Anticancer Drugs ( Ⅳ )——New Derivatives of Podophyllotoxin

Four new derivatives of podophyllotoxin, N'-podophyllic acid-N-[3-(2, 2, 5, 5-te-tramethyl-pyrrolinenyloxy)] semicarbazide(GP-11, 6), podophyllic acid [3-(2,2,5,5-te-tramethyl-pyrrolinenyloxy)]hydrazone (GP-12, 7), podophyllic acid-[4-(2, 2, 6, 6-tetramethyl-1-hydroxy piperidine)]hydrazone(GP-1-OH, 8) and podophyllic acid[4-(2,2, 6, 6-tetramethyl piperidine)]hydrazone(GP-1-H, 9) were synthesized. The inhibition effect of the four new compounds on L-1210 cells were determined. The antitumor activity and toxicity of GP-1(2), GP-1-OH(8), GP-1-H(9) and VP-16-213(1) were discussed.     

Studies on cardiotonic agents. III. Synthesis of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives

A series of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives was synthesized and examined for cardiotonic activity in anesthetized dogs. Alkylation of the 2-imidazolidinone (1) afforded the N-alkylated products, while alkylation of the 2-imidazolidinethione (12) afforded the S-alkylated derivatives accompanied with a small quantity of the N-alkylated products. The N-alkylated derivatives showed generally potent activity, and the S-alkylated ones exhibited weak activity. Insertion of an alkyl group between the piperidine and the imidazolidinone moiety generally resulted in a fall in activity.     

Synthesis and antitumor activity of fused quinoline derivatives. II. Novel 4- and 7-hydroxyindolo-[3,2-b]quinolines.

Novel indolo[3,2-b]quinoline derivatives (1c--f), which carried a methoxy or a hydroxy group at the 4- or 7-position of the lead compound 1a, were prepared and their antitumor activities against P388 in mice were examined. Except for the 4-hydroxy derivative (1d), these showed remarkably potent activity. Among these compounds, the 7-hydroxy derivative (1f) was the most potent one (optimal dose = 50 mg/kg, the median survival time of treated group/control group (T/C) greater than 330%, cure = 5/6).     

The substituent effect on mesomorphic properties of 4-octyloxyphenyl 4-(4-R-3-nitrobenzoyloxy)benzoates and 4-(4-octyloxybenzoyloxy)phenyl 4-R-3-nitrobenzoates

Abstract

The thermal properties of 4-octyloxyphenyl 4-(4-R-3-nitrobenzoyloxy) benzo-ates (1) and 4-(4-octyloxybenzoyloxy)phenyl 4-R-3-nitrobenzoates (2) have been examined, where R = hydrogen, halogens, alkyl and alkoxy groups. The derivatives of compound 1 incorporating hydrogen, halogens, methoxy and nitro groups show a smectic A phase having a bilayer arrangement, and the others with a long alkoxy group show the S_A phase with the monolayer arrangement. The derivatives of compound 2 incorporating halogens, and the nitro group show the S_A phase with the monolayer arrangement. The alkoxy derivatives show a smectic C phase as well as the nematic phase. The nitro group at the lateral position tends to increase the ratio of the S_A-N transition temperature to the N-I. The effect of the nitro group on the smectic properties has been discussed in terms of the structural and electrostatic nature of the nitro group.     

The substituent effect on mesomorphic properties of 4-octyloxyphenyl 4-(4-R-3-nitrobenzoyloxy)benzoates and 4-(4-octyloxybenzoyloxy)phenyl 4-R-3-nitrobenzoates

The thermal properties of 4-octyloxyphenyl 4-(4-R-3-nitrobenzoyloxy) benzo-ates (1) and 4-(4-octyloxybenzoyloxy)phenyl 4-R-3-nitrobenzoates (2) have been examined, where R = hydrogen, halogens, alkyl and alkoxy groups. The derivatives of compound 1 incorporating hydrogen, halogens, methoxy and nitro groups show a smectic A phase having a bilayer arrangement, and the others with a long alkoxy group show the S_A phase with the monolayer arrangement. The derivatives of compound 2 incorporating halogens, and the nitro group show the S_A phase with the monolayer arrangement. The alkoxy derivatives show a smectic C phase as well as the nematic phase. The nitro group at the lateral position tends to increase the ratio of the S_A-N transition temperature to the N-I. The effect of the nitro group on the smectic properties has been discussed in terms of the structural and electrostatic nature of the nitro group.     

