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Methods for preparation and use of psorospermin analogsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Oxygen Containing Hetero Ring, The Hetero Ring Is Six-membered, Polycyclo Ring System Having The Hetero Ring As One Of The CyclosMethods for preparation and use of psorospermin analogs description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060084698, Methods for preparation and use of psorospermin analogs. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] The present application is a continuation of U.S. patent application Ser. No. 10/152,152, filed May 20, 2002, which claims priority to U.S. Provisional Patent Application Ser. No. 60/292,189, filed May 18, 2001. The entire texts of the above-referenced disclosures are specifically incorporated by reference herein. The government owns rights in the present invention pursuant to grant number PF-99-349-01 from the American Cancer Society and grant number CA49751 from the National Institutes of Health. [0002] 1. Field of the Invention [0003] The present invention relates to fields of chemistry and cell biology generally, and more specifically, to the preparation of psorospermin and psorospermin analogs, and their use as tumor inhibitors. [0004] 2. Brief Description of the Prior Art [0005] During the last 20 years, significant advances have been made in elucidating the molecular mechanisms responsible for selective antitumor activity of antitumor agents that target DNA. For example, it is now known that adriamycin is a topoisomerase II poison, that topotecan is a topoisomerase I poison, and that cis-Pt cross-links DNA and may express its selectivity by sequestering or hijacking DNA binding proteins. More recently, signaling pathways leading to apoptosis were uncovered, and the importance of p53 status and the involvement of a multitude of other signaling molecules were inferred. Downstream effectors have become important modulators of antitumor activity, and more specific therapeutic strategies are envisioned using cytostatic agents, differentiation agents, and telomerase inhibitors. These approaches are still experimental, but they hold much hope for a gentler form of cancer treatment. [0006] One promising compound that has been shown to down-regulate downstream effector pathways involving anti-apoptotic factors is psorospermin. Psorospermin is a cytotoxic dihydrofuranoxanthone. Optically active (-) psorospermin is isolated from the roots and stembark of the African plant psorospermum febrifugum. Psorospermin is mechanistically related to the pluramycin family of antitumor antibotics, and has been shown to exhibit significant activity in vitro against various tumor cell lines and in vivo against P388 mouse leukemia (Cassady et al., 1990; Kupchan et al., 1980; Kwok et al., 1998). [0007] Psorospermin is particularly intriguing as an anticancer agent because it has low reactivity and poor sequence selectivity toward duplex DNA in comparison to similar compounds such as pluramycins, but at least equal in vitro cytotoxicity and a much more interesting profile in the NCI 60-panel screen (NCI Developmental Therapeutics Web Site). It is believed that a selectivity trigger must exist in vitro, and a variety of suggestions have been made, including DNA-protein cross-links as a consequence of psorospermin-induced abasic sites and topoisomerase I or II as potential cross-linking proteins (Permana et al., 1994). [0008] Unfortunately, optically active (-) psorospermin is no longer readily available from its natural plant source in Africa. Additionally, there are no known methods of synthesizing psorospermin in usable quantities. A need therefore exists for methods of synthesizing psorospermin and psorospermin analogues. SUMMARY OF THE INVENTION [0009] In accordance with the present invention, there is provided a process of preparing a furanoxanthone compound from which psorospermin analogs may be produced, the furanoxanthone having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; R.sub.7 is CHR, where R is alkyl or H; and R.sub.8 is H or alkyl. [0010] The process comprises obtaining a first compound having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; R.sub.7 is CH.sub.2R, where R is alkyl or H; and R.sub.8 is H or alkyl, and reacting this first compound with Pd((CH.sub.3CN).sub.4(BF.sub.4).sub.2) or Pd(OCOCF.sub.3).sub.2 and benzoquinone in DMSO. In one preferred embodiment the reaction takes place between 15.degree. C. and 30.degree. C. In one embodiment, the first compound has the following formula: and the resulting furanoxanthone compound has the following formula. There is also provided a process for preparing psorospermin analogs having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; and R.sub.8 is H or alkyl. The process comprises obtaining a first compound having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen or alkyl; R.sub.5 is H, O-alkyl, or alkyl; R.sub.7 is CH.sub.2R, where R is alkyl or H; and R.sub.8 is H or alkyl, and reacting this first compound with Pd((CH.sub.3CN).sub.4(BF.sub.4).sub.2) and benzoquinone in DMSO or with Pd(OCOCF.sub.3).sub.2 and benzoquinone in DMSO. The reaction may further comprise performing an epoxidation or an epoxide forming reaction. In one embodiment, the psorospermin analogs may have an absolute configuration of (.+-.)(2'R*, 3'R*) or (.+-.)