ABSTRACT
Stereocontrolled introduction of a nitrogen atom at either C-2' or C-3' positions of nucleosides derived from uridine, 4-N-benzoylcytidine and adenosine was investigated. An efficient and rapid procedure was employed for creating new chiral centers at C-2' and C-3' positions using [3,3]-sigmatropic aza-Claisen rearrangement of allyl thiocyanates under conventional and microwave conditions. Structure of isothiocyanate products was confirmed by 1-D and 2-D NMR spectral analyses including selective 1H 1-D-NOE experiments.
Subject(s)
Allyl Compounds/chemistry , Isothiocyanates/chemical synthesis , Nucleosides/chemical synthesis , Thiocyanates/chemistry , Isothiocyanates/chemistry , Microwaves , Molecular Structure , Nucleosides/chemistry , StereoisomerismABSTRACT
A short synthetic route to a small library of aminocyclitols 14·HCl-19·HCl has been elaborated from the common shikimic acid-derived scaffolds 20 and 21. The developed strategy features three oxidative processes â ozonolysis, dihydroxylation and epoxidation â as the key transformations. The stereochemistry of the newly created stereocentres was confirmed either via crystallographic analysis or by means of NOESY experiments conducted on advanced intermediates. Glycosidase inhibition study revealed no glucosidase inhibition and only weak inhibitory activity against recombinant Drosophila melanogaster Golgi mannosidase (GMIIb).
Subject(s)
Cyclitols/pharmacology , Enzyme Inhibitors/pharmacology , Mannosidases/antagonists & inhibitors , Shikimic Acid/chemistry , Small Molecule Libraries/pharmacology , Carbohydrate Conformation , Cyclitols/chemical synthesis , Cyclitols/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mannosidases/metabolism , Shikimic Acid/analogs & derivatives , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistryABSTRACT
Oxazolomycin A and neooxazolomycin were firstly isolated in 1985 by the group of Uemura et al. from the Streptomyces sp. bacteria. To date, there have been reported 15 different natural compounds commonly classified as part of the oxazolomycin family. All oxazolomycin compounds possess extraordinary structures and they represent a synthetic challenge. Such molecules are additionally known for their wide range of biological activity including antibacterial, antiviral and cytotoxic effects. The present review summarizes the structural elucidation and classification of oxazolomycin compounds, their biosynthesis and biological activity. It is further focused on the total syntheses of oxazolomycins and one formal synthesis reported to date.
ABSTRACT
The synthesis of novel sphingoid base-like compounds with a quaternary stereocentre was achieved in a sequence featuring [3,3]-sigmatropic rearrangements and olefin cross-metathesis transformation as the key reaction steps, which were accompanied by the rational selection of suitable functional group transformations. The stereochemistry of the desired tetra-substituted carbon bearing nitrogen functionality was determined via NOESY experiments of the advanced oxazolidine-2-thiones. Cell viability experiments revealed significant antiproliferative/cytotoxic activity of the target compounds 7, ent-7 and 29 against the Jurkat cell line, with the IC50 values of 6.6⯵M, 5.6⯵M and 6.1⯵M, respectively.
Subject(s)
Antineoplastic Agents/pharmacology , Sphingosine/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Conformation , Sphingosine/chemical synthesis , Sphingosine/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Synthetic analogues of the cytotoxic jaspine B and its stereochemical congeners have become an attractive target in the synthetic organic community owing to the search for novel therapeutic candidates with more potent anticancer activity, as cancer is the second leading cause of death worldwide. This review article provides insights into the different approaches and strategies available in the literature for the construction of jaspine B-related compounds.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Aquatic Organisms/chemistry , Chemistry Techniques, Synthetic/methods , Sphingosine/analogs & derivatives , Antineoplastic Agents/pharmacology , Humans , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , StereoisomerismABSTRACT
A flexible synthetic approach towards biologically active sphingoid base-like compounds with an integrated azobenzene framework was achieved via installing a chiral amino-alcohol fragment into the azobenzene system by utilizing the Wittig olefination of substituted (E)-triphenyl[4-(phenyldiazenyl)benzyl]phosphonium salts and d-isoascorbic acid derived aldehydes. All the prepared derivatives underwent a series of experiments to probe their photochromic properties, including the reversible E/Z isomerisation, material fatigue and thermal relaxation rate. The targeted E- and Z-isomeric sphingoid analogues were screened in vitro for anticancer activity on a panel of seven human malignant cell lines. Cell viability experiments revealed outstanding antiproliferative/cytotoxic activities of all the tested compounds with IC50 values in the low micromolar range for the most active derivatives. The biological activity of E- and Z-isomeric forms is different. Their entirely accurate differentiation is prevented by the rapid thermal relaxation of the corresponding Z-isomers.
