- Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1α pathway
-
Four series of hypoxia-inducible factor-1 alpha (HIF-1α) functioning derivatives stemming from modifications to the C-29 carboxyl group of celastrol were designed and synthesized, and their anticancer activities were evaluated. To address the structure and activity relationship of each derivative, extensive structural changes were made. HRE luciferase reporter assay demonstrated that 12 modified compounds showed superior HIF-1α inhibitory activity. Among them, compound C6 exhibited the best features: firstly, the strongest HIF-1α inhibitory activity (IC50 = 0.05 μM, 5-fold higher than that of celastrol); secondly, lower cytotoxicity (22-fold lower, C6-16.85 μM vs celastrol-0.76 μM). Thus, the safety factor of C6 was about 112 times higher than that of celastrol. Western blot assay indicated that C6 may inhibit the expression of HIF-1α protein in cells. Additionally, C6 hindered tumor cell cloning, migration and induced cell apoptosis. It is worth mentioning that in the mouse tumor xenograft model, C6 (10 mg/kg) displayed good antitumor activity in vivo, showing a better inhibition rate (74.03%) than the reference compound 5-fluorouracil (inhibition rate, 59.58%). However, the celastrol treatment group experienced collective death after four doses of the drug. Moreover, C6 minimally affected the mouse weight, indicating that its application in vivo has little toxic effect. H&E staining experiments show that it could also exacerbate the degree of tumor cell damage. The results of water solubility experiment show that the solubility of C6 is increased by 1.36 times than that of celastrol. In conclusion, C6 is a promising antitumor agent through HIF-1α pathway.
- Shang, Fan-Fan,Wang, Jing Ying,Xu, Qian,Deng, Hao,Guo, Hong-Yan,Jin, Xuejun,Li, Xiaoting,Shen, Qing-Kun,Quan, Zhe-Shan
-
-
- Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors
-
p53-MDM2/MDMX interaction inhibitors represent the prospective agents for targeted anticancer therapy in tumors expressing wild-type p53 protein. Imidazoline-based MDM2-targeted inhibitors of such type, nutlins, contain halogen-substituted phenyl rings, w
- Bazanov, Daniil R.,Kopeina, Gelina S.,Lozinskaya, Natalia A.,Maksutova, Anita I.,Pervushin, Nikolay V.,Savin, Egor V.,Sosonyuk, Sergey E.,Tsymliakov, Michael D.
-
p. 2216 - 2227
(2021/10/14)
-
- Synthesis of β-Phosphinolactams from Phosphenes and Imines
-
Various cis-β-phosphinolactams are synthesized stereoselectively for the first time from imines and diazo(aryl)methyl(diaryl)phosphine oxides under microwave irradiation. Diazo(aryl)methyl(diaryl)phosphine oxides first undergo the Wolf rearrangement to generate phosphenes. Imines nucleophilically attack the phosphenes followed by an intramolecular nucleophilic addition via less steric transition states to give final cis-β-phosphinolactams. C-Styrylimines generally give rise to β-phosphinolactams in higher yields than C-arylimines. The stereoselectivity and proposed mechanism are rationalized by DFT theoretical calculation.
- Fu, Xingyang,Li, Xinyao,Xu, Jiaxi
-
supporting information
p. 8733 - 8737
(2021/11/17)
-
- Stereoselective Synthesis of α,α′-Dihydroxy-β,β′-diaryl-β-amino Acids by Mannich-Like Condensation of Hydroarylamides
-
Dual α,α′-Dihydroxy-β-amino acids are highly interesting tools for several industrial applications. Nevertheless, only few derivatives are reported in the literature and knowledge concerning the substitution pattern as well as their enantioselective syntheses are lacking. Herein, we report on the preparation of enantiopure α,α′-dihydroxy-β,β′-diaryl-β-amino acid (dual) derivatives by an efficient Mannich-like condensation of hydroarylamides with 5,6-diethoxy-5,6-dimethyl-1,4-dioxan-2-one (triethylsilyl)ketene acetal. The synthetic protocol has been optimized affording the dual compounds in very good yields and with different aryl substitution patterns. Taking advantage of the “double stereodifferentiation” concept, a highly stereoselective reaction was performed: of the 16 possible isomers, only two diastereoisomers (d.r. up to 93:7) formed. Insights into the high stereocontrol of this condensation were given.
