- Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer
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As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to
- Hu, De-Xuan,Tang, Wen-Lin,Zhang, Yu,Yang, Hao,Wang, Wenjie,Agama, Keli,Pommier, Yves,An, Lin-Kun
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p. 7617 - 7629
(2021/06/25)
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- Enantioconvergent Cu-catalyzed intramolecular C-C coupling at boron-bound C(sp3) atoms of α-aminoalkylboronates using a C1-symmetrical 2,2′-bipyridyl ligand attached to a helically chiral macromolecular scaffold
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Enantioconvergent intramolecular coupling of α-(2-bromobenzoylamino)benzylboronic esters was achieved using a copper catalyst having helically chiral macromolecular bipyridyl ligand, PQXbpy. Racemic α-(2-bromobenzoylamino)benzylboronic esters were converted into (R)-configured 3-arylisoindolinones with high enantiopurity using right-handed helical PQXbpy as a chiral ligand in a toluene/CHCl3 mixed solvent. When enantiopure (R)- and (S)-configured boronates were separately reacted under the same reaction conditions, both afforded (R)-configured products through formal stereoinvertive and stereoretentive processes, respectively. From these results, a mechanism involving deracemization of organocopper intermediates in the presence of PQXbpy is assumed. PQXbpy switched its helical sense to left-handed when a toluene/1,1,2-trichloroethane mixed solvent was used, resulting in the formation of the corresponding (S)-products from the racemic starting material.
- Yoshinaga, Yukako,Yamamoto, Takeshi,Suginome, Michinori
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supporting information
p. 18317 - 18323
(2020/11/17)
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- Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C-H Activation Strategy
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The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be sign
- Baenziger, Markus,Baierl, Marcel,Devanathan, Krishnaswamy,Eswaran, Sumesh,Fu, Peng,Gschwend, Bjoern,Haller, Michael,Kasinathan, Gopu,Kovacic, Nikola,Langlois, Audrey,Li, Yongfeng,Schuerch, Friedrich,Shen, Xiaodong,Wan, Yinbo,Wickendick, Regina,Xie, Siwei,Zhang, Kai
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supporting information
p. 1405 - 1419
(2020/10/12)
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- Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles
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Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.
- Chen, Li-Yuan,Chuang, Ta-Hsien,Lai, Chin-Hung,Tang, Rong-Shiow
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supporting information
p. 9337 - 9341
(2020/12/21)
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- Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones
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The bisphosphine monoxide (R,R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.
- Mayer, Camilla,Ladd, Carolyn L.,Charette, André B.
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supporting information
p. 2639 - 2644
(2019/04/17)
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- Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazolinones
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An efficient and practical method for the synthesis of 1,2,4-triazolo[5,1- b ]quinazolin-9(3 H)-ones has been developed via the copper-catalyzed domino reactions of readily available substituted N ′-acetyl-2-bromobenzohydrazides with cyanamide. The protocol uses inexpensive CuI as the catalyst, and no other ligand or additive was required. The target products were prepared in good to excellent yields with tolerance of various functional groups.
- Lou, Zhenbang,Man, Ningning,Yang, Haijun,Zhu, Changjin,Fu, Hua
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supporting information
p. 1395 - 1399
(2018/05/03)
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- CF3-substituted mollugin 2-(4-morpholinyl)-ethyl ester as a potential anti-inflammatory agent with improved aqueous solubility and metabolic stability
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Although mollugin, the main ingredient of the oriental medicinal herb Rubia cordifolia, has considerable anti-inflammatory effects, it has poor aqueous solubility as well as poor metabolic and plasma stability. To overcome these shortfalls, various mollug
- Hong, Ki Bum,Kim, Darong,Kim, Bo-Kyung,Woo, Seo Yeon,Lee, Ji Hoon,Han, Seung-Hee,Bae, Gyu-Un,Kang, Soosung
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- Palladium-Catalyzed Enantioselective Intramolecular Dearomative Heck Reaction
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Enantioselective intramolecular dearomative Heck reactions have been developed by Pd-catalyzed cross-coupling of aryl halides or aryl triflates with the internal C=C bond of indoles, benzofurans, pyrroles, and furans. A variety of structurally unique spir
- Li, Xiang,Zhou, Bo,Yang, Run-Ze,Yang, Fu-Ming,Liang, Ren-Xiao,Liu, Ren-Rong,Jia, Yi-Xia
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supporting information
p. 13945 - 13951
(2018/10/20)
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- Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel
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We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [3H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.
- Yu, Zhiyi,Van Veldhoven, Jacobus P.D.,'T Hart, Ingrid M.E.,Kopf, Adrian H.,Heitman, Laura H.,Ijzerman, Adriaan P.
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supporting information
p. 50 - 59
(2015/11/23)
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- Enantioselective synthesis of planar chiral ferrocenes via Pd(0)-catalyzed intramolecular direct C-H bond arylation
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A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C-H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions.
- Gao, De-Wei,Yin, Qin,Gu, Qing,You, Shu-Li
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supporting information
p. 4841 - 4844
(2014/04/17)
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- Synthesis of 1-indanols and 1-indanamines by intramolecular palladium(0)-catalyzed C(sp3)-H arylation: Impact of conformational effects
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A range of valuable 1-indanols and 1-indanamines containing a tertiary C1 atom were synthesized by intramolecular palladium(0)-catalyzed C(sp 3)-H arylation, despite unfavorable steric interactions. The efficiency of the reaction was found to correlate with the degree of substitution at C2, as expected from the Thorpe-Ingold effect. Additionally, the nature of the heteroatomic substituent at C1 had a marked influence on the diastereoselectivity at C1 and C2; indeed, 1-indanols and 1-indanamines were obtained with the opposite relative configuration. Analysis of the X-ray and DFT-optimized structures of the corresponding reactive intermediates provided useful insights into the subtle conformational effects induced by these substituents.
