- Designed, synthesized and biological evaluation of proteolysis targeting chimeras (PROTACs) as AR degraders for prostate cancer treatment
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As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR + ) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs.
- Ke, Yu,Liang, Jian-Jia,Liu, Hong-Min,Shan, Li-Hong,Wang, Ni,Wang, Ya-Lei,Wang, Zhi-Jia,Xie, Hang,Yang, Rui-Hua,Zheng, Zi-Jun,Zhou, Chen
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Read Online
- A Spiroalkylation Method for the Stereoselective Construction of α-Quaternary Carbons and Its Application to the Total Synthesis of (R)-Puraquinonic Acid
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Cyclic α-quaternary carbon stereocenters were prepared from biselectrophillic substrates and an easily prepared chiral bicyclic sulfonyl lactam. This was achieved in two steps by spiroalkylation, employing biphasic reaction conditions with a phase-transfer catalyst, followed by reduction and alkylation with a series of alkyl halide electrophiles. The products of this method were isolated in good yields with with high levels of diastereoselectivity. This methodology was employed in the enantioselective total synthesis of (R)-puraquinonic acid (1) for a late-stage installation of the α-quaternary carbon stereocenter. This enabled the shortest synthesis of 1 to date, an eight-pot sequence providing an overall yield of 14%.
- Elmehriki, Adam A. H.,Gleason, James L.
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Read Online
- Fluorescent probe targeting androgen receptor, and preparation method thereof
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The invention discloses a fluorescent probe targeting an androgen receptor, and a preparation method thereof, particularly relates to an AR fluorescent probe obtained by linking a pomalidomide fluorophore to an androgen receptor (AR) non-steroidal antagonist skeleton, and belongs to the field of medicinal chemistry. According to the invention, the fluorescent probe has a structural general formuladefined in the specification, and can selectively image androgen receptor high-expression cells at the cellular level, and the synthesis process is simple and feasible, cheap and easily available inraw materials, low in preparation cost and easy to popularize.
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Paragraph 0047; 0048
(2020/02/20)
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- A green synthetic process for dimethyl 3-amino o-phthalate
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The invention relates to a green synthetic process for dimethyl 3-amino o-phthalate. The process includes (1) reacting 3-nitro phthalic anhydride and methanol at room temperature under the function ofa solid acid catalyst to obtain dimethyl 3-nitro o-phthalate; and (2) dissolving the obtained dimethyl 3-nitro o-phthalate into an organic solvent, and reacting under the function of a reductant to obtain the dimethyl 3-amino o-phthalate.
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Paragraph 0021; 0022; 0024; 0025
(2019/07/16)
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- A 2 - ethoxy benzimidazole - 7 - carboxylic acid methyl ester
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The invention discloses a synthesis method of 2-ethoxy benzimidazole-7-carboxylic acid methyl ester. The problem that an existing process is not high in content and is very low in yield is solved. According to the synthesis method, 3-nitryl phthalic acid is used as a raw material, rearrangement is performed in a water solution after methyl esterification, acylation and re-nitridation, then tin powder is adopted to perform reduction and loop closing so as to obtain the 2-ethoxy benzimidazole-7-carboxylic acid methyl ester. By the adoption of the synthesis method, produced impurities are very little, the content is high, and the yield is also high.
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Paragraph 0033; 0040-0043
(2018/05/24)
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- AZA-PHENALENE-3-KETONE DERIVATIVE, PREPARATION METHOD THEREOF, AND ITS APPLICATION AS PARP INHIBITOR
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Disclosed are an aza-phenalene-3-ketone derivative, a preparation method thereof and its application as a PARP inhibitor. The aza-phenalene-3-ketone derivative has the following structure: wherein R is hydrogen, methyl, ethyl, isopropyl, benzyl or 3-methyl-3-butenyl. The aza-phenalene-3-ketone derivative has very high activity for inhibiting PARP, thereby providing a good basis for new drug research of developing a nitrogen-doped phenalene-3-ketone compound as PARP inhibitor to treat cancer.
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Paragraph 0020
(2018/05/26)
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- Preparation of 2-phenyl-3-hydroxyquinoline-4(1H)-one-5-carboxamides as potential anticancer and fluorescence agents
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The synthesis of 3-hydroxyquinoline-4(1H)-one derivatives bearing substituted phenyl in position 2 and variously substituted carboxamide group in position 5 is described, with use of 3-nitrophthalic anhydride, α-haloketones and primary amines as the starting materials. The synthetic approach was inspired by the preparation of analogous derivatives reported previously. However, a different strategy had to be developed with the corresponding bis(phenacyl)-3-aminophthalates as the key intermediates. Synthesized hydroxyquinolinones, as well as their intermediates, were tested for their cytotoxic activity towards various cancer and non-malignant cell lines. The fluorescent properties of these compounds have also been evaluated. In both fields, interesting data were obtained and compared to isomeric compounds that have been studied in the past.
- Funk, Petr,Motyka, Kamil,D?ubák, Petr,Znojek, Pawel,Gurská, Soňa,Kusz, Joachim,McMaster, Claire,Hajdúch, Marián,Soural, Miroslav
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p. 48861 - 48867
(2015/06/16)
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- FUSED TETRA OR PENTA-CYCLIC PYRIDOPHTHALAZINONES AS PARP INHIBITORS
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Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
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Page/Page column 48; 49
(2013/07/19)
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- PARP INHIBITOR COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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The present invention relates to tetraaza phenalen-3-one compounds which inhibit poly (ADP-ribose) polymerase (PARP) and are useful in the chemosensitization of cancer therapeutics. The induction of peripheral neuropathy is a common side-effect of many of the conventional and newer chemotherapies. The present invention further provides means to reliably prevent or cure chemotherapy-induced neuropathy. The invention also relates to the use of the disclosed PARP inhibitor compounds in enhancing the efficacy of chemotherapeutic agents such as temozolomide. The invention also relates to the use of the disclosed PARP inhibitor compounds to radiosensitize tumor cells to ionizing radiation. The invention also relates to the use of the disclosed PARP inhibitor compounds for treatment of cancers with DNA repair defects.
