Synthesis of lipophilic aldehydes and study of their inhibition effect on human digestive lipases

[reaction: see text] Novel inhibitors of human digestive lipases, aldehyde dialkyl and alkyl-acyl glycerol analogues, were developed. The inhibitors were prepared starting from 3-(benzyloxy)-1,2-propanediol. The inhibition of human pancreatic and gastric lipases by the aldehyde derivatives was studied using the monolayer technique. (1R)-1-[(Dodecyloxy)methyl]-4-oxobutyl decanoate caused a 50% decrease in HPL and HGL activities at 0.100 and 0.053 molar fractions, respectively.     

Bis-2-oxo amide triacylglycerol analogues: a novel class of potent human gastric lipase inhibitors.

A novel class of potent human gastric lipase inhibitors, bis-2-oxo amide triacylglycerol analogues, was developed. These analogues of the natural substrate of lipases were prepared starting from 1,3-diaminopropan-2-ol. They were designed to contain the 2-oxo amide functionality in place of the scissile ester bond at the sn-1 and sn-3 position, while the ester bond at the sn-2 position was either maintained or replaced by an ether bond. The derivatives synthesized were tested for their ability to form stable monomolecular films at the air/water interface by recording their surface pressure/molecular area compression isotherms. The inhibition of human pancreatic and gastric lipases by the bis-2-oxo amides was studied using the monolayer technique with mixed films of 1,2-dicaprin containing variable proportions of each inhibitor. The nature of the functional group (ester or ether), as well as the chain length, at the sn-2 position influenced the potency of the inhibition. Among the compounds tested, 2-[(2-oxohexadecanoyl)amino]-1-[[(2-oxohexadecanoyl)-amino]methyl]ethyl decanoate was the most potent inhibitor, causing a 50% decrease in HPL and HGL activities at 0.076 and 0.020 surface molar fractions, respectively.     

Sterically hindered triacylglycerol analogues as potent inhibitors of human digestive lipases

A novel class of inhibitors of human digestive lipases have been developed. Various sterically hindered triacylglycerols based on 2-methyl- and 2-butylglycerol, and/or 2-methyl fatty acids were synthesized. The triacylglycerol analogues were tested for their ability to form stable monomolecular films at the air/water interface by recording their surface-pressure/molecular-area compression isotherms. The inhibition of human pancreatic and gastric lipases by the sterically hindered triacylglycerol analogues was studied by using the monolayer technique with mixed films of 1,2-dicaprin, which contained variable proportions of each inhibitor. Triolein analogues that contain a butyl group at the 2-position of the glycerol backbone or methyl groups both at the 2-position of glycerol, and the alpha-position of each oleic acid residue were potent inhibitors; this caused a 50% decrease in HPL activity at 0.003 molar fraction.     

Surface behaviour of human pancreatic and gastric lipases

The kinetics of the adsorption of human gastric lipase (HGL) and human pancreatic lipase (HPL) were studied by recording the changes in the surface pressure with time in the absence and presence of an egg phosphatidylcholine (PC) monomolecular film spread at the air/water interface. In the presence of PC film, the tensioactivtty of HGL increased considerably compared with its behaviour at the air/water interface, whereas HPL exhibited a comparable degree of tensioactivity whether or not a phospholipid monolayer was present at the interface. This difference in surface behaviour is consistent with the higher penetration capacity attributed to HGL. Procolipase considerably increased both the initial adsorption rate and the final surface pressure reached by HPL compared with its adsorption without colipase.

The kinetics of the hydrolysis of 1,2-didecanoyl-sn-glycerol (dicaprin) monolayers by HGL and HPL were measured using a “zero-order” trough. The large differences between the calculated characteristic adsorption times and the measured lag times indicate that the partition of the lipase molecules between the subsurface and the interface was probably limited by an energy barrier. The amplitude of this energy barrier can be partly attributed to the drastic conformational change in the enzyme, associated with the interfacial activation.

The area per dicaprin molecule (56 Ų) corresponding to the maximal activity of HPL was compared with the dimension of the hydrophobic cleft surrounding the serine (Ser 152) of the catalytic triad of HPL, as recently demonstrated by H. Van Tilbeurgh and co-workers (Nature, 359 (1992) 159; 362 (1993) 814) in their studies on the “open” and “closed” forms of the respective three-dimensional crystalline structures. The catalytic triad was not accessible to a sphere 8.4 Å in diameter, mimicking the van der Waals envelope of the dicaprin molecule, due to the steric hindrance of the side chains of aromatic and cyclic residues F 215, F 77, Y 114 and H 263. It can be concluded that the substrate molecule must also undergo some conformational changes at the contact of the enzyme to be accommodated in the active site.     