- Pecnikaj, Ilir,Foschi, Francesca,Bucci, Raffaella,Gelmi, Maria Luisa,Castellano, Carlo,Meneghetti, Fiorella,Penso, Michele
-
supporting information
p. 6707 - 6713
(2019/11/03)
-
- 2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation
-
Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents
- Bazanov, Daniil R.,Pervushin, Nikolay V.,Savitskaya, Victoria Yu.,Anikina, Lada V.,Proskurnina, Marina V.,Lozinskaya, Natalia A.,Kopeina, Gelina S.
-
supporting information
p. 2364 - 2368
(2019/06/14)
-
- Adducts of Triallylborane with Ammonia and Aliphatic Amines as Stoichiometric Allylating Agents for Aminoallylation Reaction of Carbonyl Compounds
-
Triallylborane-amines adducts are effective stoichiometric allylating agents in the aminoallylation reaction of carbonyl compounds in methanol. Moreover, copper-catalyzed diastereoselective allylation of Ellman's imine was achieved with triallylborane-methylamine adduct.
- Kuznetsov, Nikolai Yu.,Tikhov, Rabdan M.,Strelkova, Tatiana V.,Bubnov, Yuri N.
-
supporting information
p. 3549 - 3552
(2018/06/26)
-
- Deep eutectic solvent catalyzed eco-friendly synthesis of imines and hydrobenzamides
-
The urea-choline chloride-based deep eutectic solvent was found to be an efficient catalyst and reaction media for the additive-free synthesis of imines (Schiff bases) and hydrobenzamides by the reaction of aldehydes with amines and ammonia in good to high yields. Outstanding features of this protocol were the general and atom-economical reaction, absence of external catalysts and additives, simple workup, and availability and recycling of urea-choline chloride as a green solvent. Graphical abstract: (Chemical Equation Presented).
- Azizi, Najmedin,Edrisi, Mahtab
-
p. 1695 - 1698
(2015/09/21)
-
- Synthesis of the novel pyrimido[1,6-a]pyrimidine and imidazo[1,2-c] pyrimidine derivatives based on heterocyclic ketene aminals
-
A concise and efficient route for the synthesis of pyrimido[1,6-a] pyrimidines and imidazo[1,2-c]pyrimidines by simply refluxing a reaction mixture of different heterocyclic ketene aminals and N,N′-bis(arylmethylidene) arylmethane was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery.
- Alizadeh, Abdolali,Mokhtari, Javad,Ahmadi, Mehdi
-
experimental part
p. 319 - 322
(2012/01/05)
-
- Synthesis and cytotoxicity of O,O′-dialkyl {[2-(substituted phenoxy)acetamido](substituted phenyl)methyl}phosphonates
-
A series of O,O′-dialkyl {[2-(substituted phenoxy)acetamido] (substituted phenyl)methyl}phosphonates was synthesized and their cytotoxic activities were tested against various human tumor cell lines. Some compounds (5q, 5r, 5s, 5w, 5x and 5y) showed relatively high cytotoxicity. Especially, compounds 5x and 5q exhibited the best cytotoxicity against KB and CNE2 cells with IC50 7.1 and 11.4 μM, respectively. Their inhibitory activities against KB and CNE2 cells were even higher than that of fluorouracil.
