Lactone and cyclic ether analogues of platelet-activating factor. Synthesis and biological activities

Six-membered lactone and tetrahydropyran analogues of platelet-activating factor (PAF), 4-11, and related antagonistic derivatives 41-46 were synthesized. None of the delta-lactones 4-7 showed PAF-like activities, while the corresponding cyclic ethers 8, 9 and 11 were slightly active. Some of the cyclic antagonists showed more potent inhibitory activities than the open chain antagonist CV-3988 against platelet aggregation (rabbit platelet-rich plasma, IC50) and hypotension (rat, ID50) induced by C16-PAF: e.g. dl-3-[6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2- yl)methyl]phosphonoxy]hexylthiazolium (inner salt) (41d) (IC50 5.5 x 10(-7) M, ID50 0.046 mg/kg, i.v.); dl-3-[5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2- yl)methyl]phosphonoxy]pentylthiazolium (inner salt) (43c) (IC50 5.7 x 10(-7) M, ID50 0.076 mg/kg, i.v.).     

Synthesis of cyclic azobenzene analogues

Reaction of 2,2′-dinitrodibenzyl with lead metal powder in the presence of a basic triethylammonium formate buffer gave a cyclic azoxybenzene, 11,12-dihydrodibenzo[c,g][1,2]diazocine-5-oxide. The latter compound was converted into cyclic azobenzene and analogues (chloro-, bromo-, and cyano-) through subsequent transformations. Hydrolysis of the cyano cyclic azobenzene gave the corresponding carboxylic acid. This carboxylic acid was finally reacted with d-threoninol to give the corresponding amide, which readily undergoes photoisomerization upon illumination with light.     

Synthesis and photo DNA-damaging activities of fluoroquinolone analogues

Fluoroquinolone (FLQ) analogues were synthesized and their DNA photocleaving abilities were assayed. The photo-bioactivities of the fluoroquinolones were dependent on the carbonyl moieties attached to quinolone ring.     

Synthesis and antiviral activities of carbocyclic oxetanocin analogues

9-Cyclobutyladenine (4a), cis- and trans-9-[3- (hydroxymethyl)cyclobutyl]adenine (4b) and 9-[3,3-bis(hydroxymethyl)cyclobutyl]adenine(4d) were prepared from the corresponding cyclobutylamine derivatives (1a, 1b and 1d). Guanine congeners (9a, cis- and trans-9b and 9d) and carbocyclic oxetanocin G (1',2'-trans-9f) were also prepared. Carbocyclic oxetanocin A(1',2'-trans-4f), the preparation of which we have already published, and G were found to be active against herpes simplex virus (type 1 and 2) in vitro, while cis-4b and cis-9b showed an in vitro antiretroviral activity against human immunodeficiency virus (type 1).     

Synthesis of substance P analogs and agonistic and antagonistic activities.

Fourteen analogs of substances P (SP), six previously synthesized by a solution method and eight newly synthesized by a solid-phase technique, have been tested for agonistic and antagonistic activities utilizing the isolated guinea pig ileum. The primary objective is to achieve effective inhibitors of SP. These analogs had agonistic activities ranging from negligible to that equivalent to SP. Six of the fourteen analogs had some degree of antagonistic activity [D-Leu8, D-Phe9]-SP is an analog which constitutes a lead to new substitutions, because it had antagonistic activity, but only negligible agonistic activity. One concept for effective antagonistic activity requires negligible or no agonistic activity.     

Novel mass spectral fragmentation of heptafluorobutyryl derivatives of acyl analogues of platelet-activating factor

Direct derivatization of the acyl analogue of platelet-activating factor (acyl-PAF) with heptafluorobutyric anhydride results in replacement of the phosphocholine moiety with a heptafluorobutyryl (HFB) group. Electron capture (EC) mass spectrometric analysis of this compound that makes use of negative ion detection along with subsequent accurate mass measurement and tandem mass spectrometry studies revealed that in addition to expected fragmentation due to losses of elements of HF, ketene, and/or acetic acid, there is a rearrangement reaction between the HFB group and the substituent on carbon-2 of the glycerol backbone. For 2-acetyl isomers, this fragmentation yields a characteristic ion at m/z 237; for 1-acetyl isomers, the analogous ion is observed at [M-135]⁻, along with a corresponding carboxylate anion. The use of the HFB derivative is invaluable for analysis of PAF homologues and analogues because it provides detailed structural information in combination with the high sensitivity of a gas chromatography combined with EC-mass spectrometry assay.     

Synthesis and NMR investigation of cyclic pentapeptide analogues of thymopentin

The synthesis of two cyclic pentapeptides cyclo (-Arg-Lys-Xxx-D-Val-Tyr-) (Xxx=Asp or Glu) with thymopentin-analogue sequences is described. Cyclization was achieved by the carbodiimide/DMAP method. The results of the NMR investigations performed on the protected pentapeptides suggest a βII′/γ-structure in DMSO solution.     

