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.     

Synthesis of threitol ceramide and [14C]threitol ceramide,non-glycosidic analogues of the potent CD1d antigen α-galactosyl ceramide

The synthesis of threitol ceramide, which is a non-glycosidic analogue of the potent CD1d antigen α-galactosyl ceramide, is described. The synthesis of a ¹⁴C-labelled threitol ceramide analogue is also presented. This radiolabelled analogue will allow the intracellular trafficking pattern/itinerary of this iNKT-CD1d cell agonist to be studied.     

Synthesis of the glycosphingolipid beta-galactosyl ceramide and analogues via olefin cross metathesis

The preparation of the glycosphingolipid galactosyl ceramide from an orthogonally protected five-carbon building block is described. The main chain of the lipid is installed via a highly stereoselective olefin cross metathesis reaction. The methodology permits the facile preparation of glycolipids which vary in the length of the main carbon chain.     

Synthesis of novel nithiazine analogues containing the 1,4-dihydropyridine structure,and their bioactivity as insecticides

A series of novel nithiazine analogues bearing the 1,4-dihydropyridine structure have been designed and synthesized by reaction of nithiazine, malononitrile or ethyl cyanoacetate, and benzaldehyde. The synthesized compounds were identified by ¹H NMR and IR spectroscopy, and elemental analysis. Preliminary bioassays indicated that most of the compounds had moderate insecticidal activity against Aphis craccivora. The relationship between molecular structure and biological activity is discussed.     

Synthesis of brassinosteroids analogues from laxogenin and their plant growth promotion

Four steroid saponins (2–5) and three derivatives (6–8) were synthesised from laxogenin. Four of them were new compounds: (25R)-3β-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyloxy)-5α-spirostan-6-one (3), (25R)-3β-(β-d-galactopyranosyloxy)-5α-spirostan-6-one (5), 3β,16-diacetyl-26-hydroxy-5α-cholestan-6,22-dione (6) and 16-acetyl-3β,26-dihydroxy-5α-cholestan-6,22-dione (7). All the compounds showed plant growth-promoting activity in the radish hypocotyl elongation and cotyledon expansion bioassay. Above all, 2 and 6 were found to be more active.     

Synthesis, characterization, and biological evaluation of novel ferrocene-triadimefon analogues

In order to improve biological behavior of the 1H-1,2,4-triazole derivatives, a series of new ferrocene-analogues of commercial triadimefon were synthesized and their antifungal and plant growth regulatory activities evaluated. These organometallic analogues showed lower antifungal activity than parent triadimefon, but exhibited promising plant growth regulatory activity.     

Synthesis of alpha-galactosyl ceramide (KRN7000) and analogues thereof via a common precursor and their preliminary biological assessment

A new practical synthesis of alpha-GalCer and of its analogues is presented, opening the chance to easily modify the sphingosine chain. The common precursor is a disaccharide, obtained by coupling tetra-O-benzyl-D-galactose with allyl 2,3-O-isopropylidene-D-lyxofuranoside. Introduction of alkyl chains via Wittig reaction (for alpha-GalCer and OCH) or via Williamson reaction (for oxa analogues) followed by standard synthetic steps allows one to efficiently obtain such compounds. The analogues are able to activate iNKT cells when presented by CD1d expressing cells.     

Synthesis of novel benzoxaborole-containing phenylalanine analogues

The synthesis of novel benzoxaborole-containing phenylalanine analogues 2 and 3 has been developed. The key steps involve the preparation of appropriate precursors from the readily available amino acids and the formation of benzoxaborole ring directly in the corresponding amino acid fragment. The resulting compounds 2-3 show improved water solubility at physiological pH, suggesting their potential use as boron delivery agents for boron neutron capture therapy.     

Synthesis of novel pyrimidine nucleoside analogues

Two new tetrazolopyrimidinedeoxynucleosides were synthesized and their physico-chemical data are described. Results of preliminary analyses of their biological properties are also reported.     

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 of novel halogenated cryptolepine analogues

Cryptolepine (5‐N‐methyl‐10‐H‐indolo[3,2‐b]quinoline) is an indoloquinoline alkaloid present in the roots of Cryptolepis Sanguinolenta. In its hydrochloride form the alkaloid presents a number of bioactivities. The alkaloid also has cytotoxic properties that are likely to be due to its abilities to intercalate into DNA and inhibit the enzyme topoisomerase II, as well as the synthesis of DNA. In this research project five novel analogues of cryptolepine were chosen for synthesis.     

New Synthesis of ketene thioacetals,vinylsulfides and their seleno analogues

Title compounds have been prepared on reaction of thioacetals, orthothioesters and their seleno analogues with diphosphorus tetraiodide (P₂I₄) or phosphorus triiodide (PI₃).     

Synthesis and cytotoxic activity of novel curcumin analogues

Five novel curcumin analogues bearing different substituents at 4-position of phenyl group were synthesized. Their structures were confirmed by NMR and HRMS spectrum. Their cytotoxic activities against six tumor cell lines were tested by the standard MTT assay in vitro. The results indicated that four analogues （1A-1C, 1E） with solubilizing moieties showed selective potent cytotoxicity against HepG2, HeLa and CT26 cell lines, and analogue 1A and 1C exhibited more potent cytotoxicity than curcumin against CT26 cell line. It was suggested that introduction of appropriate substituents to 4-position of phenyl group might be a potential option for structural modification of curcumin.     

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 and antitumor activity of novel salvicine analogues

Systematic structure modification of the side train of the lead compound saprothoquinone provides a series of salvicine analogues,fifteen of them were first reported.Some compounds were demonstrated potent cytotoxicity against tumor cells with the 50%inhibition concentration in the micromolar range.Furthermore some compounds showed potent topoisomeraseⅡinhibitory effects.The preliminary structure-activity relationship of saprorthoquinone analogues was discussed according to their cytotoxicity against thr...     

Synthesis of novel isoxazolidine analogues of homonucleosides

A general method for the synthesis of nucleobase-derived nitrones 4a–e by treatment of N-(2-oxoethyl)nucleobases with N-methylhydroxylamine is reported. The nitrones 4a–e were applied in the synthesis of isoxazolidine homonucleosides. Moderate diastereoselectivities (de 28–82%) were observed for cycloadditions between nitrones 4a–e and allyl alcohol with cis-isoxazolidines predominating. The stereochemistry of the substituted isoxazolidines was established based on an analysis of 2D NOE experiments for uracil-containing cycloadducts 6a and 7a. Cycloadditions of uracil-based nitrone 4a with vinyl-, allyl-, vinyloxymethyl- and allyloxymethylphosphonates gave the respective phosphonylated cis-isoxazolidines as the major adducts.     

Synthesis of novel structurally simplified estrogen analogues

A library of 17 novel estrogen analogues 3 and 4 containing different substituents at rings A and D (steroid nomenclature) was prepared in a five- to seven-step synthesis. The key transformation is a Sonogashira-coupling of cyclic vinyl iodides of type 7 or 8 with phenylacetylenes of type 9. Reduction of the keto function in 3 led to the estradiol analogue 5.     

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.