevet i litteraturen som følger: (c) musettamycin og marcellomycin fra bohem-syrekompleks i
J, Antibiotics 30:525 (1977).
(d) pyrromycin i Chem.Ber. 92:1904 (1959)
(e) cinerubin A og B i UK 846.130 (se også US patent nr.
3.864.480 og Keller-Schierlein et al, Antimicrobial Agents and Chemotherapy, side 68 (1970).
Andre antracyklin-antibiotika med aglykongrupper forskjellige fra aklavinon og E-pyrromycinon er beskrevet x
f) Nogalamycin i J.Amer.Chem. Soc.99:542 (1977)
g) Steffimycin i J. Antibiotics 27:805,809 (1974).
h) Carminomycin i J. Antibiotics 27:254 (1974)i vesttysk
patent nr. 2.362.707 og i J.Amer. Chem.Soc. 97:5955 (1975).
i) Trypanomycin i Antimicrobial Agents and Chemotherapy 1:385
(1972).
j) Requinomycin i J. Antibiotics 25:393 (1972).
k) Galirubin A og B i Naturwiss. 52:539 (1965) og Chem.
Abst. 67 : 90573z (1967) .
For ytterligere opplysninger og sammendrag vedrørende antra-cyklinantibiotika, se Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-Chief, University Park Press, State College", Pennsylvania, USA (1967) som følger:
I boken Antibiotics, bind I, Mechanism of Action, redigert
av David Gottlieb og Paul D. Shaw, Springer-Verlag New York Inc., N.Y., N.Y (1967) er det på sidene 190-210 gitt en oversikt av A. DiMarco under overskriften Daunomycin and Related Antibiotics. Information Bulletin, Nr. 10, Interna-tional Center of Information of Antibiotics, i samarbeide med WHO, desember 1972, Belgia, gir en oversikt over antracykliner og deres derivater.
Foreliggende oppfinnelse vedrører fremstilling av nye antracyklin-glykosidantibiotika. Disse antibiotika er nyttige ved behandling av bakterieinfeksjoner og for inhibering av tumorer hos pattedyr. Mere spesielt vedrører oppfinnelsen fremstilling av nye antracyklinglykosid-antibiotika, betegnet MA144, -Sl og -S2. De nye forbindelsene fremstilles ved sur hydrolyse av forbindelsen med den generelle formel III, angitt i kravets karakteriserende del. Fremstilling av forbindelsene med formel III er vist i norsk patentsøknad 77.3353. Disse antibiotika fremstilles fra utgangsmaterialer erholdt ved dyrkning av MA144-produserende stammer av streptomyces eller ved kjemisk eller enzymatisk omdannelse av aclacinomycin A eller cinerubin A eller MA144-M2 eller MA144-M1 eller MA144-N1 eller rhodirubin A, MA144-Y, MA144-G1, MA144-G2, MA144-U1, MA144-U2 eller materialer som inneholder disse.
Oppfinnelsen tilveiebringer således de følgende antibiotika med antitumor-virkning, nemlig MA144, -Sl og -S2 som
a) utviser antimikrobiell aktivitet mot grampositive bakterier , b) er effektive ved inhibering av vekst av ondartede svulster hos pattedyr, og c) utviser høy cytotoksisitet og således inhiberer vekst og dannelse av RNA i pattedyr-tumorceller i kultur.
Fysio-kjemiske egenskaper for disse MA144 komponenter er som følger: MA14 4- S1 kan isoleres som et gult amorft pulver med et
smeltepunkt i området 144-147°C og er optisk aktivt med [cx] ^ + 77° (c=I .O.CHCl^; og er svakt basisk antracyklinglykosid, 2-deoksy-L-fukosyl-L-rhodosaminyl-aklavinon med den empiriske formel C-, ,H . _0. -.N.
