- RAS PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR THERAPEUTIC APPLICATIONS
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Provided herein are RAS protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RAS-mediated disorder, disease, or condition.
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Paragraph 0294
(2021/03/19)
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- Conversion of Aryl Aldehydes to Benzyl Iodides and Diarylmethanes by H3PO3/I2
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For the first time, H3PO3 was used as both the reducing reagent and the promotor in the reductive benzylation reactions with aryl aldehydes. By using a H3PO3/I2 combination, various aromatic aldehydes underwent iodination reactions and Friedel-Crafts type reactions with arenes via benzyl iodide intermediates, readily producing benzyl iodides and diarylmethanes in good yields. Intramolecular cyclization reactions also took place, giving the corresponding cyclic compounds. This new strategy features easy-handling, low-cost, and metal-free conditions.
- Lv, Fang,Xiao, Jing,Xiang, Junchun,Guo, Fengzhe,Tang, Zi-Long,Han, Li-Biao
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p. 3081 - 3088
(2021/02/01)
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- Preparation method of benzyl iodide and derivatives thereof
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The invention discloses a preparation method of benzyl iodide and derivatives thereof, which comprises the following steps: in a protective atmosphere, carrying out heating reaction on aryl aldehyde and iodine elementary substance in the presence of a solvent and phosphorous acid to obtain benzyl iodide and derivatives thereof. According to the method, cheap and green solid phosphorous acid is selected as a reduction reagent for reaction, elemental iodine is selected as an iodine source, the benzyl iodide and the derivatives thereof are efficiently prepared from the aryl aldehyde compounds which are simple and easy to obtain by a one-pot one-step method under mild conditions, and the method has the advantages of simplicity in operation, cheap and easily available reagents, environmental friendliness and the like; and the use of expensive silicon-hydrogen compounds and transition metal catalysts is avoided, and the yield can reach 94% at most, so that the method is beneficial to industrial production.
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Paragraph 0081-0084
(2021/05/01)
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- A new HPLC-UV derivatization approach for the determination of potential genotoxic benzyl halides in drug substances
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Benzyl halides, widely used as alkylation reagents in drug synthesis, are potential genotoxic impurities (PGTIs) required to be controlled at trace levels. However, the existing analytical methods for benzyl halides often suffer from matrix interferences or low derivatization efficiency of benzyl chlorides. In this paper, a simple derivatization HPLC-UV method was developed for the analysis of these residual trace benzyl halides in drug substances. 1-(4-Nitrophenyl) piperazine (4-NPP) was selected as a new derivatization reagent because it shifted well the benzyl halides derivatives away to the near visible range (392 nm), which could minimize the matrix interferences from the drug substances and related impurities. Meanwhile, potassium iodide (KI) was used to convert the mixed benzyl halides into benzyl iodides before derivatization. The derivatization parameters were also optimized using the design of experiments (DoE) for achieving the best reaction efficiency. The results showed that the new approach had high specificity and sensitivity, and the LOQs were 7-9 μg g-1 relative to 5 mg mL-1 antipyrine and 17.5-22.5 μg g-1 relative to 2 mg mL-1 oroxylin A. The method is a valuable alternative for the determination of residual benzyl halides in the drug substances.
- Ji, Shunli,Gao, Hongbin,Xia, Xingya,Zheng, Feng
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p. 25797 - 25804
(2019/08/28)
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- Discovery and preliminary structure–activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties
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Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50value of 5.3 μM. The structure–activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
- Qian, Shan,He, Tao,Wang, Wei,He, Yanying,Zhang, Man,Yang, Lingling,Li, Guobo,Wang, Zhouyu
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p. 6194 - 6205
(2016/12/06)
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- Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation
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We have previously reported on a study of the structure-activity relationship in a series of 2,3,4-substituted oxazolidines recently discovered by our group varying the substituent at the ring or stereochemistry of the oxazolidine ring. We discovered the cytotoxic and pro-apoptotic potential of compounds 1 and 2 with good selectivity against cancer cell lines. In the present study we describe the synthesis and cytotoxic evaluation against cancer cell lines (HL60, JURKAT, MDA-MB-231 and LNCaP) of a series of oxazolidines designed by isosteric replacement or rigidification of the oxymethylene spacer of compounds 1 and 2. Alkenes 3 and 4 retained the activity against MDA-MB-231 cells and they were more active on HL60, JURKAT and LNCaP cells. Considering LNCaP cells, E-isomer 4 was at least 7 times and about 3 times more potent than lead 1 and Z-isomer 3, respectively. Compound 4 exerted significant activity against LNCaP with IC50 in the low micromolar range (11 μM) without affecting VERO cells and PBMC proliferation (IC50 > 100 μM) indicating its low toxicity to normal cells.
