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Carbodiimides-Mediated Multi Component Synthesis of Biologically Relevant Structures
Full text linkMulti-component reactions are very popular because they offer a wealth of products, while requiring only a minimum effort
combining many elements of an ideal synthesis, such as operational simplicity, atom economy, bond-forming efficiency, and the access
to molecular complexity from simple starting materials. As such, multi-component reactions have become the cornerstones of both
combinatorial chemistry and diversity-oriented synthesis and thus playing a central role in the development of modern synthetic methodology
for pharmaceutical and drug discovery research. In this Insight we will highlight the development of novel multi-component
reactions based on the reactivity of carbodiimides, paying particular attention on their mechanistic features. We will address our attention
on the process developed by us and others groups, in these last years, for the synthesis of biologically relevant structures such as,
for example, heterocycles and glyco-conjugates
Mode of binding of camptothecins to double helix oligonucleotides
No full textWe report an NMR study on the interaction of topotecan (Tpt) and other camptothecins (Cpts) with several double helix and single strand oligonucleotides. The results obtained by (31)P NMR spectroscopy, nuclear Overhauser experiments (NOE) and molecular dynamics (MD) simulations show that Cpt drugs do not intercalate into the double helix, as suggested by many authors. Phosphorus NMR spectra indicated that no deformation occurs at any level of the phosphodiester backbone, while 2D NOESY experiments allowed the detection of several contacts between the aromatic protons of Cpts and those of the double helix. Models of the drug/oligonucleotide complexes, built on the basis of NOE data, show that the drug is located at the end of the double helix, by stacking the A and B rings with the guanine or cytidine of the terminal CG base pairs, with a preference for the 3[prime or minute]-terminal end sites. Cpts interact with double strand, as well as with single strand oligomers, as can be seen from the NMR shift variation observed on the drug protons; but this shielding effect cannot be an evidence of intercalation, as it is largely due to external non-specific interactions of the positively charged drug with the negatively charged ionic surface of the oligonucleotide. The molecular weight of one of the complexes was obtained from the correlation time value. The conformational behaviour of the DNA fragment d(CGTACG)(2) was studied by MD simulations on a ns time scale in the presence of water molecules and Na(+) ions. Different models were examined and the deformations induced on the phosphodiester backbone by molecules that are known to intercalate, were monitored by MD simulations
Diversity oriented combinatorial synthesis of multivalent glycomimetics through a multicomponent domino process
No full textBoth multicomponent reactions and diversity oriented synthesis are indispensable tools for the modern medicinal chemist. However, their employment for the synthesis of multivalent glycomimetics has not been exploited so far although the importance that such compounds play in exploring multivalency on glycoside inhibition. Herein, we report the combinatorial synthesis of diversity oriented hetero di- and trivalent glycomimetics through a multicomponent domino process. The process is high yielding and very general, working efficiently with easily accessible sugar starting materials such as glycosylamines, glycosylazides, and glycosylisothiocyanates, having the reactive functional groups tethered either directly to the anomeric carbon, through a suitable linker, or to the primary 6 position of hexoses (or 5 position of pentoses), leading, in the latter case, to glycomimetics with artificial enzymatically stable backbone. The process has been also exploited for the multicomponent synthesis of aminoglycoside (neomycin) conjugates
Mode of binding of the cytotoxic alkaloid berberine with the double helix oligonucleotide d(AAGAATTCTT)(2).