Subject(s)
Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , Sphingosine/pharmacology , Animals , Antineoplastic Agents/chemistry , Azo Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A flexible synthetic approach to biologically active sphingoid base-like compounds with a 3-amino-1,2-diol framework was achieved through a [3,3]-sigmatropic rearrangement and late stage olefin cross-metathesis as the key transformations. The stereochemistry of the newly created stereogenic centre was assigned via a single crystal X-ray analysis of the (4S,5R)-5-(hydroxymethyl)-4-vinyloxazolidine-2-thione. In order to rationalise the observed stereoselectivity of the aza-Claisen rearrangement, DFT calculations were carried out. The targeted isomeric sphingoid bases were screened in vitro for anticancer activity on a panel of seven human malignant cell lines. Cell viability experiments revealed that C17-homologues are more active than their C12 congeners.
Subject(s)
Sphingosine/analogs & derivatives , Sphingosine/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Immunoglobulin G/chemistry , Immunoglobulin G/pharmacology , Melphalan/chemical synthesis , Melphalan/chemistry , Melphalan/pharmacology , Molecular Structure , Sphingosine/chemistry , Sphingosine/pharmacology , Stereoisomerism , Synthetic BiologyABSTRACT
Two approaches to a small library of cytotoxic dihydrosphingosine analogues are described. [3,3]-Sigmatropic rearrangements along with an OCM reaction were used as the key steps for the construction of the two isodihydrosphingosines ent-6 and 10, whereas the functional group manipulations, including Grubbs' metathesis chemistry, were applied to known isothiocyanate scaffolds 15 and 16 to provide access to the enantiomeric forms of ent-6 and 10 and diastereomeric isophytosphingosines ent-7.HCl and 14. Cell viability experiments revealed that the target isomeric sphingoid bases were more potent than the traditional anticancer agent cisplatin, with IC50 values in the low micromolar range for the most active compounds.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Sphingosine/chemistry , Sphingosine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , StereoisomerismABSTRACT
A straightforward synthesis of l-lyxo- and l-xylo-phytosphingosine along with their isomeric analogues has been accomplished. The salient features of this approach are the utilization of [3,3]-sigmatropic rearrangements to install a C-N bond and application of a late stage Wittig or OCM reaction to incorporate the hydrophobic chain unit. The final compounds were evaluated regarding their ability to alter both leukaemia and solid tumor cancer cells viability.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Sphingosine/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Isomerism , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacologyABSTRACT
The convergent synthesis of broussonetinines related congeners 3 and 4 with the simple C13 alkyl side chain and differently configured pyrrolidine skeleton has been achieved. Our approach relied on the [3,3]-sigmatropic rearrangements of chiral allylic substrates derived from d-xylose. Cross metathesis of the common oxazolidinone intermediates 7 and 8 with tridec-1-ene followed by alkylative cyclization completed the construction of both C-alkyl iminosugars. The targeted compounds 3 and 4 were screened for antiproliferative/cytotoxic activities against multiple cancer cell lines by MTT assay. Compound 3 exhibited very good in vitro potency on Caco-2 and Jurkat cell lines with IC50 value of 5.1 µM and 5.8 µM, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Caco-2 Cells , Cell Proliferation/drug effects , Humans , Jurkat Cells/drug effects , Oxazolidinones/chemistry , Pyrrolidines/chemistry , Structure-Activity RelationshipABSTRACT
The total synthesis of the anticancer agent (+)-spisulosine has been accomplished. The strategy involved a substrate-controlled aza-Claisen rearrangement to establish the erythro-configured amino-alcohol motif followed by deoxygenation to create a methyl side-chain. Subsequent Wittig olefination then permitted the construction of the carbon backbone of the target molecule. To investigate the antiproliferative effect of 1, its biological profile was examined on a panel of 6 human malignant cell lines and demonstrated the significant anticancer activity of 1 on at least five of the evaluated lines with IC50 < 1 µM (MCF-7, HTC-116, Caco-2, Jurkat and HeLa).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Lipids/chemical synthesis , Lipids/pharmacology , Antineoplastic Agents/chemistry , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , HeLa Cells , Humans , Jurkat Cells , Lipids/chemistry , MCF-7 Cells , Molecular StructureABSTRACT
Conformationally constrained sphingolipids such as anhydrophytosphingosines represented by jaspine B (also known as pachastrissamine) and its stereoisomers have become an attractive and timely target for total synthesis due to their significant biological activity as well as the unique structures. This review article describes the biological activity and chemistry of the natural jaspine B and its seven stereoisomers.
