Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester

A series of heterocyclic analogues of glutamic acid diethyl ester (GDEE), an antagonist at central excitatory amino acid receptors, have been synthesized and tested biologically. (RS)-Ethyl alpha-amino-alpha-(3-ethoxyisoxazol-5-yl)acetate (7), (RS)-ethyl 2-amino-3-(3-ethoxy-5-methylisoxazol-4-yl)propionate (16) and closely related analogues were synthesized. Compound 7, a diethyl derivative of the naturally occurring excitatory amino acid ibotenic acid (IBO), was synthesized from 3-hydroxy-5-methylisoxazole (1) via 3-ethoxyisoxazol-5-ylacetic acid (5) and its ethyl ester. Nitrosation of this ester followed by catalytic reduction gave 7. The ethyl ester of IBO, 9, was synthesized in a similar manner from 3-benzyloxyisoxazol-5-ylacetic acid (8). Ethyl derivatives of the synthetic excitatory amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) were synthesized from 3-hydroxy-4,5-dimethylisoxazole (10) through a diethyl acetylaminomalonate derivative, which upon deprotection gave the 3-ethoxy derivative of AMPA (15). Esterification of 15 gave the diethyl derivative 16 and the ethyl ester of AMPA (18) as well as N-ethylated derivatives of AMPA, 21 and 22 were synthesized. The final products were tested microelectrophoretically. The derivatives 7, 9, 15, 16 and 18 were weak and non-selective excitatory amino acid antagonists, whereas 21 and 22 were found to be inactive.     

Synthesis,characterization, and antioxidant activity of heterocyclic Schiff bases

Schiff base derivatives have gained great importance due to revealing a great number of biological properties. Schiff bases were synthesized by treatment of 4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one ( 1 ) with various aldehydes in methanol at reflux. In addition, diamine was reacted with an aldehyde to yield the corresponding Schiff bases. The structures of synthesized Schiff bases were elucidated by spectroscopic methods such as microanalysis, ¹H-NMR, ¹³C-NMR, and FTIR. Antioxidant activities of synthesized Schiff bases were carried out using different antioxidant assays such as 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH^•) scavenging, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging, and reducing power activity. (E)-4-((1H-indol-3-yl)methyleneamino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one ( 3 ), (E)-1,5-dimethyl-4-((2-methyl-1H-indol-3-yl)methyleneamino)-2-phenyl-1H-pyrazol-3(2H)-one ( 5 ), (E)-1,5-dimethyl-2-phenyl-4-(thiophen-2-ylmethyleneamino)-1H-pyrazol-3(2H)-one ( 7 ), (E)-1,5-dimethyl-2-phenyl-4-(quinolin-2-ylmethyleneamino)-1H-pyrazol-3(2H)-one ( 9 ), (1S,2S,N1,N2)-N1,N2-bis((1H-indol-3-yl)methylene)cyclohexane-1,2-diamine ( 11 ), and (1S,2S,N1,N2)-N1,N2-bis((2-methyl-1H-indol-3-yl)methylene)cyclohexane-1,2-diamine ( 12 ) were synthesized in high yields. Compound 5 displayed a good ABTS^•+ activity. Compound 3 revealed the outstanding activity in all assays. Compound 7 has the best-reducing power ability in comparison to other synthesized compounds. Although compounds 5, 11, 12 are new, compounds 3, 7, 9 are known. Due to revealing a good antioxidant activity, the synthesized compounds ( 3, 5, 7 ) have the potential to be used as synthetic antioxidant agents.     

