- Structure based design, stability study and synthesis of the dinitrophenylhydrazone derivative of the oxidation product of lanosterol as a potential P. falciparum transketolase inhibitor and in-vivo antimalarial study
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The growing resistance to the current antimalarial drugs in the absence of a vaccine can be effectively tackled by identifying new metabolic pathways that are essential to the survival of the malaria parasite and developing new drugs against them. Triterpenes and steroids are the most abundant group of natural products with a great variety of biological activities. However, lanosterol is not known to possess any significant biological activity. In this study the binding and interactions of a dinitrophenyl hydrazine (DNP) derivative of lanosterol, LAN (a derivative that incorporates a substantially polar moiety into the steroid) with P. falciparum?transketolase was studied by molecular docking and MD simulation with the view to exploit the DNP derivative as a lead in antimalarial chemotherapy?development considering that the P. falciparum?transketolase (PfTk) is a novel target in antimalarial chemotherapy. The enzyme catalyses the production of ribose sugars needed for nucleic acid synthesis; it lacks a three-dimensional (3D) structure necessary for docking because it is difficult to obtain a crystalline form. A homology model of PfTk was constructed using Saccharomyces cerevisiae transketolase (protein data bank ID of 1TRK) as the template. The compound was observed to have Free Energy of Binding higher than that of the cofactor of the protein (Thiamine Pyrophosphate, TPP) and a synthetic analog (SUBTPP) used as reference compounds after MD Simulation. The compound was synthesized in a two-step, one-pot reaction, utilizing a non-acidic and mild oxidant to oxidize the lanosterol in order to avoid the rearrangement that accompanies the oxidation of sterols using acidic oxidants. The LAN was characterized using IR spectroscopy and NMR experiments and tested in-vivo for its antimalarial chemo suppression using a murine model with Chloroquine as a standard. The LAN at a concentration of 25?mg/kg was found to have a comparable activity with Chloroquine at 10?mg/kg and no mortality was observed among the test animals 24?days post drug administration showing that the compound indeed has potential as an antimalarial agent and a likely inhibitor of PfTk considering that there is a strong agreement between the in-silico results and biological study.
- Fadare, Olatomide A.,Omisore, Nusrat O.,Adegbite, Oluwaseun B.,Awofisayo, Oladoja A.,Ogundolie, Frank A.,Adesanwo, Julius K.,Obafemi, Craig A.
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- Anticancer compound and use thereof
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The invention relates to an anticancer medicine which is a lanosterol derivative. The compound has an anticancer effect, and can inhibit the growths of lung cancer cells, liver cells, mammary gland cells, brain cancer cells, and pancreatic cancer cells. The medicine is a compound with a general formula of (I), (II), (III), or (IV). The invention also provides an application of the compound or pharmaceutically acceptable salt thereof in preparing medicines used for treating cancers. The medicine can be used independently, and can be used in combination. Especially, the medicine can be used in combination with gemcitabine or nexavar. The medicine can be used in treating cancers such as lung cancer, liver cancer, pancreatic cancer, breast cancer, brain cancer, and the like.
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Paragraph 0114; 0115; 0116
(2017/06/27)
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- Compound and applications of compound in treatment of cataract
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The present invention discloses a compound and applications of the compound in treatment of cataract, wherein the structural formula of the compound is represented by a formula I, the compound represented by the formula I and the prodrug or pharmaceutically acceptable salt thereof can be used for preventing, alleviating, or reversing the aggregation of crystallin in cells, more than 90% of the protein components are crystallin (CRY) in the lens cell, and comprise alpha-CRY family, beta-CRY family and gamma-CRY family, and after the crystallin is subjected to mutation, the intracellular protein aggregation can be caused so as to cause the cataract disease. According to the present invention, the effect of the compound is detected by selecting the alpha-CRY family mutants such as alpha-Y118D and alphaB-R120 G, the beta-CRY family mutant such as betaB2-V187E, and the gamma-CRY family mutants such as gammaC-G129C and gammaD-W43R as the research model of the cataract disease; and compared to the existing small molecule (such as C29, Science, 350, 674), the small molecule having the novel structure of the present invention has good activity in the inhibition of the intraocular lens protein mutation induced protein aggregation, can improve the absorption of body on the drug, and does not have toxic-side effect on the normal lens cells.
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Paragraph 0126-0128
(2017/11/18)
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- Anti-trypanosoma activity and synergistic effects of natural and semi-synthetic triterpenes and predominant cell death through autophagy in amastigote forms
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Chagas’ disease is a parasitic disease with unsatisfactory treatment, mainly in chronic stage. This study aimed to evaluate the trypanocidal activity and action mechanisms of α/β-amyrin and its semi-synthetic derivatives, together with four isolated natural triterpenes, tested against trypomastigote and amastigote forms. The structure-activity relationship was suggested and cytotoxicity was measured. In general, greater polar compounds may have improved the selectivity to the protozoan. Action mechanisms were only performed for the amastigotes of Trypanosoma cruzi by evaluating the ultrastructural alterations, membrane permeability, mitochondrial membrane potential and cell volume, since the majority of compounds displayed promising antiamastigote activities. Triterpenes promoted changes on mitochondrial membrane potential and ultrastructural features that suggest autophagy processes. Both combinations between α/β-amyrin and 3-O-acetyl-11-oxo-α/β-amyrin and 3-O-acetyl-α/β-amyrin with benznidazole displayed synergistic effects against amastigotes and antagonistic effects on LLCMK2 cells. The antiamastigote activities, chemical derivatization, drug combinations and action mechanisms revealed to be crucial approaches toward this chronic disease.