Subject(s)
Aquatic Organisms/chemistry , Cytotoxins/chemical synthesis , Cytotoxins/pharmacology , Sphingosine/analogs & derivatives , Animals , Chemistry Techniques, Synthetic , Cytotoxins/chemistry , Humans , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , StereoisomerismABSTRACT
A straightforward access to 2-epi-jaspine B (4.HCl) has been developed. Key to the approach was the use of Overman rearrangement for the instalment of a stereocentre bearing a nitrogen atom. Subsequent rational execution of the stereoselective transformations furnished the functionalized scaffold 38, whose coupling with a lipophilic segment under Wittig conditions, followed by deprotection and a THF core construction, completed the convergent synthesis of 2-epimer of 1. The final anhydrophytosphingosine 4.HCl was screened for its antiproliferative/cytotoxic activity employing multiple human cancer cell lines. In vitro evaluation revealed that 2-epi-jaspine B exhibited significant antitumour growth inhibitory activity against all used cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Sphingosine/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Inhibitory Concentration 50 , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacologyABSTRACT
Synthesis of the HCl salts of two anhydrophytosphingosines, jaspine B (1) and its 4-epi-congener 5 from easily available dimethyl l-tartrate and/or l-arabinose, is described. The key transformations are the efficient incorporation of a chiral amino group via [3,3]-sigmatropic rearrangements, a Wittig olefination for the instalment of the carbon backbone and the acid-promoted building-up of a tetrahydrofuran framework. Evaluation for in vitro antiproliferative/cytotoxic activity with a panel of human tumour cell lines using a MTT assay revealed for some compounds of our strategy noteworthy activity. Compound 1·HCl (IC50: 0. 41-2.35 µM), its antipode ent-1·HCl (IC50: 4.07-5.69 µM) and also stereoisomer 4·HCl (IC50: 4.28-6.10 µM) exhibited significant potency compared with clinically available anticancer drugs such as cisplatin (IC50: 11.4-14.7 µM) and etoposide (IC50: 1.2-21.2 µM) on MDA-MB-231, MCF-7 and Jurkat cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Sphingosine/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , StereoisomerismABSTRACT
An efficient synthesis of the polar part of sulfamisterin and its analogs starting from d-xylose is described. The corresponding allylic thiocyanates and trichloroacetimidates were subjected to aza-Claisen rearrangement that effectively generated a quaternary carbon having an amino group as one of the substituents. Subsequent functional group interconversions afforded the highly functionalized branched aminopolyol 29 that is expected to have the crucial application in the construction of sulfamisterin. On the other hand, the second diastereoisomer 34 would be transformed to 2-epi-congener. With respect to the appropriate stereochemical arrangement, the prepared polar segments 29 and 34 can also be utilized for the synthesis of mycestericins (E, G) and their analogs.
Subject(s)
Chemistry Techniques, Synthetic/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Sphingosine/analogs & derivatives , Xylose/chemistry , Models, Molecular , Molecular Conformation , Sphingosine/chemical synthesis , Sphingosine/chemistryABSTRACT
A facile synthetic route to d-ribo-C(20)-phytosphingosine 31 and its C2 epimer 32 is described. The Overman rearrangement of allylic trichloroacetimidates derived from the known ribose derivative 7 has been used as the key step. The subsequent functional group interconversions in rearranged products 14 and 15 followed by Wittig olefination, Pd/C-mediated reduction and the removal of protecting groups successfully constructed the final molecules.
Subject(s)
Ribose/chemistry , Sphingosine/analogs & derivatives , Molecular Structure , Sphingosine/chemical synthesis , Sphingosine/chemistry , StereoisomerismABSTRACT
An approach to the stereocontrolled synthesis of the protected form of sphingofungin E (32) starting from the known protected d-glucose derivative 3 is described herein. For the construction of a tetrasubstituted carbon atom that is substituted with nitrogen, the [3,3]-sigmatropic rearrangement of thiocyanate 8 was employed. Subsequent functional group interconversions afforded the highly functionalized fragment, allylic bromide 26. Its coupling reaction with the known C(12) hydrophobic segment 2, followed by further manipulation, completed the total synthesis.
Subject(s)
Thiocyanates/chemistry , Alcohols/chemical synthesis , Alcohols/chemistry , Amino Acids/chemical synthesis , Amino Acids/chemistry , Aza Compounds/chemistry , Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids, Unsaturated/chemistry , Glucose/chemistryABSTRACT
C-Glycosyl-(S)- and (R)-alanines 12a and 12b were synthesized from the known beta-C-glycoside 1. The nitrogen function was introduced by aza-Claisen rearrangement of the allylic thiocyanate 7, derived from the corresponding alcohol 6. The absolute configuration of the newly created chiral carbon center (C-3) was assigned by X-ray diffraction analysis of the intermediate 3(S)-isothiocyanato-D-glycero-D-galacto-decose 8a.
Subject(s)
Alanine/chemical synthesis , Glycosides/chemical synthesis , Alanine/chemistry , Crystallography, X-Ray , Glycosides/chemistry , Models, MolecularABSTRACT
A study of microwave-induced and standard thermal Overman rearrangement of selected allylic trichloroacetimidates 1a-1f, 6-8 to the corresponding acetamides 2a-2f, 9-11 is reported. The microwave-assisted rearrangement of trifluoroacetimidate 13 is also described. Using this methodology, an efficient access to versatile allylic trihaloacetamides building synthons was established.
Subject(s)
Acetamides/chemical synthesis , Aza Compounds/chemistry , Imidoesters/chemistry , Microwaves , Acetamides/chemistry , Isomerism , Molecular Structure , TemperatureABSTRACT
A stereoselective approach has been developed to the new sugar amino acid and potential potent turn mimic 5-O-(tert-butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-alpha-D-xylofuranose 3-C-carboxylic acid (12), via the [3,3]-sigmatropic rearrangement of allylic thiocyanates (Z)-6 and (E)-7, prepared from D-xylose. The synthesis of a new dipeptide 13 is also described.