Synthesis and Reactions of Some Novel Nicotinonitrile,Thiazolotriazole, and Imidazolotriazole Derivatives for Antioxidant Evaluation

The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation of compound 2 with thiosemicarbazide and/or hydrazine hydrate afforded the mercaptotriazole and the corresponding acetic acid hydrazide derivatives 3 and 4, respectively. The latter compound reacted with ethyl acetoacetate, ethyl cyanoacetate, and maleic anhydride to give compounds 5, 6, and 7, respectively. Alkylation of compound 3 with methyl iodide or chloroacetic acid afforded methylsulfanyltriazole and thiazolotriazole derivatives 8 and 9, respectively. Compound 8 reacted with glycine to afford the imidazotriazole derivative 10. Both compounds 9 and 10 reacted with glucose and benzaldehyde to give compounds 11, 12, 13, and 14, respectively. Some of the prepared products were selected and subjected to screening for their antioxidant activity.     

Synthesis of benzophenone-containing analogues of phosphatidylcholine

As part of a collaborative study of cellular efflux of cholesterol and phospholipids, photoactivable analogues 4-8 of phosphatidylcholine (PC) having benzophenone groups in the choline moiety and at the end of the C2 and C1 alkyl chains have been synthesized. The efficient preparation via Suzuki coupling of the appropriate long-chain benzophenone-containing carboxylic acid and alcohol and their incorporation by adaptation of known approaches into the acyl- and ether-linked PC analogues 6-8 are described. Development of a method for radiolabeling these PC analogues, via hydrogenation of a double bond in modified side chains, is also described.     

Substitutionen und oxidative Additionen an 2-Chlor-4, 4, 5, 5-tetrakis(trifluormethyl)-1, 3, 2-dioxaphospholan

Substitution Reactions and Oxidative Addition on 2-Chloro-4, 4, 5, 5-tetrakis (trifluoromethyl)-1, 3, 2-dioxaphospholane Substitution of chlorine in the title compound 1 yields the phosphites XP[OC(CF₃)₂C(CF₃)₂O] ( 2 : X = I, 4 : X = OCH(CF₃)₂, 5 : X = OC(O)CF₃, 7 : X = OSiMe₃). Compound 2 is easily reduced by hydrogen iodide and mercury to give HP[OC(CF₃)₂C(CF₃)₂O], 3 . The acylphosphite 5 decomposes into trifluoracetic acid anhydride and the μ-oxo diphosphite 6 at elevated temperatures. 6 is obtained also in the reaction of triphenylhydroxystannane and 1 , whereas trimethylhydroxystannane formes the phosphonic acid ester 11 which furnishes the phosphoric acid ester 12 upon reacting with hexafluoroacetone. 12 is obtained directly from the monoammonium-salt of hexafluoroacetonehydrate 13 and 1 exhibiting a prototropic rearrangement. Compound 7 is oxidized by chlorine to yield the trichlorophosphorane 9 and the diphosphate 10 . Antimony pentachloride and iodochloride oxidize 1 to give the dichlorophosphonium hexachloroantimonate 14 and the trichlorophosphorane 9 , respectively.     

Synthesis and biological activity of tetralone abscisic acid analogues

Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active.     

Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives

Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.     

Cucurbit[n]uril analogues: synthetic and mechanistic studies

[reaction: see text] The synthesis of cucurbit[n]uril analogues (18, 19, (+/-)-20, 33, 34, 35, 36, and 37) is presented. These CB[5], CB[6], and CB[7] analogues all contain bis(phthalhydrazide) walls that are incorporated into the macrocycle. The tailor-made synthesis of these CB[n] analogues proceeds by the condensation of the appropriate bis(electrophile) (4, 7, or 9) with bis(phthalhydrazide) (17), which delivers the CB[6] and CB[7] analogues in good yield, whereas the CB[5] analogue is formed in low yield. To improve the solubility characteristics of the CB[n] analogues for recognition studies in water or organic solution, the CO2Et groups were transformed to CO2H and CO2(CH2)9CH3 groups. On the basis of the results of product resubmission experiments, we conclude that these macrocycles are kinetic products. To help rationalize the good yields obtained in the CB[6] and CB[7] analogue macrocyclization reactions, we performed mechanistic studies of model methylene bridged glycoluril dimers, which suggest an intramolecular isomerization during CB[n] analogue formation.     