Spectroscopic study of liquid crystalline N-[4-(4-n-alkoxybenzoyloxy)2-hydroxybenzylidene]hydroxyanilines

New homologous series of N-[4-(4-n-alkoxybenzoyloxy)-2-hydroxybenzylidene]hydroxyanilines were synthesized. All 4-hydroxyaniline derivatives exhibited a nematic phase, while 3-hydroxyaniline and 2-hydroxyaniline derivatives exhibited only a nematic phase as the terminal alkoxy group was lengthened. Infrared spectra suggest that the 4-hydroxyaniline derivatives form intermolecular hydrogen bonding of the single bridge type, while the 3-hydroxy and 2-hydroxy derivatives form the polymer type. The Raman band at around 1360 cm^-1 exhibited large differences in intensity among these derivatives. This can be explained by the effect of intermolecular or hydrogen bonding molecular conformation.     

Spectroscopic study of liquid crystalline N-[4-(4-n-alkoxybenzoyloxy)2-hydroxybenzylidene]hydroxyanilines

New homologous series of N-[4-(4-n-alkoxybenzoyloxy)-2-hydroxybenzylidene]hydroxyanilines were synthesized. All 4-hydroxyaniline derivatives exhibited a nematic phase, while 3-hydroxyaniline and 2-hydroxyaniline derivatives exhibited only a nematic phase as the terminal alkoxy group was lengthened. Infrared spectra suggest that the 4-hydroxyaniline derivatives form intermolecular hydrogen bonding of the single bridge type, while the 3-hydroxy and 2-hydroxy derivatives form the polymer type. The Raman band at around 1360 cm^-1 exhibited large differences in intensity among these derivatives. This can be explained by the effect of intermolecular or hydrogen bonding molecular conformation.     

4-(1-Haloalkyl)-3-nitrotetrahydrofurans as versatile scaffolds for the synthesis of diversely functionalized tetrahydrofurans

4-(1-Haloalkyl)-3-nitrotetrahydrofurans, which are accessible by tandem oxidative oxa-Michael addition/radical cyclization/ligand transfer reactions, can be processed to diversely substituted tetrahydrofuran derivatives. Selective epimerization at the nitro function provides tetrahydrofuran diastereomers, which cannot be prepared by the tandem process. Intramolecular alkylations furnish interesting bridgehead nitro oxabicyclo[3.1.0]hexane derivatives in high yields. Intermolecular substitution reactions of the halide functions succeed only with nucleophiles, which are not basic enough to trigger intramolecular alkylations. The aryl substituent in 2-aryl-3-nitrotetrahydrofurans can be selectively oxidatively transformed to carboxylic acid derivatives using catalytic Ru(III) and NaIO₄ without affecting the nitro group. Reduction and hydrogenation reactions provide differently substituted 3-aminotetrahydrofuran derivatives depending on the conditions with moderate to good chemoselectivity.     

1,2,2,6,6-五甲基哌啶醇与紫外吸收剂和猝灭剂在对聚丙烯膜光稳定作用中并用效应的研究

<正> 最近的研究发现,五甲基哌啶醇与四甲基哌啶醇的光稳定机理有一定的不同。我们还观察到2,2,6,6-四甲基哌啶醇与2-羟基-4-辛氧基二苯甲酮(UV-531)同时添加到聚丙烯膜中具有明显的协同效应。本实验探讨了1,2,2,6,6-五甲基哌啶醇(PMP)与几种紫外吸收剂及猝灭剂的并用效应,并比较四甲基哌啶醇及五甲基哌啶醇与紫外吸收剂并用效应的差别。     

Chromium trioxide oxidation products from 4-spiro-1-phenylisochromans

Chromium trioxide oxidation of 1-phenylisochroman-4-spiro-1′-cyclopentane (Ia) in acetic acid led to the expected 1-(2-benzoylphenyl)cyclopentanecarboxylic acid (IIa), while its 6,7-dimethoxy analogue Ib and 6,7-dimethoxy-1-phenylisochroman-4-spiro-4′-(1′-methyl)piperidine (Ic) under the same conditions gave a mixture of their related 1-hydroxy derivatives VIIIb and VIIIc and of the p-benzoquinones, 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)cyclopentane (IXb) and 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)-1-methylpiperidine (IXc). Cyclization of Ila with hydrazine or monomethylhydrazine led to the 5-spiro-substituted 1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones IIIa or XIa.     

Synthesis and reactions of 7-substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids as an antibacterial agent

1-Cyclopropyl- and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having a sulfinyl or sulfonyl group at C-7 were synthesized from 2,6-dichloro-5-fluoronicotinic acid derivatives by the route involving the Dieckmann-type cyclization. The displacement reactions of these compounds with pyrrolidine and piperidine gave mainly the 7-(1-pyrrolidinyl)- and 7-(1-piperidinyl)-1,8-naphthyridine derivatives 24-27 , respectively. Enoxacin, a potent antibacterial agent, was also synthesized with the analogous route.     