- Bossolani, Gleison D. P.,Ueda-Nakamura, Tania,Silva, Sueli O.,Dias Filho, Benedito P.,Costa, Tulio O. G.,Quintanilla, Raúl H. R.,Martinez, Sabrina T.,Veiga, Valdir F.,Pinto, Angelo C.,Nakamura, Celso V.
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p. 2473 - 2489
(2017/10/24)
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- Commands and method of treating cancer via RHO pathway
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Lanosterol derivatives useful as anti-cancer agent, which can inhibit the growth of lung cancer cells, liver cancer cells, mammary cancer cells, brain cancer cells and pancreatic cancer cells, possibly by acting on the RHO pathway. These lanosterol derivatives are represented by compound LD030:
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Paragraph 0052
(2016/02/03)
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- Process for preparing delta-7,9(11) steroids from Ganoderma lucidum and analogs thereof
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Processes for preparing lanostane triterpenes from the medicinal mushroom Ganoderma lucidum, and related compounds are described. Compounds, compositions, and methods for treating cancer are also described.
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Page/Page column 21-22; 29
(2016/08/03)
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- Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diaryliodonium Salts
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By developing a new Ir(III)-catalyzed C-C cross-coupling, a versatile method for direct arylation of sp2 and sp3 C-H bonds in ketoximes, nitrogen-containing heterocycles, various arenes, and olefins has been established. The key to this arylation depends on the appropriate choice of catalyst and the use of diaryliodonium triflate salts as the coupling partners. This transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage C-H arylation of complex compounds. Mechanistic studies by density functional theory calculations suggested that the sp3 C-H activation was realized by a triflate-involved concerted metalation-deprotonation process, and the following oxidation of Ir(III) to Ir(V) is the most favorable when a bistriflimide is contained in the diaryliodonium salt. Calculations indicated that both steps are enabled by initial anion exchange between the reactant complexes.
- Gao, Pan,Guo, Wei,Xue, Jingjing,Zhao, Yue,Yuan, Yu,Xia, Yuanzhi,Shi, Zhuangzhi
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p. 12231 - 12240
(2015/10/12)
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- Sterol C24-methyltransferase: Physio- and stereo-chemical features of the sterol C3 group required for catalytic competence
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Sterol C24-methyltransferases (24-SMTs) catalyze the electrophilic alkylation of Δ24-sterols to a variety of sterol side chain constructions, and the C3- moiety is the primary determinant for substrate binding by these enzymes. To determine what specific structural features of the C3-polar group ensure sterol catalysis, a series of structurally related C3-analogs of lanosterol that differed in stereochemistry, bulk and electronic properties were examined against the fungal 24-SMT from Paracoccidioides brasiliensis (Pb) which recognize lanosterol as the natural substrate. Analysis of the magnitude of sterol C24-methylation activity (based on the kinetic constants of Vmax/Km and product distributions determined by GC-MS) resulting from changes at the C3-position in which the 3β-OH was replaced by 3α-OH, 3β-acetyl, 3-oxo, 3-OMe, 3β-F, 3β-NH2 (protonated species) or 3H group revealed that lanosterol and five substrate analogs were catalyzed and yielded identical side chain products whereas neither the 3H- or 3α-OH lanosterol derivatives were productively bound. Taken together, our results demonstrate a chemical complementarity involving hydrogen bonding formation of specific active site contacts to the nucleophilic C3-group of sterol is required for proper orientation of the substrate C-methyl intermediate in the activated complex.
- Howard, Alicia L.,Liu, Jialin,Elmegeed, Gamal A.,Collins, Emily K.,Ganatra, Kalgi S.,Nwogwugwu, Chizaram A.,Nes, W. David
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body text
p. 43 - 50
(2012/08/07)
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- Semisynthesis and biological evaluation of ganodermanontriol and its stereoisomeric triols
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The first synthesis of ganodermanontriol, a bioactive lanostane triterpene from the medicinal mushroom Ganoderma lucidum, has been achieved in 15.3% yield over nine steps, along with its three stereoisomeric triols and ganoderol A. The key steps leading t
- Kennedy, Erin M.,P'Pool, Steven J.,Jiang, Jiahua,Sliva, Daniel,Minto, Robert E.
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experimental part
p. 2332 - 2337
(2012/01/15)
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- N-tert-Butylbenzenesulfenamide-catalyzed oxidation of alcohols to the corresponding carbonyl compounds with N-chlorosuccinimide
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N-tert-Butylbenzenesulfenamide (1)-catalyzed oxidation of various primary and secondary alcohols to the corresponding aldehydes and ketones was efficiently carried out by using N-chlorosuccinimide (NCS) in the coexistence of potassium carbonate and molecular sieves 4? at easy-to-control temperatures ranging from 0°C to room temperature. The present catalytic oxidation was performed without giving any damage to the functional groups in alcohols, and was particularly effective in the oxidation of alcohols that formed labile aldehydes because of its mild reaction conditions. Further, selective oxidation of primary hydroxy groups took place in 1-catalyzed oxidation of several diols. Mechanistic investigation suggested that the chlorination of the sulfenamide 1 by NCS led to the formation of a key species, N-tert-butylbenzenesulfinimidoyl chloride (2), which in turn oxidized alcohols in the presence of potassium carbonate to afford carbonyl products by accompanying regeneration of the catalyst 1.
- Matsuo, Jun-Ichi,Iida, Daisuke,Yamanaka, Hiroyuki,Mukaiyama, Teruaki
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p. 6739 - 6750
(2007/10/03)
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