Synthesis and study of a lipophilic alpha-keto amide inhibitor of pancreatic lipase

[reaction: see text] A lipophilic alpha-keto amide, inhibitor of pancreatic lipase, was synthesized using a lipidic 2-amino alcohol as backbone. The chiral key intermediate 2-(tert-butyloxycarbonylamino)-D-undecen-5-ol was synthesized starting from D-glutamic acid. The inhibitor formed a stable monomolecular film at the air/water interface as shown by a force/area curve. Inhibition studies using the monomolecular film technique with mixed films of 1,2-dicaprin containing variable proportions of the inhibitor showed a 50% decrease in lipase activity at a 0.14 molar fraction.     

Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase

The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (Ki = 6 microM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 microM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.     

Polyhydroxylated homoazepanes and 1-deoxy-homonojirimycin analogues: Synthesis and glycosidase inhibition study

The Johnson-Claisen rearrangement of D-gluco and L-ido-derived allylic orthoesters afforded gamma,delta-unsaturated ester that on ester reduction, epoxidation, regioselective oxirane opening by sodium azide and hydrogenation led to sugar amino alcohols--immediate precursors for 1-deoxy-homonojirimycin 3a,b, and polyhydroxylated homoazepanes 4a,b. Our synthetic approach and glycosidase inhibitory activity is reported.     

Synthesis and V-ATPase inhibition of simplified lobatamide analogues

[structure: see text] Simplified analogues of the lobatamides have been synthesized and evaluated for inhibition of bovine V-ATPase. The salicylate phenol, enamide NH, and the ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.     

Synthesis of muramoyltripeptides and their isotope-labeled analogues

The synthesis has been effected of the methyl ester of N-acetylmuramoyl-L-alanyl-D-isoglutamylglycine and its hexadecyl -glycoside and the corresponding [1-¹⁴C]glycine analogues.M. V. Frunze Simferapol' State University. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 245–248, March–April, 1990.     

Synthesis and applications of phosphatidylinositols and their analogues

There is an upsurge of interest in the chemistry and biochemistry of phosphoinotides, their analogues and the related enzymes due to their involvement in the inositol phosphates mediated cellular signal transduction pathways. The present review deals with the recent developments in the synthesis and applications of phosphatidylinositol and its derivatives. NCL commun, no. 6014     

Synthesis analogues of milbemycin and their bioactivity evaluation

<正>Eight new 13-O-aminocarbonylivermectin aglycones and 4'-O-aminocarbonylivermectin monosaccharide were synthesized from ivermectin agiycone and ivermectin monosaccharide by the selective protection of C_5-OH group.Their bioactivities were evaluated against spider mites(Tetranychus cinnabarimts),aphid(Aphis fabae) and oriental armyworm(Mytliimma sepatara). Their structures were confirmed by ~1H NMR.MS.     

Synthesis of various 2H-benzopyran compounds and their kinetic resolution by asymmetric hydrolysis of their racemic acetates mediated by lipases

The preparation of 2H-benzopyrans from bromophenols and tertiary allylic alcohols is described. The reaction is characterised by its mildness, good yields and ease of work-up. Kinetic resolution of the latter up to 95% ee was obtained by using enzyme-catalysed enantioselective hydrolysis.     

Synthesis of isosteric methylene-oxy pseudodipeptide analogues as novel amide bond surrogate units

The syntheses of several fully protected dipeptide isosteres which incorporate a methylene-oxy bond replacing the amide bond are described. The novel methylene-oxy modification offers a polar, flexible, proteolytically resistant peptide bond surrogate which can be easily incorporated into biologically active peptides. The standard geometries of the trans-amide, methylene-oxy and methylene-thio units are compared, showing a very close geometrical resemblance of the ψ[CH₂-0] unit to the amide bond.     