- Janody, Simon,Jazzar, Rodolphe,Comte, Arnaud,Holstein, Philipp M.,Baudoin, Olivier,Vors, Jean-Pierre,Ford, Mark J.
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supporting information
p. 11084 - 11090,7
(2014/10/15)
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- Palladium-catalyzed ring-opening of cyclopropyl benzamides: Synthesis of benzo[c]azepine-1-ones via C(sp3)-H functionalization
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A variety of difficult to obtain benzo[c]azepine-1-ones are synthesized via a novel palladium-catalyzed, silver-promoted intramolecular cyclization of cyclopropyl benzamides. This biologically important class of molecules is prepared in an efficient and high-yielding manner from easily accessible starting materials. Both aryl bromides and iodides are effective substrates for the transformation. Mechanistic studies indicate that the reaction proceeds through a cyclopropyl C(sp3)-H cleavage step, followed by ring-opening, deprotonation, and reductive elimination.
- Ladd, Carolyn L.,Roman, Daniela Sustac,Charette, André B.
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supporting information
p. 4479 - 4487
(2013/06/26)
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- Enantioselective synthesis of axially chiral biaryls by the pd-catalyzed suzuki-miyaura reaction: Substrate scope and quantum mechanical investigations
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We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80-92%, and with enantioselectivity in the range 88-94% ee employing an asymmetric Suzuki-Miyaura process with Pd(OAc)2 and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051-12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H??O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C-C coupling.
- Shen, Xiaoqiang,Jones, Gavin O.,Watson, Donald A.,Bhayana, Brijesh,Buchwald, Stephen L.
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supporting information; experimental part
p. 11278 - 11287
(2010/10/04)
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- HETEROCYCLIC DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heterocyclic compounds of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a R1-substituted heteroaryl, R1 is an heteroaryl ring substituted with an ester or carboxylic acid containing radical, X-T is N-CR5R6, C=CR5 or CR13-CR5R6, Y is a bond or -C(O)-, a and b represent an integer selected from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The heterocyclic compounds are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, atherosclerosis, obesity, diabetes, neurological disease, Metabolic Syndrome, insulin resistance, cancer, liver steatosis, and non-alcoholic steatohepatitis.
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Page/Page column 97-98
(2010/09/17)
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- HIV integrase inhibitors
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The invention encompasses a series bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.
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Page/Page column 41
(2010/11/27)
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- A New Synthesis of FPL 64176 and Analogues: The Discovery of Benzoylpyrrole Calcium Channel Activators with Low Nanomolar Potency
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Heavy metal assisted halogen displacement on 2-halobenzoylpyrroles (2 and 3) leads to a simple synthesis of FPL 64176 (1) and a variety of analogues (4-10).The difluoro derivative (4), EC 50 1nM, and the amino linked analogue (7), EC 50 2.7nm, are present
- Baxter, Andrew J. G.,Teague, Simon
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p. 9089 - 9094
(2007/10/02)
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- Peri Fluoro Steric Effects: Syntheses and Comparative Acid-Catalyzed Isomerization of the 8-, 9-, and 11-Fluoro-1,2,3,4-tetrahydro-7,12-dimethylbenzanthracenes to Exo Methylene Tautomers
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Facile and regiospecific syntheses for 8-, 9-, and 11-fluoro-1,2,3,4-tetrahydro-7,12-dimethylbenzanthracenes (4, 5, and 7) from 5,6,7,8-tetrahydro-1-naphthaldehyde and the respective 2-(2-fluoro-6-iodophenyl)oxazoline 14, 2-(2-bromo-5-fluorophenyl)oxazoline 15, and 2-(3-fluorophenyl)oxazoline 16 are described.Comparative acid-catalyzed isomerization of these polycyclic aromatic hydrocarbons (PAH) to exo methylene tautomers in refluxing benzene is compared to our previously published studies employing the parent hydrocarbon 1 and the 5-, 6-, and 10-fluoro analogues(2, 3, and 6).The peri steric effect of 11-fluoro compound 7- was the most dramatic, providing 7-exo methylene isomer 45 in nearly quantitative yield.Substitution of fluorine at peri positions 6 and 8 afforded product ratios at equilibrium, whereas the 7-exo methylene tautomers (41 and 42) also were thermodynamically favored over the parent anthracene PAH or the respective 12-exo methylene isomers (48 and 49).Like the unsubstituted PAH 1, where fluorine does not occupy a peri position such as in the 9- and 10-fluoro species 5 and 6, no appreciable quantities of exo methylene tautomers were detected.Comparative ΔGo values for isomerization of 6-, 8-, and 11-fluoro isomers revealed that sandwiching the C12-CH3 group between the 11-fluoro and C1-CH2 functions in 7 and removing any possible 7-CH2-F interaction in exo methylene product 45 led to a relative relief in steric interaction of approximately 1 kcal/mol.
- Witiak, Donald T.,Goswami, Shyamaprosad,Milo, George E.
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p. 345 - 352
(2007/10/02)
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