姜黄素类似物合成与抗抑郁活性研究

<正>世界卫生组织(WHO)提出:抑郁是世界第四大健康问题,到2020年,抑郁将成为第二大健康负担[1,2]。尽管在三环类抗抑郁药和单胺氧化酶抑制剂(MAOIs)之后又陆续出现了新的抗抑郁药如:选择性5-HT再摄取抑制剂(SSRI,氟西汀);     

Molecular docking study on platelet-activating factor antagonistic activity of bioactive compounds isolated from Guttiferae and Ardisia species

A handful of bioactive compounds from plants have been reported to possess platelet-activating factor (PAF) antagonist activity. However, their mode of action is not well understood. Selected bioactive compounds that exhibit PAF antagonist activity and synthetic PAF antagonists were subjected to docking simulations using the MOE 2007.09 software package. The docking study of PAF antagonists was carried out on the PAF receptor (PAFR) protein which involves in various pathological responses mediated by PAF. The docking results revealed that amentoflavone (3) showed good interactions with the PAFR model where the flavone and phenolic moieties were mostly involved in these interactions. Knowledge on PAF antagonists' interactions with the PAFR model is a useful screening tool of potential PAF antagonists prior to performing PAF inhibitory assay.     

Synthesis of febrifuginol analogues and evaluation of their biological activities

A new series of febrifuginol analogues was prepared from l-glutamic acid. An antimalarial activity evaluation against chloroquine-sensitive (T96) and chloroquine-resistant (K1) Plasmodium falciparum indicated that all the tested compounds had very strong inhibitory activity. Compounds 4 and 17b′ were inactive against KB, MCF7, HepG2 and LU1 cell lines even at a concentration of 100 μM, while they exhibited significant inhibition towards P. falciparum. Comparison of the antimalarial activity and the cytotoxic properties revealed that the 2′S isomers were more active than the corresponding 2′R isomers for this series of febrifuginol analogues, indicating that the C-2′ position is critical for the biological activity of this class of compounds.     

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.     

Synthesis of bisubstrate analogues targeting alpha-1,3-fucosyltransferase and their activities

We designed two bisubstrate analogues targeting alpha-1,3-fucosyltransferases, based on the three dimensional structure of Lewis X, which is the product of a alpha-1,3-fucosyltransferase reaction. We selected guanosine-5'-diphospho-L-galactose as a donor mimic and 2-hydroxyethyl beta-D-galactoside as an acceptor mimic, and tethered these two mimics with a methylene or ethylene linker. For the synthesis, the 6-position of L-galactose and the 6-position of D-galactose were first tethered via a methylene or ethylene linker. The L-galactose moiety was then converted to a GDP derivative. Both bisubstrate analogues were moderate inhibitors against alpha-1,3-fucosyltransferase V and VI. The fact that they were substrates of alpha-1,3-fucosyltransferase VI suggested that these compounds bound to the donor binding site, but not to the acceptor binding site.     

Synthesis and physiological activities of both enantiomers of coriolic acid and their geometric isomers

Both enantiomers of coriolic acid and their geometric isomers are synthesized highly selectively. These acids are found to exhibit similar inhibition activity toward spore germination of rice blast fungus.     

Synthesis of a 2,5-diaryloxazoline as a potential platelet-activating factor antagonist

2,5-Bis-(3,4,5-trimethoxyphenyl)-2-oxazoline ( 5 , MDL 100,270) was designed as a potential platelet-activating factor (PAF) antagonist on the basis of computer modeling comparison studies with known PAF antagonists. An efficient, four-step synthesis of oxazoline 5 was developed, starting from 3,4,5-trimethoxybenzaldehyde ( 6 ). Oxazoline 5 was found to inhibit the PAF-induced aggregation of human platelets with an IC₅₀ value of 708 μM.     

Synthesis of glycophostones: cyclic phosphonate analogues of biologically relevant sugars

Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction.     

Synthesis of bisubstrate and donor analogues of sialyltransferase and their inhibitory activities

[reaction: see text] Sialyltransferases (STs) are involved in the biosynthesis of glycoconjugates with important biological activities. Most STs utilize cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac) as a common donor substrate. A bisubstrate analogue containing the donor substrate (CMP-Neu5Ac mimic) and the acceptor substrate (galactose) was synthesized. Four donor analogues having the partial structure of the bisubstrate analogue were also synthesized to support study of the structure-activity relationship. Each analogue contains an ethylene group in place of the exocyclic anomeric oxygen of CMP-Neu5Ac. The bisubstrate analogue exhibited only weak inhibitory activity to rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 1.3, 2.4 mM). Conversion of the C-1 carboxylate of the Neu5Ac moiety to carboxyamide, hydroxymethyl, or methylene phosphate each resulted in a reduction in inhibitory activity. Among the synthesized analogues, cytidin-5'-yl sialylethylphosphonate (4) was the most potent inhibitor against rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 0.047, 0.34 mM).     

Synthesis and properties of cyclic ethylene-bridged 3,6-fluorene dimer and its linear analogues

Three oligomers of ethylene-bridged 3,6-fluorene were synthesized starting from phenanthrenequinone. McMurry reaction was applied to synthesize the cyclic compound. Horner-Emmons reaction was used to synthesize the linear compounds with all-trans configuration. The crystal structure of the cyclic compound was described. The optical and electronic properties of these compounds were fully characterized and compared.     

Synthesis of new symmetric cyclic and acyclic halocurcumin analogues typical precursors for hybridization

Research on Chemical Intermediates - It is believed that the synthesis of hybrid molecules containing different biologically relevant moieties would furnish multifunctional drugs with the possible...     

Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells

Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino- 6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1- pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2- yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl S-nucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.