- Ning, Lihong,Wang, Wei,Liang, Yongju,Peng, Hao,Fu, Liwu,He, Hongwu
-
experimental part
p. 379 - 384
(2012/03/13)
-
- Novel method for the synthesis of α-amino-α- hydroxyalkylphosphinic acids and bis(α-aminoalkyl)phosphinic acids: Nuclephilic addition of α-hydroxy-H-phosphinic acids to diimines
-
We report here a novel and simple method for the synthesis of α-amino-α-hydroxyalkylphosphinic acids in good yields in two simple steps without any protection-deprotection steps. We have developed an efficient method for the synthesis of α-amino-α-hydroxyalkylphosphinic acids via the reaction of easily available α-hydroxyalkylphosphinic acids with diimines. Treatment of α-hydroxyalkylphosphinic acids with diimines in the presence of trimethylsilyl chloride (TMSCl) gives α-amino-α- hydroxyalkylphosphinic acids in good yields. The reaction gave a mixture of two diastereomeric forms of α-amino-α-hydroxyalkylphosphinic acids. The difference in solubility in organic solvents allowed us to readily separate the diastereoisomers. Georg Thieme Verlag Stuttgart · New York.
- Kaboudin, Babak,Haghighat, Hamideh,Alaie, Saied,Yokomatsu, Tsutomu
-
supporting information; experimental part
p. 1965 - 1969
(2012/09/22)
-
- Synthesis and biological evaluation of novel phosphonates derivatives of as potential antitumor agents
-
A series of dialkyl [2-(4,6-dimethoxypyrimidin-2-yloxy)benzamido](aryl) methylphosphonates derivatives were designed and synthesized. All the new compounds were identified by elemental analysis, IR, 1H NMR, 31P NMR, and MS. Their antitumor activity against KB and CNE1 cells was examined. Some of the compounds showed potential antitumor activity, which provided some hints for further study of structure modification. In particular, the compounds 6i and 6j displayed more potent cytotoxic activities against KB in comparison with 5-FU. Copyright Taylor & Francis Group, LLC.
- Jin, Chuanfei,Liang, Yong-Ju,He, Hongwu,Fu, Liwu
-
experimental part
p. 2096 - 2103
(2011/12/01)
-
- Synthesis and complexation properties of N, N-bis(phosphinomethyl)amine as a new class of 1-aminophosphinic acids with transition metals and lanthanide ions in aqueous solution
-
The treatment of aromatic aldehydes with ammonia and hypophosphorus acid gave novel C2-symmetric N,N-bis(phosphinomethyl)amines as a new class of 1-aminophosphinic acid compounds. Complexation properties of N,N-bis(phosphinomethyl)amines with transition metals such as Co2+, Ni2+, Zn2+, Cu2+, and Cd2+ and lanthanide ions La3+ and Gd3+ were studied in aqueous solution by the pH-potentiometric method. Dissociation constants (pK) of the compound were determined by the pH-potentiometric technique. The complexation studies with compound dl-2a showed the best fit of the titration curves were obtained when the ligand-metal stoichiometric ratio was 1:1 and 2:1.
- Kaboudin, Babak,Saadati, Fariba,Golshan, Azadeh,Abdollahi, Hamid,Yokomatsu, Tsutomu
-
experimental part
p. 3651 - 3656
(2012/01/06)
-
- Studies on the reaction of diimines with thiourea: Synthesis and solvent-induced cis/trans-isomerization of 1,3,5-triazinane-2-thiones
-
The reaction of N,Nc-bis(arylmethylidene)arylmethane diimines with thiourea under reflux in methanol was studied. The reaction gave a diastereomeric mixture of 4,6-disubstituted 1,3,5-triazinane-2-thiones in good yields. Two diastereoisomers of 4,6-diphenyl-1,3,5-triazinane-2-thione were detected in a solution of CDCl3 by NMR analysis. According to the NMR studies, the cisdiastereoisomer undergoes a solvent-induced cis/trans-isomerization process, producing the trans-diastereoisomer in DMSO. The stereochemistry of the trans-diastereoisomer was determined by Xray crystallographic analysis.