Pyridazine Derivatives and Related Compounds,Part 1. Some Reactions with 4-Cyano-5,6-Diphenyl-2,3-Dihydropyridazine-3-One

4-Cyano-5,6-diphenyl-2,3-dihydropyridazine-3-onc 1 reacts with phosphorous oxychloride to give 70% of the corresponding 3-chloro derivative 2. Treating 2 with anthranilic acid in butanol, 4-cyano-2,3-diphenyl-10H-pyridazino[6,1-b]quinoxaline-10-one, 3 was obtained. Compound 1 reacts with phosphorous pentasulphide to give 3-mercapto derivative 4, which was converted by acrylonitrile to S-(2-cyanoethyl)pyridazine derivative 5. Compound 4 reacts with ethyl bromoacetate and with phenacyl bromide gave the corresponding thieno[2,3-c] pyridazine derivatives 8, 9, Alkylation of 1 with ethyl chloroacetate afforded 3-0-carbethoxymethyl derivative 10. Compound 10 reacts with amines (aniline, hydrazine) to give the corresponding amide and acid hydrazide 13, 12 respectively. Hydrolysis of 10 with sodium hydroxide gave the corresponding acid derivative 11. Treating 1 with methyl iodide, 3-0-methyl derivative 14 was obtained, which was converted by ammonium acetate/acetic acid to 3-amino-4-cyano-5,6-diphenyl pyridazine 15. Compound 1 reacts with methyl magnesium iodide gave 4-acetyl derivative 16, which was reacted with hydrazine, phenyl hydrazine and with hydroxylamine to give the substituted I H pyrazolo [3,4-c] pyridazine 17 a,b and isoxazolo [5,4-c] pyridazine 18 derivatives respectively.     

Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design,Synthesis, X-ray Structure and Therapeutic Potential

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(−)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2′,6′-dimethoxy-4′-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (K_i = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [³⁵S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC₅₀ = 2.59 nM, E_(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.     

含取代基碲碳菁染料的研究

本文报道了含取代基碲碳菁染料(8a～b)的合成方法。4－氯苯胺用等摩尔的乙酸汞、氯化锂及过量的乙酸酐处理可高收率地得到芳基氯化汞(2)。2 在冰乙酸中与等摩尔的四氯化碲回流生成3(内盐)。以水合肼还原3得到化合物4，后者可进一步用硼氢化钠还原并用碘甲烷烷化生成5。化合物6可在不同条件下分别由3、4或5得到。在碘甲烷或碘乙烷作用下，6可以烷基化生成季铵盐(7a～b)，后者与原甲酸乙酯在乙酸酐中缩合即生成对称的碲碳菁染料(8a～b)。对染料的可见吸收光谱也进行了讨论。     

Synthesis of 1, 5- and 1, 7-dichloro-9H-thioxanthen-9-ones

1, 5-Dichloro-9H-thioxanthen-9-one ( 2 ) was prepared by cyclization of 2-chloro-6-[(2-chlorophenyl)thio]-benzoic acid ( 10 ) obtained from 2-chloro-6-iodobenzoic acid ( 9 ) and 2-chlorobenzenethiol. Similarly, 1, 7-di-chloro-9H-thioxanthen-9-one ( 6 ) was prepared from 9 via 2-chloro-6-[(4-chlorophenyl)thio]benzoic acid ( 11 ). Compound 6 was also obtained by condensation of 2-chloro-6-mercaptobenzoic acid ( 12 ) with chlorobenzene in the presence of sulfuric acid.     