^ 36 45 13 MA144- S2 kan isoleres som et rødt amorft pulver med et smel
tepunkt i området 154-158°C, og er svakt basisk antracyklinglykosid, 2-deoksy-L-f ukosyl-L-rhodo saminy 1-6--pyr romycinon, med den empiriske formel <C>^<gH>^^<O>^^<N>. Fig. 1 viser infrarødt absorpsjonsspektrum for MA144-S1 i kaliumbromid. Fig. 2 viser infrarødt absorpsjonsspektrum for MA144-S2 i kaliumbromid.
Foreliggende oppfinnelse tilveiebringer to nye antracyklin-antibiotika; MAI44 -Sl og -S2 som er funnet å utvise anti-bakteriell og antitumor aktivitet. Mere spesielt utviser forbindelsene i henhold til oppfinnelsen aktivitet mot gram-positive bakterier, inhiberer veksten av forskjellige patte-dyrtumorer såsom L1210 og P 388 leukemi hos mus samt utviser lav toksisitet.
Følgelig er forbindelsene ifølge oppfinnelsen nyttige som antibakterielle og antitumor-midler. Som brukt i det etter-følgende betegner MA14 4 bestanddeler et antibiotikum omfat-tende minst én av MA144-S1 eller -S2.
I henhold til fremgangsmåten omdannes forbindelsene fremstilt i henhold til norsk søknad nr. 77.3353, nemlig aclacinomycin A, cinerubin A rhodirubin A, MA144-M1, MA144-M2, MA144-NJ., MA144-G1, MA144-G2, MA144-U1, MA144-U2, MA144-Y eller blan- . dinger av disse, kjemisk til MA144-S1, -S, -NI eller bland-inger derav. Utgangsmaterialene kan anvendes i ren form, som et salt eller i uren form, dvs. en form hvor materialene som inneholder antracyklinbestanddelene er et fermenteringsmedium eller et råekstrakt fra et slikt medium.
Den kjemiske omdannelse kan lettere sees fra det følgende reaksjonsskjerna:
I i Dvs. at MA144-S1 og -S2 kan fremstilles ved sur hydrolyse av ! aclacinomycin A (japansk patentsøknad Sho 51-15690), MA1&i4-Ml (japansk patentsøknad Sho 51-39688) , MA144-N1, MA144+-M2 (japansk patentsøknad Sho 51-39688), cinerubin A, MA144- j Gl, MA144-U1, MA144-U2, MA144-Y eller rhodirubin A (japansk i patentsøknad Sho 51-98113). 1 ;
i
Fysiokjemiske egenskaper for MA144 komponenter j
De fysiokjemiske egenskapene for MA144-S1 og -S2 er som følger:
Strukturen av MA144-S1 og -S2 fremstilt i henhold til oppfinnelsen ble bestemt på følgende måte: Ved sur hydrolyse med 0,1N saltstyre i 30 min. ved 85°C ; stemte de fysiokjemiske egenskaper, så som absorpsjonsspek-tra for ultraviolett, synlig og infrarøde områder, masse-og kjernemagnetisk resonans, smeltepunkt, elementæranalyse og Rf-verdier for silika-gel-tynnsjikt av aglycon-delen erholdt fra MA14 4-SL fullstendig med de for aklavinon
(Tetrahedron Lett. nr. 8, 28-34, 1960), og de erholdt fra aglycon-delen erholdt fra MA144-G2, -S2 og -U2 fullstendig med de for £-pyrromycinon (Chem.Ber. 92, 1880-1903, 1959). På den annen side ble sukkerenhetene som eksisterte i den
vannoppløslige fraksjon av de ovenfor nevnte hydrolysater bestemt ved silikagel-tynnsjikt-kromatografi (Merck Co. "60F2^^" silikagelplate, n-butanol:eddiksyre:vann = 4:1:1) ved å sammenligne deres Rf-verdier, etternøytralisering og konsentrasjon, med de for autentiske sukre, erholdt fra åklacinomycin A (J.Antibiotics, 28, 830-834, 1975) og streptolydizin (J. Amer. Chem. Soc. 86, 3592-3594, 1972):.
i I
Rf-verdier for sukkerenhetene erholdt fra MA144 komponentene er vist i den etterfølgende tabell, og det finnes 2 typer sukre i MA144-S1 og -S2.