- Kaboudin, Babak,Ghasemi, Tahereh,Yokomatsu, Tsutomu
-
experimental part
p. 3089 - 3093
(2009/12/28)
-
- Regioselective synthesis of cis- and trans-2,4,5-triarylimidazolines and 2,4,5-triarylimidazoles from available reagents
-
Novel data were obtained concerning the reaction of aromatic aldehydes with ammonia. A preparative method for the synthesis of new substituted 1,3,5-triaryl-2,4-diazapenta-1,4-dienes was developed. These products are the starting reactants for syntheses of cis- and trans-2,4,5-triaryl-2-imidazolines and 2,4,5-triarylimidazoles.
- Lozinskaya,Tsybezova,Proskurnina,Zefirov
-
p. 674 - 678
(2007/10/03)
-
- Synthesis of N1-unsubstituted β-lactams via a facile deprotection of N1-[(α-thiophenyl)benzyl] group
-
A diastereoselective synthesis of (±) c/s-β-1actams (5 and 6) via cycloaddition reactions of N1-(α-thiophenyl)benzyl imines (3) with acid chlorides (4) in the presence of triethylamine is described. The deprotection of N1-(α-thiophenyl)benzyl group has been achieved by oxidation using potassium persulfate to give N-unsubstituted β-lactams (7) in good yields.
- Karupaiyan,Srirajan,Deshmukh,Bhawal
-
p. 4375 - 4386
(2007/10/03)
-
- Formation of N,N'-Disubstituted Methanediamine Derivatives from Hexamethyldisilazane and Aldehydes via Stepwise Reactions
-
The ZnCl2-catalyzed reaction of aldehydes with hexamethyldisilazane (HMDS) resulted in the formation of N,N'-disubstituted methanediamines, which were found to be formed stepwisely via 1:1- and 1:2-adducts of HMDS and aldehydes.
- Nishiyama, Kozaburo,Saito, Masaki,Oba, Makoto
-
p. 609 - 611
(2007/10/02)
-
- Mechanism of Base-Promoted Eliminative Fragmentations of 2-Alkyl-3-Phenyloxaziridines
-
The base-promoted fragmentations of 2-benzyl-3-(4-substituted-phenyl)oxaziridines 1 and 2-(4-substituted-benzyl)-3-phenyloxaziridines 2 in anhydrous organic solvents give benzaldehydes and unstable benzylideneimines.The subsequent trimerization of the imines provides the benzylidene animals with the liberation of ammonia.The fragmentations can be regarded as an α,β-elimination and have been studied kinetically with triethylamine in acetonitrile at 40 deg C.The (Z)-oxaziridines react more rapidly than the corresponding (E)-oxaziridines.The Hammett ρ values for the E isomers of 1 and 2 are 0.68 and 0.89, respectively.The primary kinetic β-deuterium isotope effects (kH/kD) are 6.1 for (E)-2-benzyl-3-(4-nitrophenyl)oxaziridine and 6.9 for (E)-2-benzyl-3-(4-methoxyphenyl)oxaziridine .From these results and considerations on the magnitudes of the Broensted β (0.46), the activation parameters and the Arrhenius parameters for (E)-1a, the triethylamine-promoted fragmentations of 1 and 2 are best interpreted in terms of a near central E2 mechanism; for the transition state fragmentations of 1 and 2 are best interpreted in terms of a near central E2 mechanism; for the transition state of (E)-1a the Nα-O bond breaking is slightly ahead of the β-proton removal.The triethylamine-promoted fragmentations of (E)- and (Z)-2-methyl-3-(4-nitrophenyl)oxaziridines (9) in acetonitrile are slower than those of 1a, but give comparable primary isotope effects; kH/kD = 6.1 for (Z)-9 and 6.6 for (E)-9.The Arrhenius plot for (Z)-9 shows excellent linearity, suggesting neither change in mechanism nor the necessity for a tunneling correction.The fragmentation of (Z)-9 in chloroform is slightl y slower than that in acetonitrile, with kH/kD = 6.2.These data suggest that the tertiary amine promoted fragmentations of 2-alkyl-3-phenyloxaziridines with β-hydrogen exclusively proceed through an E2 mechanism.
- Suda, Kohji,Hino, Fumio,Yijima, Chino
-
p. 4232 - 4239
(2007/10/02)
-