Synthesis and anticancer evaluation of some novel N,O,S heterocyclic compounds pendant to 3-methyl-5-cyano-6-(3,4-dimethoxyphenyl)pyrimidine and other related fused pyrimidines

The key starting compound 5-cyano-6-(3,4-dimethoxyphenyl)-2-thiouracil ( 1 ) was synthesized and allowed to undergo electrophilic substitution with methyl iodide to give the corresponding 6-(3,4-dimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile ( 2 ). Nucleophilic substitution on compound 2 with hydrazine hydrate led to the corresponding 2-hyrazinopyrimidone intermediate 3 . Compound 3 underwent several substitution and cyclization reactions with β-ketoester, β-ketone, alkyl halides, arylisothiocyanate, or aromatic aldehydes followed by cyclization reactions to give the corresponding N,O,S heterocyclic compounds incorporated into pyrimidine moiety and/or the related S-triazino[3,4-b]pyrimidine derivatives 4 - 18 . Anticancer evaluation of some representative examples of newly synthesized compounds was carried out against MCF-7, HCT116 cell lines. Some of the newly synthesized compounds showed significant activity.     

Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1 alpha,25-dihydroxy-22-oxavitamin D3 analogues.

Six analogues of 1 alpha,25-dihydroxy-22-oxavitamin D3 (OCT) (2), 26,27-dimethyl OCT (5), 26,27-diethyl OCT (6), 24-norOCT (7), 24-homoOCT (8), 24-dihomoOCT (9), and 24-trihomoOCT (10) were synthesized from the 20(S)-alcohol (11) as the common starting material. In the activity inducing differentiation of human myeloid leukemia cells (HL-60) into macrophages, 26,27-dimethyl OCT (5) and 24-homoOCT (8) showed the highest activities. The binding properties of these analogues to the chick embryonic intestinal 1 alpha,25-dihydroxyvitamin D3 (1) receptor are also described.     

Synthesis of 9-(2-fluorobenzyl)-6-methylamino-9H-purine

Synthesis of 9-(2-fluorobenzyl)-6-methylamino-9H-purine ( 1 ) from nine different precursors is reported. Compound 1 was prepared by methylamination of 6-chloro-9-(2-fluorobenzyl)-9H-purine ( 4 ), by alkylation of 6-methylaminepurine ( 5 ) or form 9-(2-fluorobenzyl)-1-methyladeninium iodide ( 8 ) via the Dimroth rearrangement. Selective 2-step methylation of 6-aminopurine 6 was accomplished by hydride reduction of 6-formamidopurine 9 , 6-dimethylaminomethyleneaminopurine 10 or 6-phenylthiomethyl purine 11 to give 1. Compound 1 was also prepared by dethiation or reductive dechlorination of 2-methylthiopurine 16 or 8-chloropurine 19 , respectively, or by hydrolysis of 6-N-methylformamidopurine 12 , which was prepared from 6-dimethylaminopurine 13 by selective oxidation.     

A Green Protocol for Simple One‐pot Synthesis of New Pyrimidine Derivatives Both Microwave Irradiation and Conventional Heating: Reactions,Characterization, and Theoretical Calculations

In this research, 5‐benzoyl‐6‐phenyl‐4‐(4‐trifluoromethylphenyl)‐2‐{oxo and thioxo}‐3,4‐dihydro‐1H‐pyrimidines ( 1 , 2 ) were synthesized by using multicomponent cyclocondensation reaction under microwave irradiation and classical heating. Compounds 3 , 4 , 6 , 7 , and 8 obtained reactions of 5‐benzoyl‐6‐phenyl‐4‐(4‐trifluoromethylphenyl)‐2‐thioxo‐3,4‐dihydro‐1H‐pyrimidine ( 1 ) and acetic anhydride, diethyl 2‐bromomalonate, bromoacetic acid, 3‐bromopropionic acid, methyl iodide, respectively. Compound 4 was both acetylated and hydrolyzed in acetic acid to give compound 5 . The structures of all compounds were determined by using spectroscopic techniques like FT‐IR, ¹H/¹³C NMR, and elemental analyses, and the structures of compounds 1 and 3 were analyzed by X‐ray crystal analysis. In addition, the quantum chemical parameters and full geometry optimizations for all compounds were computed using density functional theory based on B3LYP and the 6‐31G (d, p) basis set.     