Fra en sammenligning med R^-verdier, forskjellige fargereak-
i sjoner og optisk rotasjon for autentiske sukre, ble en sukker-enhet tilsvarende R^ = 0,16 identifisert som L-rhodosamin,
Rf = 0,60 var 2-deoksy-L-fukose, Rf = 0,7 2 var L-rhodinose og R^ = 83 var L-cinerulose, mens sukrene med R^ = 0,20 og
0,78 var ukjente.
■ ,. /
I I
MA144-S1 og -S2 inneholder to typer sukkerenheter, nemlig : L-rhodosamin og 2-deoksy-L-fukose. Metyl-2-deoksy-L-fukof i sid og 1-deoksypyrromycin eller pyrromycin ble dannet vek metanolyse og følgelig ble den følgende struktur for 2-deoksy-L-fukosyl-L-rhodosaminyl-aklavinon eller £-pyrromycinon på- | vist for MA144-S1 og -S2. j
i ;
Antimikrobiell aktivitet for MA144 bestanddelene ' i<j>
i
MA 144-Sl og -S2 utviser antimikrobiell aktivitet overfor forskjellige typer mikroorganismer. Den minimale inhiberende konsentrasjon av det foreliggende antibiotika ble bestemt vedi ! buljongfortynningsmetoden og er vist i den etterfølgende! tabell: Som vist foran utviser MA144 komponentene ifølge oppfinnelsen antimikrobiell aktivitet, spesielt mot gram-positive bakterier, og de er derfor terapeutisk nyttige ved behandling av difteri, tuberkulose, lungebetennelse, tetanus og andre infeksjonssykdommer forårsaket av gram-positive bakterier .
Antitumor aktivitet og akutt toksisitet for MA144 bestanddelene
MA144 komponentene fremstilt ifølge oppfinnelsen utviser mar-kert antitumor-aktivitet og lav toksisitet i eksperimentelle dyreforsøk og er således terapeutisk nyttige ved inhibering av vekst av pattedyrstumorer. Spesielt viste forbindelser ifølge oppfinnelsen er markant inhiberende effekt mot muse-leukemi L1210. F.eks. ble BDF^ med vekt 19-22 g inokulert' introperitonealt med 1 x 10^ L1210 celler/mus og 24 h etter onokulering ble forbindelsen fremstilt i henhold til oppfinnelsen injisert intraperitonealt én gang daglig i 9 på hver-andre følgende dager. På den 30. dag ble den prosentvise for-lengelse av overlevelsestiden i forhold til kontrollmus og fremgår av den etterfølgende tabell sammen med de respektive LDj-Q-verdier for en enkelt intraperitoneal injeksjon i mus.
Forbindelsene fremstilt ifølge foreliggende oppfinnelse inhiberer vekst pattedyrtumorceller i en kultur, spesielt ved lav konsentrasjon, og inhiberer fullstendig RNA syntese.
Ved dette forsøk ble L1210 celler inokulert i RPMI 1640 medium (Nissui, Rosewell Park Memorial Institute 1640) inneholdende 20% kalveserum og kultivert ved 37°C i 3 døgn i en CC^inkubator. På den første dag ble forbindelsen ifølge foreliggende oppfinnelse tilsatt i en konsentrasjon på 0,1 yug/ml.
14
I forsøket hvor C ble innarbeidet, ble forbindelsene ifølge oppfinnelsen tilsatt ved en konsentrasjon på 0,5 pg/ml for RNA syntese og 0,1 jug/ml for DNA syntese, og ytterligere ble
14 o
C -thymidin eller -uridin tilsatt mediet i 60 min. ved 37 C. Effektene på vekst og syntese av DNA og RNA ble indikert som prosent inhibering i forhold til kontroll i den etterfølgende tabell. Fra resultatene fremgår det at MAI44 komponentene markant inhiberer veksten og RNA syntesen for kultiverte L1210 celler ved lav konsentrasjon. Disse resultater under-støttes av den terapeutiske effektivitet på eksperimentelle tumorer hos dyr.