No full textBerberine, an isoquinoline plant alkaloid, belongs to the structural class of protoberberines. Recently, the ability of these compounds to act as Topoisomerase I or II poisons, was related to the antitumor activity. The binding of protoberberins to DNA has been studied and the partial intercalation into the double helix has been considered responsible for their activity. We have studied the interaction of berberine with the double helix oligonucleotides d(AAGAATTCTT)(2), d(GCGATCGC)(2), d(CGTATACG)(2), d(CGTACG)(2), 5'-d(ACCTTTTTGATGT)-3'/5(ACATCAAAAAGGT)-3' and with the single strand 5'-d(ACATCAAAAAGGT)-3', by 1H, 31P NMR and UV spectroscopy. Phosphorus resonance experiments were performed to detect small conformational changes of the phosphoribose backbone, in the case that an intercalation process occurs. Our data reveal that berberine does not intercalate into the duplexes studied, and binds preferentially to AT rich sequences. The structure of the complex with d(AAGAATTCTT)(2) was determined by using proton 2D NOESY spectra, which allowed to obtain several NOE contacts between the drug and the nucleotide. Structural models were built up by Molecular Mechanics (MM) and Molecular Dynamics (MD) calculations, by using the inter-proton distances derived from the NOE values. Berberine results to be located in the minor groove, lying with the convex side on the helix groove and presenting the positively charged nitrogen atom close to the negative ionic surface of the oligomer. The large 1H chemical shifts variation, observed for the drug when it is added to the above duplexes, as well as to the single strand oligomer, was interpreted with non-specific ionic interactions. The binding constants were measured by UV and NMR spectroscopy. They are strongly affected by the ionic strength and by the self-association process, which commonly occurs with this type of drugs. A dimerisation constant was measured and the value was included in the calculations of the binding constants. The results obtained show that the non-specific ionic interactions represent the major contribution to the values of the binding constants. These parameters, as well as the protons chemical shift variation of the ligand, are thus not diagnostic for the identification of a drug/DNA complex
Multicomponent synthesis of peptide-sugar conjugates incorporating hexafluorovaline
No full textThe development of new methods for linking sugars to peptides or proteins is an active area of research because natural glycopeptides or neoglycoconjugates play important roles in biology and medicine and are indispensable tools for probing several biological processes. Herein we report a
novel one-pot, three-component process for the synthesis of peptide-urea conjugates incorporating a hexafluorovaline residue under very mild conditions and high yields using commercially available starting materials such as carbodiimides, a-amino acid derivatives and 4,4,4-trifluoro-3-trifluoromethylcrotonic acid. The reaction has been exploited for the synthesis of a library of structurally diverse peptidesugar conjugates incorporating hexafluorovaline through a four-component, one-pot sequential process by generating the carbodiimides in situ from
easily accessible sugar containing azides and commercial available isocyanates through the Staudinger (aza-Wittig) reaction
Three-component sequential synthesis of N,N'-disubstituted 5-arylidenedihydropyrimidine-2,4-dione
No full textA three-component sequential process consisting in (1) in situ formation of carbodiimides by Staudinger
reaction, (2) reaction with 2-(bromomethyl)-3-aryl-2-propenoic acids, and (3) final cyclization of the
resulting N-acylurea intermediates in order to obtain the synthesis of an array of N,N0-disubstituted 5-
arylidenedihydropyrimidine-2,4-dione under mild conditions is presented
Synthesis ofN-Glycosyl Conjugates through a Multicomponent Domino Process
Full text linkThe development of efficient methods for the combinatorial
synthesis of N-glycosyl conjugates is vital for many fields of
modern synthetic organic chemistry. Herein, we report a
multicomponent domino process for the regioselective synthesis
of a large array N-glycosyl-Asp-urea conjugates,
which could be further functionalized in a chemoselective way, starting from easily accessible reactants such as N-glycosylamines,
fumaric acid monoesters, azides, and isocyanates.
The process occurs under very mild conditions, does not
require the use of strong bases/acids or high temperature,
and is highly versatile, working efficiently with a range of
protecting groups and substituents
Multi-component synthesis of peptide-sugar conjugates
No full textRecent years have witnessed a growing interest in the development of new methods for linking sugars to peptides or proteins because natural glycopeptides or neoglycoconjugates with well defined chemical structures are very important tools to study diverse biological phenomena. Herein we report a novel, one-pot, three-component process for the synthesis of peptide-urea conjugates incorporating a hexafluorovaline or an aspartic acid alkyl ester residue under very mild conditions and high yields. The reaction has been exploited for the synthesis of a wide array of structurally diverse peptide-sugar conjugates through a regiospecific four-component, one-pot sequential domino process, by generating the reacting sugar-carbodiimides in situ from readily accessible starting materials
Catalytic asymmetric synthesis of secondary alcohols using chiral cis- 1-amino-2-hydroxy- 1,2,3,4-tetrahydronaphthalene as chiral ligand
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