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Process for producing anticancer agent ll-d45042Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Preparing Heterocyclic Carbon Compound Having Only O, N, S, Se, Or Te As Ring Hetero AtomsProcess for producing anticancer agent ll-d45042 description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060115879, Process for producing anticancer agent ll-d45042. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a divisional of copending U.S. patent application Ser. No. 10/842,277, filed on May 10, 2004, the entire disclosure of which is hereby incorporated by reference, which claims priority from provisional Application No. 60/469,719 filed May 12, 2003. FIELD OF THE INVENTION [0002] The present invention relates to a process for producing an anticancer agent designated LL-D45042 by fermentation, to methods for its recovery and concentration from crude solutions and to a process for its purification. The present invention includes within its scope a novel strain of streptomyces hygroscopicus designated LL-D45042. BACKGROUND OF THE INVENTION [0003] Rapamycin a macrocyclic lactone has been shown to have antitumor activity (U.S. Pat No. 4,885,171). The biological effects of rapamycin are reviewed in Transplantation Reviews, 1992, 6, 39-87. Semisynthetic analogs of Rapamycin are described in WO 95/14023 and further described in WO 93/16189 are macrocyclic lactones produced by the cultures Streptomyces hygroscopicus (FERM BP-3688), Actinoplanes sp. (FERM BP-3832) or Streptomyces toyocaensis subsp. humicola (ATCC 39471) to produce macrocyclic lactones of the formula [0004] Additional Rapamycin analogs produced by fermentation means described in the art include: 7,29-bisdesmethyl-rapamycin (U.S. Pat. No. 5,093,338); 16-nor-rapamycin (WO 94/10843); 14-methylene rapamycin and 9-methylene rapamycin (WO 93/11130); 7,42-bis (O-demethyl)rapamycin (WO 94/18208) and a process to produce 7-O-dimethylrapamycin by cultivating ATCC 55368. [0005] Microbial desmethylation of FK506/FR900520 by actinoplanes sp. ATCC 53771 forming products with immunosuppressive activity is reported by Tom S. Chen, et al., The Journal of Antibiotics, 45, 118-123 (1992). [0006] Rapamycin structures formed by microbial manipulations of Actinoplanes sp. N902-109 are described by Hiroyuki Nishida, et al., The Journal of Antibiotics, 48, 657-666 (1995). [0007] The precursor feedings and fermentation of s. hygroscopicus LEK III and the ability to synthesize rapamycins is reported by Lake II Khaw, et al., Journal of Bacteriology, 180, 809-14 (1998). [0008] New antitumor compounds are continually in demand, for the treatment of cancer in man and the production of new macrolide anticancer compounds by fermentation means is an important feature of developing antitumor agents for further studies. Equally important are novel strains of cultures used in the production processes for preparing these compounds. BRIEF SUMMARY OF THE INVENTION [0009] The invention relates to the production of anticancer agent LL-D45042, by cultivation, to methods for the recovery and concentration of this anticancer agent from crude solutions, and to processes for the purification of this anticancer agent as well as a new microorganism useful in the preparation of this compound. [0010] The invention includes within its scope the anticancer agent in diluted form, as crude concentrate and in pure form. [0011] The anticancer agent designated LL-D45042 is formed during the cultivation under controlled conditions of a new strain of Streptomyces hygroscopicus, designated LL-D45042. [0012] Cultivation means aerobic growth of an organism in the presence of assimilable sources of carbon, nitrogen and inorganic anion and cation salts. The structure of LL-D45042 is: The physicochemical characteristics of LL-D45042 are as follows: [0013] a) Apparent molecular Formula: C.sub.49H.sub.77NO.sub.12 [0014] b) Molecular Weight: Positive Ion Electrospray MS m/z=893.6 (M+Na).sup.+; Negative Ion Electrospray MS m/z=871.1 (M-H).sup.-; High Resolution Fourier Transform MS m/z=894.534230 (M+Na).sup.+ [0015] c) Proton Magnetic Resonance Spectrum: (500 MHz d.sub.6-DMSO): See FIG. 1 [0016] d) Carbon-13 Magnetic Resonance Spectrum: (125 MHz d.sub.6-DMSO): See FIG. 2 [0017] e) Infrared Absorbance Spectrum (thin film, NaCl plates): See. FIG. 3 [0018] f) Ultraviolet Absorption Spectrum: .gamma..sub.max nm (acetonitrile/water)=270, 280, 292: See FIG. 4 [0019] The anticancer agent LL-D45042 is formed during the cultivation under controlled conditions of Streptomyces strain designated LL-D45042. [0020] This microorganism is maintained in the culture collection of Wyeth Research, Pearl River, N.Y. 10965, as culture LL-D45042. A viable culture of this microorganism is deposited under the Budapest Treaty with the Patent Culture Collection Laboratory, Northern Regional Research Center, U.S. Department of Agriculture, Peoria, Ill. 61604, and added to its permanent collection. Culture LL-D45042 has been assigned the NRRL accession number NRRL30642. BRIEF DESCRIPTION OF THE DRAWINGS [0021] FIG. 1 Characteristic proton nuclear magnetic resonance (NMR) spectrum of LL-D45042 (500 MHz, d.sub.6-DMSO). [0022] FIG. 2 Characteristic carbon nuclear magnetic resonance (NMR) spectrum of LL-D45042 (125 MHz, d.sub.6-DMSO). [0023] FIG. 3 Characteristic infrared (IR) spectrum of LL-D45042 (thin film, NaCl plates). [0024] FIG. 4 Characteristic ultraviolet (UV) spectrum of LL-D45042 (acetonitrile/water). [0025] FIG. 5: Immunoblotting data for inhibition of cellular phosphorylation of p70 S6K1 and 4E-BP1 in LNCap prostate cancer cells by LL-D45042. 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