Effekt av- MA 144-S1 og -S2 på vekst og makromolekylær syntese i kultiverte L1210 celler.
Terapeutisk anvendelse av
MA144 komponenter
Som ovenfor er MA144-S1 og -S2 nye antibiotika som er nyttige både som human og veterinær medisin, og som ytterligere utviser en markant inhiberende virkning mot ondartede tumorer hos dyr og mot gram-positive bakterier.
Forbindelsene fremstilt i henhold til foreliggende oppfinnelse danner ikke-toksiske syreaddisjonssalter med et antall or-ganiske og uorganiske saltdannende forbindelser og danner ikke-toksiske komplekser med deoksyribonukleinsyre. Således kan syreaddisjonssalter dannet med slike farmasøytisk aksep-terbare syrer, som svovelsyre, fosforsyre, saltsyre, eddik-syre, propionsyre, oleinsyre, palmitinsyre, sitronsyre, rav-syre, vinsyre, glutaminsyre, pantotensyre etc.
EKSEMPEL
400 g MA144-M1 erholdt i henhold til eksempel 7 i norsk søknad 77.3353 ble oppløst i 100 ml 0,5%ig saltsyre og hydro-lysert ved 20°C i 15 min. Etter nøytralisering med fortynnet alkali til pH 7,0 ble MA144-S1 ekstrahert 2 ganger med 200 ml kloroform og kloroformlagene slått sammen og inndam-pet under nedsatt trykk. Aktive fraksjoner inneholdende MA144-S1 som ble erholdt under kolonnnekromatografi over silikagel (3 x 25 cm kolonne) under anvendelse av metanol-toluenblandingen (5 : 100) ble slått sammen, konsentrert og satt til n-heksan. Det ble erholdt 237 mg gult pulver av MA144-S1.
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktive antracyklin- glyko'sider med den generelle formel IIeller ikke toksisk syreaddisjonssalt derav, hvorier hydrogen eller en hydroksylgruppe, karakterisert ved at en forbindelse av den generelle formel IIIivori R^ har den ovenfor angitte betydning og R^ er hydrolyseres med en mineralsyre.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12023776A JPS5344555A (en) | 1976-10-05 | 1976-10-05 | Anthracyclin.glycoside antibiotics |
| JP6090877A JPS5463067A (en) | 1977-05-24 | 1977-05-24 | Oncostatic drugs and their preparation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO781949L NO781949L (no) | 1978-04-06 |
| NO147953B true NO147953B (no) | 1983-04-05 |
| NO147953C NO147953C (no) | 1983-07-20 |
Family
ID=26401967
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO773353A NO148959C (no) | 1976-10-05 | 1977-09-30 | Fremgangsmaate ved fremstilling av tumor-motvirkende antracyklinglykosidantibiotika, betegnet ma 144 |
| NO78781949A NO147953C (no) | 1976-10-05 | 1978-06-05 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive antracyklinglukosider |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO773353A NO148959C (no) | 1976-10-05 | 1977-09-30 | Fremgangsmaate ved fremstilling av tumor-motvirkende antracyklinglykosidantibiotika, betegnet ma 144 |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US4207313A (no) |
| AU (1) | AU505971B2 (no) |
| CA (1) | CA1100895A (no) |
| CH (1) | CH637160A5 (no) |
| DE (1) | DE2743654B2 (no) |
| DK (1) | DK145200C (no) |
| ES (1) | ES471823A1 (no) |
| FI (1) | FI57444C (no) |
| FR (1) | FR2403350A1 (no) |
| GB (1) | GB1589536A (no) |
| GR (1) | GR63996B (no) |
| HU (1) | HU181999B (no) |