- Andrade, Saulo F.,Teixeira, Claudia S.,Ramos, Jonas P.,Lopes, Marcela S.,Pdua, Rodrigo M.,Oliveira, Mnica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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supporting information
p. 1693 - 1699
(2014/12/11)
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- A direct transformation of Aryl Aldehydes to Benzyl Iodides Via reductive iodination
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A facile transformation of aryl aldehydes to benzyl iodides through one-pot reductive iodination is reported. This protocol displays remarkable functional group tolerance and the title compound was obtained in good to excellent yield.
- Ruso, Jayaraman Sembian,Rajendiran, Nagappan,Kumaran, Rajendran Senthil
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- INDAZOLE GUANIDINE F1F0-ATPASE INHIBITORS AND THERAPEUTIC USES THEREOF
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The invention provides indazole guanidine compounds that inhibit F1F0-ATPase, and methods of using indazole guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
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Paragraph 00247
(2014/01/08)
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- Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors
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Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloromethyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC50 values comparable to molybdate, while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule may increase stability of the generated radicals.
- Jung, Mankil,Lee, Yongnam,Park, Moonsoo,Kim, Hanjo,Kim, Heekyeong,Lim, Eunyoung,Tak, Jungae,Sim, Minjoo,Lee, Dongeun,Park, Namsoo,Oh, Won Keun,Hur, Kyu Yeon,Kang, Eun Seok,Lee, Hyun-Chul
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p. 4481 - 4486
(2008/02/13)
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- Novel cyanine-TCNQ dye for high density data storage media
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This invention is to provide a kind of cyanine-TCNQ complex dyes mixture (II, III, and IV) used as the data storage media having the structural formula (I): wherein Q and Q′ denote aromatic or polyaromatic, R1 and R2 are selected from the group consisting
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- Prodrugs of benzofuranylethyl carbamate NK1 antagonists
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The instant invention provides aqueous soluble prodrugs of formula (I) or a pharmaceutically acceptable salt thereof wherein R is —CH2OZ, —C(═O)OCH2OZ or Z, wherein Z is formula (a), —P(═O)(OH)2or —C(═O)Q: n is an integer of from 0 to 3; m is an integer of from 0 to 1, of certain tachykinin antagonists (NK1antagonists) useful in the treatment of emesis.
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- Phosphate prodrugs of PD154075
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In the preparation of phosphate prodrugs of PD154075, several strategies of linking a phosphate group to the indole moiety were studied. A novel linker, p-hydroxymethylbenzoyloxymethoxycarbonyl, was discovered to provide the phosphate prodrug of PD154075 (compound 9) with significantly increased aqueous solubility, sufficient stability in aqueous solution and good bio-reconversion in vivo. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Zhu, Zhijian,Chen, Huai-Gu,Goel, Om P.,Chan, O. Helen,Stilgenbauer, Linda A.,Stewart, Barbra H.
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p. 1121 - 1124
(2007/10/03)
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- Synthesis of new benzylic ethers of oximes derived from 1-phenyl- pyrazole compounds
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In the scope of a research program aiming at the synthesis and pharmacological evaluation of new antithrombotic agents via rational molecular design, we describe in this paper the synthesis of benzyl ethers of aryl-pyrazolic oxime derivatives. Ethers' (2a-2c) and (3a-3c) are derived from 4-formyl-1-N-phenylpyrazole (4) in good yield. Designed as interphenylenic analogues of the ridogrel (1), one expects these compounds to present dual properties, i.e., thromboxane A2 receptors antagonism and thromboxane synthetase inhibition.
- Muri, Estela M. F.,Barreiro, Eliezer J.,Fraga, Carlos A. M.
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p. 1299 - 1321
(2007/10/03)
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- REAGENTS AND SYNTHETIC METHODS 52. SILANE REDUCTION OF CARBONYL COMPOUNDS IN THE PRESENCE OF IODINE.
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Synthetic utility of 1,1,3,3,-tetramethyldisiloxane (TMDS) reagent under the influence of iodine is described.TMDS reagent in combination with iodine produces alkyl iodides from carbonyl compounds and oxiranes in good to excellent yields.Reduction of quinones into hydroquinones is also described.The mentioned transformations are explained from mechanistic points of view.
- Lecea, B.,Aizpurua, J. M.,Palomo, C.
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p. 4657 - 4666
(2007/10/02)
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