Synthetic investigations on the chemistry of polyene compounds. LVI. Synthesis of (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid

For communication LV see [1].     

Synthesis and characterization of new 10-acylderivatives of the antipsoriatic agent dithranol: coupling products of dithranol with all-trans-retinoic acid, 13-cis-retinoid acid and an aromatic analogue of retinoic acid: all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl- nona-2,4,6,8-tetraenoate

The synthesis of new 10-acylderivatives of dithranol 1 is described. Compound 1 was reacted with the acid chlorides of all-trans retinoic acid 5, 13-cis-retinoic acid 6 and all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8- tetraenoate 7 in toluene and collidin as a base to give the coupling products 2, 3 and 4. The different structures were confirmed by high resolution 1H- and 13C-NMR spectroscopy. Initial investigations with the enzyme glucose-6-phosphate dehydrogenase indicate that all of them are inhibitors of the protein and therefore might have antipsoriatic activity.     

Fluorine-containing amino acids and their derivatives. 4. Synthesis and antibacterial activity of threo and erythro 1-fluorodehydroxylated chloramphenicol analogues

Both threo and erythro 1-fluorodehydroxylated chloramphenicol analogues were synthesized and tested for antimicrobial activity. None showed antibacterial or antifungal activity, clearly demonstrating that substitution of the secondary hydroxyl group with fluorine abolishes the antibacterial activity of the parent compound, chloramphenicol. This finding sharply contrasts with that of previous workers, in which fluorination of the 3-hydroxyl group enhanced antibacterial activity against many chloramphenicol-resistant strains.     

Synthesis and anticonvulsant activity of analogues of 4-amino-N-(1-phenylethyl)benzamide

A group of amides and amines related to 4-amino-N-(1-phenylethyl)benzamide, 1, were prepared in a study on the relationship of structure to anticonvulsant activity in this compound. Acylation and alkylation of the amino group of 1 resulted in almost total loss of anticonvulsant activity. Insertion of a methylene between the 4-amino group and the aromatic ring of 1 produced a slight increase in anticonvulsant potency and a significant increase in toxicity. Hydride reduction of the amide carbonyl in 1 also yielded compounds having a slightly lower ED50 against convulsions induced by electroshock and a much lower TD50 in the rotorod assay. Modification of the 1-phenylethyl group of 1 also decreased anticonvulsant potency.     

Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues

A new series of 12 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2NC = (NH); Xaa = Gly, Sar, D-Ala; Y = OH, OCH3, NH2) were prepared by traditional methods in solution and tested for opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the new analogues showed a negligible affinity for the kappa binding site and a preference for mu- over delta-receptors with an evident dependence on N- and/or C-terminal modifications; H-Tyr-D-MetO-Phe-Gly-OCH3 was shown to be one of the most selective mu-receptor ligands reported to date. All these tetrapeptides display dose-related naloxone-reversible antinociceptive effects following intracerebroventricular (icv) or subcutaneous (sc) administrations in mice. In comparison to morphine, H-Tyr-D-MetO-Phe-Sar-NH2 and the guanidino derivative H2NC = (NH)-Tyr-D-MetO-Phe-Gly-NH2 showed lower affinity for mu, delta, and kappa sites but exceptionally stronger analgesia: respectively they are 560 and 1550 times as potent an analgesic as morphine. Among analogues tested after sc administration, H-Tyr-D-MetO-Phe-Sar-NH2 and H-Tyr-D-MetO-Phe-D-Ala-OH displayed the highest activities; they were respectively 22 and 30 times more potent than morphine on a molar basis. These results indicate that N- or C-terminal modifications and substitution at position 2 or 4 of dermorphin-(1-4) peptide do not only influence the affinity of the resulting analogues to opioid receptors but also may favorably alter their pharmacokinetic properties.     

白藜芦醇苷的合成及其维甲酸代谢阻断活性研究

目的 设计并合成白藜芦醇的多种糖苷衍生物,测定其与全反式维甲酸（ATRA）联合用药后对人类急性早幼粒细胞白血病细胞株（NB4）的诱导分化作用。方法 应用保护基策略,采用Schmidt成苷法制得目标产物;采用NBT还原法测定细胞分化百分率。结果与结论 合成了10个白藜芦醇的单糖苷化衍生物,其中,Res-3-Rha、Res-4′-Rha、Res-4′-Xyl、Res-4′-Ara是未见文献报道的新化合物;Res-3-Xyl和Res-3-Ara为首次合成的化合物,其结构均经核磁共振氢谱和质谱确证。白藜芦醇及其10个糖苷衍生物与ATRA的联合给药初筛结果表明,-Res-3-Glc、Res-3-Ara、Res-3-Rha、Res-4′-Glc、Res-4′-Ara、Res-4′-Xyl及5 μmol·L^-1的白藜芦醇和Res-4′-Rha均能明显提高ATRA的诱导细胞分化活性。     

Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues

Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells.     