| IE (1) | IE46236B1 (no) |
| LU (1) | LU78242A1 (no) |
| NL (1) | NL176004C (no) |
| NO (2) | NO148959C (no) |
| SE (1) | SE425798B (no) |
| YU (1) | YU40483B (no) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4123608A (en) * | 1977-07-18 | 1978-10-31 | Bristol-Myers Company | Antibiotic compound |
| JPS5543012A (en) * | 1978-09-20 | 1980-03-26 | Sanraku Inc | Novel anthracycline derivatine and its preparation |
| JPS6023679B2 (ja) * | 1979-07-13 | 1985-06-08 | メルシャン株式会社 | ロドマイシン群抗生物質とその製造法 |
| EP0030255B1 (en) * | 1979-09-07 | 1986-01-29 | Sanraku Incorporated | 2-hydroxyaclacinomycin a, pharmaceutical composition containing it; 2-hydroxyaclavinone and fermentative process for preparing same |
| JPS5648893A (en) * | 1979-09-07 | 1981-05-02 | Sanraku Inc | Preparation of anthracycline glycoside |
| CH648327A5 (de) * | 1980-10-16 | 1985-03-15 | Hoffmann La Roche | Anthracycline. |
| JPS5874694A (ja) * | 1981-10-29 | 1983-05-06 | Sanraku Inc | アントラサイクリン誘導体 |
| JPS5995891A (ja) * | 1982-11-26 | 1984-06-02 | Kitasato Inst:The | 新規な制癌性抗生物質８０−２１７およびその製造法 |
| JPS61236792A (ja) * | 1985-04-12 | 1986-10-22 | Sanraku Inc | 新規アントラサイクリン抗生物質 |
| DE3524117A1 (de) * | 1985-07-05 | 1987-02-05 | Hoechst Ag | Neue anthracyclin-tetrasaccharide, ein verfahren zu ihrer herstellung und ihre verwendung als cytostatik |
| DE3641833A1 (de) * | 1986-12-08 | 1988-06-09 | Behringwerke Ag | Zytostatisch wirksame anthracyclinderivate |
| US4977084A (en) * | 1989-02-16 | 1990-12-11 | Board Of Trustees Operating Michigan State University | Production, isolation, and identification of novel antifungal compounds |
| US5013549A (en) * | 1989-02-16 | 1991-05-07 | Board Of Trustees Operating Michigan State University | Production, isolation, and identification of novel antifungal compounds |
| US5066585A (en) * | 1990-07-09 | 1991-11-19 | Board Of Trustees Operating Michigan State University | Method of inhibiting fungus using novel antifungal compounds |
| KR970000591B1 (ko) * | 1993-09-03 | 1997-01-14 | 동국제약 주식회사 | 신균주 스트렙토마이세스 라벤도폴리아 DKRS 및 이를 이용한 아클라시노마이신 A, B, Y 및 아글리콘(Aglycone)의 제조방법 |
| US6589591B1 (en) * | 2001-07-10 | 2003-07-08 | Baylor College Of Medicine | Method for treating medical devices using glycerol and an antimicrobial agent |
| US20040256561A1 (en) * | 2003-06-17 | 2004-12-23 | Allyson Beuhler | Wide band light sensing pixel array |
| TW200510719A (en) * | 2003-08-06 | 2005-03-16 | Pharmacia Italia Spa | Method for detecting contaminants in pharmaceutical products |
| US7238363B2 (en) * | 2004-04-02 | 2007-07-03 | Baylor College Of Medicine | Modification of medical prostheses |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB846130A (en) | 1956-03-23 | 1960-08-24 | Ciba Ltd | New antibiotic and derivatives and salts thereof, preparations containing the same and process for the manufacture of these substances |
| US3092550A (en) * | 1957-10-29 | 1963-06-04 | Ciba Geigy Corp | Antibiotic danubomycin and process for its manufacture |
| CH362490A (de) | 1957-10-29 | 1962-06-15 | Ciba Geigy | Verfahren zur Herstellung eines neuen Antibiotikums |