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Page/Page column 22
(2009/04/24)
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- Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening
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A series of indenopyrazoles 8 and 9 were designed and synthesized as EGFR tyrosine kinase inhibitors by in silico high-throughput screening. Compounds 8b and 8d showed significant inhibition of A431 cell growth (GI50 = 0.062 and 0.057 μM, respectively). Compounds 8b and 9a showed inhibitory activity toward both EGFR and VEGFR-2 (KDR) tyrosine kinases, whereas 8d inhibited VEGFR-2 tyrosine kinase, exclusively.
- Usui, Taikou,Ban, Hyun Seung,Kawada, Junpei,Hirokawa, Takatsugu,Nakamura, Hiroyuki
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p. 285 - 288
(2008/09/17)
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- 4'-O-SUBSTITUTED ISOINDOLINE DERIVATIVES AND COMPOSITIONS COMPOSITIONS COMPRISING AND METHODS OF USING THE SAME
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Provided are 4'-O substituted isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.
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Page/Page column 48-49
(2008/12/07)
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- Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification
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The development of myeloperoxidase (MPO) inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA. Most of the synthesized molecules had an activity in the same range as flufenamic acid but none of them were able to inhibit the MPO-dependent LDL oxidation. The experiments however gave some useful indications for a rational conception of MPO inhibitors.
- Van Antwerpen, Pierre,Prevost, Martine,Zouaoui-Boudjeltia, Karim,Babar, Sajida,Legssyer,Moreau, Patrick,Moguilevsky, Nicole,Vanhaeverbeek, Michel,Ducobu, Jean,Neve, Jean,Dufrasne, Francois
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p. 1702 - 1720
(2008/09/20)
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- Isoindole-imide compounds and compositions comprising and methods of using the same
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This invention relates to isoindole-imide compounds, and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.
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Page/Page column 66
(2010/11/26)
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- User- and eco-friendly hypervalent iodine reagent and method of synthesis
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The present invention is a user- and eco-friendly hypervalent iodine reagent (mIBX) capable of selectively oxidizing allylic and benzylic alcohols in water and other eco-friendly solvents and having generally the following structure: 1Allylic and benzylic alcohols are cleanly oxidized to the corresponding carbonyl compounds in water or water-THF mixtures, or other mixtures, using a water-soluble o-iodoxybenzoic acid derivative of the present invention.
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Page 2; Sheet 1
(2010/02/05)
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- Synthesis and oxidation reactions of a user- and eco-friendly hypervalent iodine reagent
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Allylic and benzylic alcohols are cleanly oxidized to the corresponding carbonyl compounds in water or water-THF mixtures using a water-soluble derivative of o-iodoxybenzoic acid. A mechanism involving single electron transfer steps is proposed for this facile and eco-friendly oxidation protocol.
- Thottumkara, Arun P,Vinod, Thottumkara K
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p. 569 - 572
(2007/10/03)
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- Nonacid nitration of benzenedicarboxylic and naphthalenecarboxylic acid esters
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When treated with nitrogen dioxide in the presence of ozone and a catalytic amount of iron(III) chloride in inert organic solvent at -10 to +5 °C, benzenedicarboxylic acid diesters 1, 4, and 6 underwent smooth nitration to give the corresponding mononitro derivatives 2/3, 5, and 7, respectively, in good yield (kyodai nitration). Naphthalenecarboxylic acid esters 8 and 11 and naphthalene-1,8-dicarboxylic acid diester 16 were similarly nitrated in the absence of catalyst to give the expected nitro compounds 9/10, 12-15, and 17-22, respectively. Different from conventional nitration based on the combined use of concentrated nitric and sulfuric acids, no hydrolytic cleavage of the ester function was observed under these conditions. The isomer distribution has been determined for the nitration of naphthalenecarboxylic acid esters 8, 11, and 16, and spectral data were collected for less common nitro derivatives. A unique changeover of the orientation mode observed in the kyodai nitration of diester 16, from the initial exclusive meta to the final meta/para, has been discussed in terms of the competition between the electrophilic substitution process involving the nitronium ion (NO2+) and the addition-elimination sequence involving the nitrogen trioxide radical (NO3).
- Nose,Suzuki,Suzuki
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p. 4356 - 4360
(2007/10/03)
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- Nitrodienamines: An Easy Synthesis and Cycloaddition Reactions with α,β-Unsaturated Carbonyl Compounds and Quinones
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The nitrodienamine 6 was synthesized through the vinamidinium salt 7.The reactivity of 6 was investigated with the α,β-unsaturated carbonyls and styrene 8-14, and the quinones 15, 16, 25, 29, 31, 33, 37, and 41.Keywords: nitrodienamine; synthesis; cycloaddition; α,β-unsaturated carbonyl; quinone; vinamidinium salt
- Takeuchi, Naoki,Ohki, Junji,Tobinaga, Seisho
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p. 481 - 487
(2007/10/02)
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- Regiospecific synthesis of anthracyclinone compounds such as daunomycinone
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A regiospecific synthesis for anthracyclinones asymmetric is disclosed. The synthesis is based upon a regiospecific bromination of the C-7 position of the α-tetralone which after transposing the keto group to the β-position and reaction with an organo-lithium compound is condensed with a phthalate ester.
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