Roles of two basic nitrogen atoms in 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives in production of opioid agonist and antagonist activities

To ascertain roles of the two basic nitrogen atoms in 1-substituted 4-[2,(3-hydroxyphenyl)-1-phenylethyl]-piperazine derivatives (1) in the expression of opioid agonist and antagonist activities, a methine group (CH) was isosterically substituted for nitrogen atom at the 1-position (N-1) in compound 1 to obtain 4-substituted 1-[2-(3-hydroxyphenyl)-1-phenylethyl]piperidine derivatives (2). Their analgesic action and ability to produce physical dependence (jump-producing activity) as the mu-opioid receptor specific in vivo actions, and narcotic antagonist action in mice were compared with those of compound 1. Results of this study showed that, in cases of the racemate and the (S)-(+) enantiomer, opioid agonist activities (analgesic and jump-producing activities) were not greatly affected by the methine-substitution for N-1 in compound 1, but that the narcotic antagonist activity of the (R)-(-) enatiomer was abolished by this substitution. It thus appears that N-1 in compound 1 contributes to the expression of narcotic antagonist activity, whereas the nitrogen atom at the 4-position corresponds to the tyramine moiety necessary for the expression of mu-opioid agonist activity.     

Electrochemical Conversions of 2-Methyl-3-nitro-4-phenylquinoline, Its Quinolinium Salts, and Hydrogenated Derivatives

Classical polarography, cyclic voltammetry, and EPR spectroscopy was used to study electrochemical reduction and oxidation of 3-nitro derivatives of 2-methyl-4-phenylquinoline, the corresponding quinolinium perchlorates, and 1,2- and 1,4-dihydroquinolines. The nitro derivatives of quinoline and 1,2-dihydroquinoline are reduced in the first step at the nitro group; the quinolinium cations are reduced at the heterocycle followed by reduction of the nitro group; and in 1,4-dihydroquinolines, the nitro group is not reduced. Electrochemical reduction processes associated with electron transfer in the heterocycle mainly display the same behavior as established for pyridine derivatives. But important differences were observed in electrochemical oxidation: the N-methyl derivative of 1,4-dihydroquinoline is oxidized significantly more easily than the corresponding N-unsubstituted derivative of 1,4-dihydroquinoline (in the 1,4-dihydropyridine series, the difference in pot! enti als is fairly small), and even more easily than the corresponding N-methyl derivative of 1,2-dihydroquinoline.     

Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns

SAR-943 (32-deoxo rapamycin) is a proliferation signal inhibitor via interaction with the mammalian target of rapamycin (mTOR). Most importantly, SAR-943 has improved chemical stability compared to rapamycin (sirolimus) and is currently under investigation as a drug coated on coronary stents. It was the goal of this study to identify the SAR-943 metabolites generated after incubation with human liver microsomes using high-resolution mass spectrometry (MS) and MS/iontrap (MS(n)) and comparison of fragmentation patterns of the metabolites with those of SAR-943 and other known rapamycin derivatives. Our study showed that SAR-943 is mainly hydroxylated and/or demethylated by human liver microsomes. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl and 27-O-desmethyl SAR-943; hydroxylated metabolites: hydroxy piperidine SAR-943, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 46-hydroxy and 49-hydroxy SAR-943; didemethylated metabolites: 16,39-O-didesmethyl and 27,39-O-didesmethyl SAR-943; demethylated-hydroxylated metabolites: 39-O-desmethyl, 23- or 24-hydroxy and 39-O-desmethyl, hydroxy piperidine SAR-943 and dihydroxylated metabolites: 12-,23- or 24-dihydroxy SAR-943. In addition, several other demethylated-hydroxylated and dihydroxylated metabolites were detected. However, their exact structures could not be identified.     

Mass spectrometry of imidazole-4(5)-carboxaldehyde and some 1-methyl and nitro derivatives

The mass spectra of imidazole-4(5)-carboxaldehyde, its two 1-methyl derivatives, 4(5)-nitroimidazole, 5(4)-nitroimidazole-4(5)-carboxaldehyde and 1-methyl-5-nitroimidazole-4-carboxaldehyde are presented and discussed in comparison with those of other imidazole-carboxaldehydes and nitroimidazoles earlier reported. The imidazole-carboxaldehydes and their 1-methyl derivatives exhibit the characteristic fragmentation of aromatic aldehydes, and differences between the isomers can be observed. The nitroimidazoles show the fragmentation typical of aromatic nitrocompounds. In the o-nitroimidazole-carboxaldehydes, the typical losses of aldehydes do not occur, but primary ortho effects between the formyl and nitro groups give rise to important fragmentation routes. In their 1-methyl derivatives, the presence of the methyl group adjacent to the nitro group originates additional double and secondary ortho effects. For some of these transformations, fragmentation mechanisms are proposed.     