| FR1533151A (fr) | 1962-05-18 | 1968-07-19 | Rhone Poulenc Sa | Nouvel antibiotique et sa préparation |
| FR1527892A (fr) | 1967-03-15 | 1968-06-07 | Rhone Poulenc Sa | Nouveau procédé de préparation de l'antibiotique 13057 r.p. |
| YU33730B (en) * | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
| US3803124A (en) * | 1968-04-12 | 1974-04-09 | Farmaceutici It Soc | Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives |
| US3686163A (en) * | 1968-05-14 | 1972-08-22 | Farmaceutici Italia | Dihydrodaunomycin antibiotic and derivatives thereof |
| FR1593235A (no) | 1968-11-18 | 1970-05-25 | ||
| US3616624A (en) * | 1969-11-04 | 1971-11-02 | Becton Dickinson Co | Laminar flow work bench |
| US3828021A (en) * | 1972-06-14 | 1974-08-06 | Merck & Co Inc | Gentamicin c1 derivatives |
| GB1440626A (no) * | 1973-05-02 | 1976-06-23 | Farmaceutici Italia | |
| GB1426637A (en) | 1973-12-04 | 1976-03-03 | Vnii Izyskaniju Novykh Antibio | Manthracyclic antibiotic and a method of production thereof |
| US3864480A (en) * | 1974-05-06 | 1975-02-04 | Merck & Co Inc | Cinerubin A and B As Antiparasitic Agents |
| JPS5134915B2 (no) * | 1974-07-27 | 1976-09-29 | ||
| US4009328A (en) * | 1975-05-02 | 1977-02-22 | Schering Corporation | Aminoglycoside 66-40C, method for its manufacture, method for its use as an intermediate in the preparation of known antibiotics and novel antibacterials |
| JPS5231051A (en) * | 1975-09-03 | 1977-03-09 | Kowa Co | Preparation of amino sugar derivatives |
| US4039736A (en) * | 1976-04-15 | 1977-08-02 | Bristol-Myers Company | Antibiotic compounds marcellomycin and musettamycin |
-
1977
- 1977-09-22 NL NLAANVRAGE7710380,A patent/NL176004C/xx not_active IP Right Cessation
- 1977-09-22 CH CH1159577A patent/CH637160A5/fr not_active IP Right Cessation
- 1977-09-28 DE DE2743654A patent/DE2743654B2/de active Granted
- 1977-09-30 DK DK435577A patent/DK145200C/da not_active IP Right Cessation
- 1977-09-30 IE IE2007/77A patent/IE46236B1/en unknown
- 1977-09-30 HU HU77ZA402A patent/HU181999B/hu not_active IP Right Cessation
- 1977-09-30 SE SE7710972A patent/SE425798B/xx not_active IP Right Cessation
- 1977-09-30 CA CA287,886A patent/CA1100895A/en not_active Expired
- 1977-09-30 FR FR7729595A patent/FR2403350A1/fr active Granted
- 1977-09-30 NO NO773353A patent/NO148959C/no unknown
- 1977-10-03 GB GB41047/77A patent/GB1589536A/en not_active Expired
- 1977-10-03 GR GR54487A patent/GR63996B/el unknown
- 1977-10-03 FI FI772915A patent/FI57444C/fi not_active IP Right Cessation
- 1977-10-03 YU YU2352/77A patent/YU40483B/xx unknown
- 1977-10-03 US US05/838,617 patent/US4207313A/en not_active Expired - Lifetime
- 1977-10-04 AU AU29337/77A patent/AU505971B2/en not_active Expired
- 1977-10-04 LU LU78242A patent/LU78242A1/xx unknown
-
1978
- 1978-06-05 NO NO78781949A patent/NO147953C/no unknown
- 1978-07-17 ES ES471823A patent/ES471823A1/es not_active Expired
-
1979
- 1979-05-10 US US06/037,804 patent/US4245045A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| NO781949L (no) | 1978-04-06 |
| CH637160A5 (fr) | 1983-07-15 |
| US4245045A (en) | 1981-01-13 |
| FR2403350B1 (no) | 1981-04-30 |
| NO147953C (no) | 1983-07-20 |