Design,Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC₅₀ 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G₂/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer.     

Synthesis and Biological Evaluation of New Dipyridylpteridines,Lumazines, and Related Analogues

Condensation of 4,5‐diaminopyrimidines 2 and 3 with 2,2ʹ‐dipyridil ( 4 ) afforded 6,7‐bis(2‐pyridyl)pteridine‐2‐one analogues 5 and 7 , respectively. Analogously, 6,7‐bis(2‐pyridyl)luamzine derivatives 13 , 15 , 17 , and 23 were synthesized from reaction of 5,6‐diamino‐2‐thiopyrimidines 13 , 14 , and 22 with 4 , respectively, while condensation of 4,5,6‐triaminopyrimidines ( 25 ) or 5,6‐diamino analogue 26 with 4 furnished the 4‐amino‐pteridine analogue 27 and 28 , respectively. Thiation of the new pteridines and lumazines afforded the 4‐thio analogues 6 , 8 , 16 , and 24 . Treatment of 6 and 8 with methanolic ammonia afforded the 4‐isopterine analogues 9 and 10 , respectively. Alkylation of 15 with substituted phenacyl chloride furnished 18 and 19 , which cyclized to the thiazolo‐pteridine derivatives 20 and 21 , respectively, on treatment with polyphosphoric acid. Alternatively, 27 was prepared from treatment of 24 with methanolic ammonia under drastic conditions. Condensation of 2 or 29 with 2‐oxo‐2‐(thiophen‐2‐yl)acetaldehyde oxime ( 11 ) gave the 6‐(2‐thienyl)‐pteridine‐4‐one ( 12 ) and 5‐chloro‐2‐(2‐thienyl)pyrido[3,4‐b ]pyrazine ( 31 ), respectively. All compounds were evaluated for their antiviral activity against the replication of HIV‐1 and HIV‐2 in MT‐4. Some of the synthesized compounds were tested against the bacterial species, Escherichia coli and Staphylococcus aureus , as well as fungal species, Candida tropicalis and Candida albicans .     

2-Acyl-tetrahydroisoquinoline-3-carboxylic acids: lead compounds with triple actions, peroxisome proliferator-activated receptor α/γ agonist and protein-tyrosine phosphatase 1B inhibitory activities

2-Acyl-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2,4-Hexadienoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14) showed peroxisome proliferator-activated receptor γ (PPARγ) and PPARα agonist activities and protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activities. PPARγ agonist activity of 14 was comparable to that of rosiglitazone, and PTP-1B inhibitory activity was about 10-fold weaker than that of ertiprotafib, a PTP-1B inhibitor. Compound 14 showed high oral absorption in rats and potent hypoglycemic effects in KK-A(y) mice. In conclusion, 14 would be an excellent lead compound for a new type of anti-diabetic drug with triple actions.     

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

A novel series of 2,4‐disubstituted oxazole derivatives were synthesized, screened for their anti‐tumor activity against three cell lines MCF‐ 7 , TK‐10, and UACC‐62. Molecular docking study was carried out against epidermal growth factor receptor. A new series of 2‐phenyl‐4‐substituted oxazole derivatives were synthesized. A series of chiral α‐amino acid derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 were synthesized by coupling various l ‐acylated amino acid azide 3. The synthesized compounds were tested for their in vitro antitumor activity against MCF‐7, TK‐10, and UACC‐62 cell lines. Compound 6 exhibited the strongest inhibitory activity against TK cell lines, while compound 12 showed the highest activity against MCF‐7 cell lines. Compound 14 was the most active against UACC‐62 cell lines. Furthermore, a molecular docking study of the most active compounds was carried out using epidermal growth factor receptor X‐ray 3D structure (protein data bank ID 1 M17). Docking results revealed that compound 6 showed the highest binding energy of ΔG = ?78.17 Kcal/mol.