Pyrrolnitrin analogues. X. Synthesis and biological activity of 1-chlorophenyl-3- or 5-nitrophenyl-pyrazole-4-carboxylic acids

The synthesis and the in vitro antimicrobial activity of all the possible 1-chlorophenyl-3-nitrophenyl-5-methylpyrazole-4-carboxylic acids and 1-chlorophenyl-3-methyl-5-nitrophenylpyrazole-4-carboxylic acids are reported. Some acids showed an interesting activity against some strains of gram-positive bacteria. The results are discussed and compared with those of other related compounds.     

Synthesis and Toll-like receptor 4 (TLR4) activity of phosphatidylinositol dimannoside analogues

A series of five PIM(2) analogues were synthesized and tested for their ability to activate primary macrophages and modulate LPS signaling. Structural changes included replacement of the fatty acid esters of the phosphatidyl moiety of PIM(2) with the corresponding ether or amide. An AcPIM(2) analogue possessing an ether linkage was also prepared. The synthetic methodology utilized an orthogonally protected chiral myo-inositol starting material that was conveniently prepared from myo-inositol in just two steps. Important steps in the synthetic protocols included the regio- and α-selective glycosylation of inositol O-6 and introduction of the phosphodiester utilizing phosphoramidite chemistry. Replacement of the inositol core with a glycerol moiety gave compounds described as phosphatidylglycerol dimannosides (PGM(2)). Biological testing of these PIM compounds indicated that the agonist activity was TLR4 dependent. An ether linkage increased agonist activity. Removal of the inositol ring enhanced antagonist activity, and the presence of an additional lipid chain enhanced LPS-induced cytokine production in primary macrophages. Furthermore, the interruption of the LPS-induced 2:2 TLR4/MD-2 signaling complex formation by PIM(2) represents a previously unidentified mechanism involved in the bioactivity of PIM molecules.     

Pyrrolnitrin analogues. IX. Synthesis and biological activity of 1-tolyl-3-nitrophenyl-5-methylpyrazole-4-carboxylic acids and 1-tolyl-3-methyl-5-nitrophenylpyrazole-4-carboxylic acids

The syntheses of all the possible 1-tolyl-3-nitrophenyl-5-methylpyrazole-4-carboxylic acids, 1-tolyl-3-methyl-5-nitrophenylprazole-4-carboxylic acids and of the corresponding carboxylates are reported. Several 1,3- and 1,5-diarylpyrazole derivatives were subjected to in vitro antibacterial screenings. Some acids showed activity against some strains of gram-positive bacteria. The results are discussed on the basis of structure-activity relationships.     

Pyridonecarboxylic acids as antibacterial agents. 4. Synthesis and antibacterial activity of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its analogues

The title compounds (28-56) with an amino- and/or hydroxy-substituted cyclic amino group at C-7 were prepared with 1-substituted 7-chloro-, 7-(ethylsulfonyl)-, and 7-(tosyloxy)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acids and their ethyl esters (3-7) with cyclic amines such as 3-aminopyrrolidine. The N-1 substituent includes ethyl, vinyl, and 2-fluoroethyl groups. As a result of in vitro and in vivo antibacterial screenings, three compounds, 1-ethyl- and 1-vinyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids (33a and 33b) and 1-vinyl-7-[3-(methylamino)-1-pyrrolidinyl] analogue 34b, were found to be more active than enoxacin (2) and to be worthy of further biological study. Structure-activity relationships are discussed.     

7-(4-酰氨基硫代甲酰基-1-哌嗪基)喹诺酮类化合物的合成及其体外抗菌活性

目的合成新型含氟喹诺酮类抗菌化合物.方法与结果将酰氯与硫氰酸钠反应并经分子内热重排生成的酰基硫代异氰酸酯对诺氟沙星、环丙沙星的7-位哌嗪基进行修饰,合成了12个7-(4-酰氨基硫代甲酰基-1-哌嗪基)喹诺酮类似物,利用核磁共振、元素分析和红外光谱进行了结构确认.结论初步体外抗菌活性测试结果表明,所合成的化合物有一定的抗菌活性,且高于对照药诺氟沙星.     

吡酮酸类抗茵药物的研究XVI．6-氟-1-（2-氟-5-吡啶基）-7-（1一哌嗪基）-1，4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗茵作用

合成了14个6-氟-1-(2-氟-5-吡啶基)-5．7．8-不同取代-1．4-二氢-4-氧代喹啉-3-羧酸及其类似物．测定了它们对14株革兰氏阳性和革兰氏阴性细菌的MIC值．并与环丙沙星对照。结果表明,这些化合物的抗菌活性均很弱。     

Synthesis and activity of nonhydrolyzable pseudomonic acid analogues

Several series of pseudomonic acid analogues have been prepared that incorporate modified functionalities in place of the C1-C3 alpha,beta-unsaturated ester group. The inhibition of isoleucyl-tRNA synthetase and the in vitro activity of these compounds against various Gram-positive and Gram-negative strains are described. Several derivatives showed enzyme inhibition equivalent to or better than that of methyl pseudomonate (3), while lacking the hydrolyzable ester group at C1. These analogues include the corresponding phenyl ketone and the ether 12. The long-chain ketone 24 exhibited similar in vitro activity as the parent ester.     

Synthesis and antitubercular activity of (4-pyridyl)glyoxylic acid

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 22, No. 9, pp. 1087–1091, September, 1988.