| IE46236L (en) | 1978-04-05 |
| FI772915A (fi) | 1978-04-06 |
| NL176004C (nl) | 1985-02-01 |
| DE2743654B2 (de) | 1979-12-13 |
| AU505971B2 (en) | 1979-12-06 |
| NL176004B (nl) | 1984-09-03 |
| GB1589536A (en) | 1981-05-13 |
| YU235277A (en) | 1982-06-30 |
| LU78242A1 (no) | 1978-01-26 |
| CA1100895A (en) | 1981-05-12 |
| ES471823A1 (es) | 1979-02-01 |
| AU2933777A (en) | 1979-04-12 |
| GR63996B (en) | 1980-01-18 |
| DK145200B (da) | 1982-10-04 |
| IE46236B1 (en) | 1983-04-06 |
| NO773353L (no) | 1978-04-06 |
| NL7710380A (nl) | 1978-04-07 |
| DK145200C (da) | 1983-02-28 |
| SE425798B (sv) | 1982-11-08 |
| NO148959B (no) | 1983-10-10 |
| NO148959C (no) | 1984-01-18 |
| YU40483B (en) | 1986-02-28 |
| DE2743654C3 (no) | 1980-08-21 |
| DE2743654A1 (de) | 1978-04-06 |
| HU181999B (en) | 1983-11-28 |
| FI57444B (fi) | 1980-04-30 |
| SE7710972L (sv) | 1978-04-06 |
| DK435577A (da) | 1978-04-06 |
| FR2403350A1 (fr) | 1979-04-13 |
| US4207313A (en) | 1980-06-10 |
| FI57444C (fi) | 1980-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO147953B (no) | Analogifremgangsmaate ved fremstilling av terapeutisk aktive antracyklinglukosider | |
| IE42751B1 (en) | Antitumour antibiotics aclacinomycins a and b | |
| US4247545A (en) | 11-Deoxy anthracycline antibiotics, their preparation and use | |
| US4425430A (en) | Process for production of antibiotics and novel antibiotics produced thereby | |
| US4219622A (en) | Process for producing antibiotics MA 144-M1 and MA 144-M2 | |
| US4209588A (en) | Process for producing new antitumor anthracycline antibiotics | |
| US4127714A (en) | Anthracycline glycosides | |
| US4198480A (en) | Process for producing antibiotic baumycin complex and components | |
| EP1075483A2 (en) | Hygromycin a derivatives | |
| EP0110155B1 (en) | Novel anthracycline derivatives, a process for preparing the same by a microorganism strain, the novel strain streptomyces cyaneus, and use of the anthracycline derivatives as medicaments | |
| Furumai et al. | STUDIES ON THE BIOSYNTHESIS OF BASIC 16-MEMBERED MACROLIDE ANTIBIOTICS, PLATENOMYCINS. II PRODUCTION, ISOLATION AND STRUCTURES OF 3-O-PROPIONYL-5-OMYCAMINOSYL PLATENOLIDES I AND II, 9-DEHYDRO DEMYCAROSYL PLATENOMYCIN AND DEMYCAROSYL PLATENOMYCIN | |
| US4374980A (en) | 3'-Deamino-3'-morpholino carminomycin | |
| US4975370A (en) | Process for preparing 14-hydroxy-6-O-methyl-erythromycin A | |
| US4204038A (en) | Process for preparing antibiotics MA 144-M1 and MA 144-M2 | |
| US4942155A (en) | Biosynthetic anthracyclines related to daunorubicin | |
| US4001399A (en) | Process for the production of monopropionyl-josamycin-2 | |
| US4565861A (en) | Serirubicum | |
| US4411834A (en) | Preparation of II-deoxy anthracycline antibiotics | |
| EP0311054B1 (en) | Anthracycline Antibiotics | |
| US4743594A (en) | Antibiotic, antitumor compounds and their use | |
| US5171740A (en) | Coumamidine compounds | |
| US4728612A (en) | Boxazomycin A and B, new antibiotics containing benzoxazole nucleus | |
| US4192915A (en) | Anthracycline glycosides from streptomyces | |
| US3928317A (en) | Antibiotic BM408{60 | |
| US3959252A (en) | Alkamoyl-josamycins |