Silica Sulfuric Acid: An Efficient,Reusable, Heterogeneous Catalyst for the One-Pot,Five-Component Synthesis of Highly Functionalized Piperidine Derivatives

A series of highly functionalized piperidine derivatives was synthesized through one-pot, five-component reaction of aldehydes, amines, and β-ketoesters. Silica sulfuric acid efficiently catalyzes the reaction to afford the corresponding piperidine derivatives in good yields. As a representative example, heating of 4-methylaninle, 4-fluorobezaldehyde, and methyl-acetoacetate in methanol in the presence of silica sulfuric acid furnished the corresponding ethyl 2,6-bis(4-fluorophenyl)-1-p-tolyl-4-(p-tolylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate in excellent yield (85%). Most of the synthesized compounds were screened in vitro for their antibacterial and antifungal activities. Most of compounds showed significant antibacterial activity.     

Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120

This paper describes selected modification and structure-activity relationship of the small molecule HIV-1 inhibitor, 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806). The results revealed: i) that both the presence and configuration (R vs. S) of the 3-methyl group on the piperazine moiety are important for the antiviral activity, with the 3-(R)-methyl derivatives showing the highest activity; ii) that the electronegativity of the C-4 substituent on the indole or azaindole ring seems to be important for the activity, with a small, electron-donating group such as a fluoro or a methoxy group showing enhanced activity, while a nitro group diminishes the activity; iii) that the N-1 position of the indole ring is not eligible for modification without losing activity; and iv) that bulky groups around the C-4 position of the indole or azaindole ring diminish the activity, probably due to steric hindrance in the binding. We found that a synthetic bivalent compound with two BMS-378806 moieties being tethered by a spacer demonstrated about 5-fold enhanced activity in an nM range against HIV-1 infection than the corresponding monomeric inhibitor. But the polyacrylamide-based polyvalent compounds did not show inhibitory activity at up to 200 nM.     

芳基噻唑联哌啶酰胺类化合物的合成及生物活性

为了寻找具有生物活性的新型芳香基噻唑联哌啶酰胺类先导化合物,设计并合成了15个未见文献报道的芳基噻唑联哌啶酰胺类化合物,其结构经1HNMR、13CNMR和HRMS确证,生物活性测定结果显示,部分目标化合物表现出高效的抑菌和杀虫活性,如在200μg/mL浓度下,5-(3-溴苯基)-4-甲基-2-(1-((4-硝基苯基)磺酰基)哌啶-4-基)噻唑(6b)对黄瓜霜霉病的抑菌活性为100%,优于嘧菌酯,5-(4-溴苯基)-2-(1-((4-氯苯基)磺酰基)哌啶-4-基)-4-甲基噻唑(6c)对水稻纹枯病的抑菌活性为58.86%,与嘧菌酯相当;在500μg/m L浓度下,(4-(5-(3-溴苯基)-4-甲基噻唑-2-基)哌啶-1-基)(间甲基苯基)酮(6h)对粘虫的杀虫活性为100%.     

4-(1-硫杂-2亚氨基-3,4-二氮杂-1,4-亚丁基)-4-脱氧阿维菌素B1a的合成

以阿维菌素B1a为原料经选择性C-5羟基保护、氧化合成5-O-烯丙氧羰基-5-氧代-5-脱氧阿维菌素B1a (3), 然后与N-取代氨基硫脲偶联, 缩合产物经MnO2氧化关环、脱保护得到10个未见文献报道的4-(1-硫杂-2-亚氨基- 3,4-二氮杂-1,4-亚丁基)-4-脱氧阿维菌素B1a (7a～7j). 目标化合物结构经1H NMR, 13C NMR和MS确证.     

Novel thermally stable polyimides based on flexible diamine: synthesis, characterization, and properties

A novel diamine with built-in sulfone, ether, and amide structure was prepared via three-step reactions. Nucleophilic reaction of 4-aminophenol with 4-nitrobenzoyl chloride in the presence of propylene oxide led to preparation of N-(4-hydroxy phenyl)-4-nitrobenzamide (HPNB). The nitro group of this compound was reduced with hydrazine and Pd/C to afford 4-amino-N-(4-hydroxy phenyl)benzamide (AHPB). Two moles of AHPB were reacted with bis-(4-chloro phenyl)sulfone to provide a novel sulfone ether amide diamine (SEAD). All the prepared compounds were characterized by common spectroscopic methods. The prepared diamine (SEAD) used to prepare related polyimides by reaction with different aromatic dianhydrides. The obtained poly(sulfone ether amide imide)s were characterized and their properties were studied.