(2'R*,3'S*). [0011] In another ebodiment, there is provided a process for preparing (-) psorospermin analogs having formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; and R.sub.8 is H or alkyl. The process comprises obtaining a first compound having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; R.sub.7 is CH.sub.2R, where R is alkyl or H; and R.sub.8 is H or alkyl, and reacting this first compound with Pd((CH.sub.3CN).sub.4(BF.sub.4).sub.2) and benzoquinone in DMSO or with Pd(OCOCF.sub.3).sub.2 and benzoquinone in DMSO to yield a second compound. The process further comprises performing an asymmetric dihydroxylation of the second compound to form a third compound comprising (+) diastereomers and (-) diastereomers, isolating the (-) diastereomers of the third compound, and performing an epoxidation or an epoxide forming reaction. [0012] In one embodiment, the resulting psorospermin analogs may have an absolute configuration of (-)(2'R, 3'R) or (-)(2'R, 3'S). Additionally, the asymmetric dihydroxylation may comprise reacting the first compound with (1) tBu-OH, CH.sub.3CN, H.sub.2O, OsO.sub.4, and a chiral ligand, (2) a chiral ligand, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, and K.sub.2OsO.sub.4.2 H.sub.2O, or (3) tBu-OH, CHCl.sub.3, H.sub.2O, OsO.sub.4, and a chiral ligand. The (-) diastereomers of the third compound may be isolated by chromatography. [0013] In yet another embodiment, a process is provided for preparing a (-) psorospermin analog having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; and R.sub.8 is H or alkyl. The process comprises obtaining a first compound having a formula: wherein R.sub.1 is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.2-R.sub.4, is H, OH, O-alkyl, OCH.sub.3, halogen, or alkyl; R.sub.5 is H, O-alkyl, or alkyl; R.sub.7 is CH.sub.2R, where R is alkyl or H; and R8 is H or alkyl, and reacting the first compound with chiral ligand, Pd((CH.sub.3CN).sub.4(BF.sub.4).sub.2), and benzoquinone in DMSO or with a chiral ligand, Pd(OCOCF.sub.3).sub.2, and benzoquinone in DMSO. In one preferred embodiment, the chiral ligand may comprise ip-boxax, bisoxaxoline binapthyl, or spiro-bis(isoxazoline). The process may also comprise performing an epoxidation or an epoxide forming reaction. The resulting psorospermin analogs may have an absolute configuration of (-)(2'R, 3'R) or (-)(2'R, 3'S). [0014] In another embodiment, a process is disclosed for preparing a psorospermin analog having a formula: wherein R is hydrogen, an alkyl, a hydroxyl, a hydroxyalkyl, a halogen, a benzyl, an amine, an alkylamine, a thiol, or an alkylthiol. The process comprises obtaining a first compound having a formula: wherein X is a protecting group, reacting the first compound with Pd((CH.sub.3CN).sub.4(BF.sub.4).sub.2) benzoquinone in DMSO or with Pd(OCOCF.sub.3).sub.2 and benzoquinone in DMSO, performing a deprotection reaction, introducing the R group at the oxygen located at the 5' position, and performing an epoxidation or epoxide forming reaction. [0015] The step of introducing the R group may comprise performing a chemical reaction with an alkylating agent and a base. In one preferred embodiment, introducing the R group comprises performing a chemical reaction with CH.sub.3I and K.sub.2CO.sub.3, AcCl and K.sub.2CO.sub.3, or BnBr and K.sub.2CO.sub.3. The protecting group, X, may comprise tert-butyl silane. [0016] In yet another embodiment, a method is provided for preparing a psorospermin analog having a formula: wherein R is a hydrogen, an alkyl, a hydroxyl, a hydroxyalkyl, a halogen, a benzyl, an amine, an alkylamine, a thiol, or an alkylthiol. The method comprises obtaining a first compound having a formula: performing a reaction to remove the CH.sub.3 group from the oxygen at the 1 position, performing a chemical reaction with an alkylating agent and a base, and performing an epoxidation or an epoxide forming reaction. In one embodiment, the performing a reaction to remove the CH.sub.3 group from the oxygen at the 1 position may comprise performing a chemical reaction using BCl.sub.3. The performing a chemical reaction with an alkylating agent and a base may comprise performing a chemical reaction with EtI and Cs.sub.2CO.sub.3, isopropyl bromide, KI, Cs.sub.2CO.sub.3, AcCl and K.sub.2CO.sub.3, or BnBr and K.sub.2CO.sub.3. [0017] A method of inhibiting cell proliferation is also provided. The method comprises contacting a cell with an effective amount of a compound having the following formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. The cell may be a cancer cell, and more particularly may be a pancreatic cancer cell, a prostate cancer cell, a leukemias cell, a lymphomas cell, a myeloma cell, an ovarian cancer cell, or a breast cancer cell. The cancer cell may also be a multi-drug resistant (MDR) cancer cell. The MDR cancer cell may be resistant to a topoisomerase II inhibitor and may be mediated by MRP-1 or glycoprotein. The cell may also be in a mammal. [0018] A method is also provided for directing the sequence-specific alkylation of DNA. The method comprises contacting a cell with an effective amount of a compound having the following formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. In another embodiment, a method is provided for inhibiting the activity of topoisomerase II, the method comprising contacting a cell with an effective amount of a compound having the following formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. [0019] In yet another embodiment, a method of down-regulating oncogenes is provided. The method comprises contacting a cell with an effective amount of a compound having the following formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. The oncogene may be BMI-1. [0020] In a further embodiment, a method is provided for identifying patients with a BMI-1 related cancer. The method comprises obtaining a first sample from a patient, measuring the amount of BMI-1 protein or nucleic acid in the first sample, comparing the amount of BMI-1 protein or nucleic acid in the first sample with a second sample obtained from a non-cancerous subject, wherein an increased amount of BMI-1 protein or nucleic acid in the first sample relative to the second sample indicates a BMI-1 related cancer. [0021] Additionally, the present invention is also directed to pharmaceutical compositions comprising a compound having the formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. [0022] A psorospermin analog is also disclosed, the psorospermin analog having a formula: wherein R.sub.1 and R.sub.2 are independently hydrogen, a benzyl, an alkyl, an acetyl, a hydroxyl, a hydroxyalkyl, a halogen, an amine, an alkylamine, a thiol, or an alkylthiol. Continue reading about Methods for preparation and use of psorospermin analogs... 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