Synthesis and x-ray crystal structures of isonipecotinamide derivatives as reverse amide analogues of fentanyl

Several isonipecotinamide derivatives which represent reverse amide derivatives of the potent analgetic agent fentanyl were prepared and evaluated for analgetic activity. The synthetic approaches utilized and stereochemical assignments are discussed. The most potent compound, 3 , displayed much weaker analgetic activity than fentanyl itself.     

Synthesis and medicinal importance of oxicams and their analogues

The biological and medicinal properties of oxicams and its analogues are attracting attention of chemist aimed at developing synthetic routes to these heterocycles. This review focuses on the synthesis and medical importance of oxicams and their analogues.     

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);     

Synthesis of C-terminal fragments of bombesin and their analogues

With the aim of structural-functional studies in the bombesin series, a number of bombesin fragments and analogues have been synthesized. The synthesis was performed by the carbodiimide method and by the activated-ester method. Fragments with the sequences 7–14, 8–14, and 9–14 were obtained by 4+4, 3+4, and 2+4 schemes and a pentapeptide with the sequence 9–13 by a 3 + 2 scheme. Acetylation of the octapeptide BN(7–14) was carried out by the action of acetic anhydride in pyridine. Analogues of the C-terminal nonapeptide of bombesin [DPhe⁷]BN(6–14) and [Pro⁶, Gly⁷, DAla¹¹]BN(6–14) were synthesized by fragment condensation using the 5 + 4 scheme. The individuality of the compounds obtained was confirmed by their chromatographic behavior on plates coated with silica gel, and by the results of amino acid analysis, high-voltage electrophoresis, and high-performance liquid chromatography, and their structures were confirmed by the results of high-resolution¹H NMR spectroscopy (360 MHz). In experiments on rabbits, in a dose of 1 µg with central administration the full hypothermic effect of bombesin was shown by the preparation [AcGln⁷]BN(7–14), while the preparation [DPhe⁷]BN(6–14) and [Pro⁶,Gly⁷,DAla¹¹]BN(6–14) possessed only a slight effect (1% of the activity of bombesin).Leningrad State University. Institute of Organic Synthesis, Latvian SSR Academy of Sciences, Riga. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 554–564, July–August, 1989.     

Synthesis of C-terminal fragments of bombesin and their analogues

With the aim of structural-functional studies in the bombesin series, a number of bombesin fragments and analogues have been synthesized. The synthesis was performed by the carbodiimide method and by the activated-ester method. Fragments with the sequences 7–14, 8–14, and 9–14 were obtained by 4+4, 3+4, and 2+4 schemes and a pentapeptide with the sequence 9–13 by a 3 + 2 scheme. Acetylation of the octapeptide BN(7–14) was carried out by the action of acetic anhydride in pyridine. Analogues of the C-terminal nonapeptide of bombesin [DPhe⁷]BN(6–14) and [Pro⁶, Gly⁷, DAla¹¹]BN(6–14) were synthesized by fragment condensation using the 5 + 4 scheme. The individuality of the compounds obtained was confirmed by their chromatographic behavior on plates coated with silica gel, and by the results of amino acid analysis, high-voltage electrophoresis, and high-performance liquid chromatography, and their structures were confirmed by the results of high-resolution¹H NMR spectroscopy (360 MHz). In experiments on rabbits, in a dose of 1 µg with central administration the full hypothermic effect of bombesin was shown by the preparation [AcGln⁷]BN(7–14), while the preparation [DPhe⁷]BN(6–14) and [Pro⁶,Gly⁷,DAla¹¹]BN(6–14) possessed only a slight effect (～1% of the activity of bombesin).     

Synthesis of bengamide E analogues and their cytotoxic activity

A series of bengamide E analogues were prepared from the corresponding polyketide chain and amino acids via amide coupling reactions. Opening of the polyketide chain lactone ring with α-aminolactams was successfully achieved under microwave irradiation in the presence of sodium 2-ethyl hexanoate. A cytotoxic activity evaluation against a panel of cancer cell lines (KB, HepG-2, Lu-1, MCF-7, HL-60 and Hela) indicated that the 2′R analogues were generally more cytotoxic than the 2′S analogues. Additionally, several analogues exhibited selective inhibition against various cancer cell lines: compounds 32a and 32b selectively inhibited MCF-7 cells, while 33b and 35b were more sensitive toward Lu-1 and HepG-2, respectively. Notably, some of the synthetic analogues possess cytotoxic activities with IC₅₀ values less than 1 µM.