Selective enhancement of (6-4) photoproduct formation in dithymine dinucleotides driven by specific sugar puckering.

Four dinucleotide analogs of thymidylyl(3'-5')thymidine (TpT) have been designed and synthesized with a view to increase the selectivity, with respect to CPD, of efficient UV-induced (6-4) photoproduct formation. The deoxyribose residues of these analogs have been modified to increase north and south conformer populations at 5'- and 3'-ends, respectively. Dinucleotides whose 5'-end north population exceeds ca. 60% and whose 3'-end population is almost completely south display a three-fold selective enhancement in (6-4) adduct production when exposed to UV radiation, compared to TpT. These experimental results undoubtedly provide robust foundations for studying the singular ground-state proreactive species involved in the (6-4) photoproduct formation mechanism.

Atropisomerism about aryl-C(sp3) bonds: chemically driven rotational pathway in cannabidiol derivatives.

The conformational behaviour arising from the restricted C(sp2)-C(sp3) axis in ortho O-substituted naphthylcyclohexane and naphthylcyclohexene oxide derivatives of cannabidiol was examined by means of VT-NMR experiments and DFT calculations. Atropisomeric compounds with barriers in the range of 91.1 to 95.1 kJ mol-1 were obtained at 298 K. Two possible transition states (TS1 and TS2) were located, one is more stable depending on the chemical modification made on the monoterpene ring close to the pivot bond. Extended analysis of TS structures to previously reported phenyl derivatives bearing the same O-substituent led to similar rotational pathways according to the series: through TS1 in arylcylohexenes and TS2 in arylcyclohexanes. Likewise, conversion of arylcyclohexenes into both series affects the rotation speed by decelerating it, and the nature of the aryl ring seems to have a very minor effect on this phenomenon.

Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions Analysis.

It is nowadays widely accepted that sweet taste perception is elicited by the activation of the heterodimeric complex T1R2-T1R3, customarily known as sweet taste receptor (STR). However, the interplay between STR and sweeteners has not yet been fully clarified. Here through a methodology coupling molecular dynamics and the independent gradient model (igm) approach we determine the main interacting signatures of the closed (active) conformation of the T1R2 Venus flytrap domain (VFD) toward aspartame. The igm methodology provides a rapid and reliable quantification of noncovalent interactions through a score (Δginter) based on the attenuation of the electronic density gradient when two molecular fragments approach each other. Herein, this approach is coupled to a 100 ns molecular dynamics simulation (MD-igm) to explore the ligand-cavity contacts on a per-residue basis as well as a series of key inter-residue interactions that stabilize the closed form of VFD. We also apply an atomic decomposition scheme of noncovalent interactions to quantify the contribution of the ligand segments to the noncovalent interplay. Finally, a series of structural modification on aspartame are conducted in order to obtain guidelines for the rational design of novel sweeteners. Given that innovative methodologies to reliably quantify the extent of ligand-protein coupling are strongly demanded, this approach combining a noncovalent analysis and MD simulations represents a valuable contribution, that can be easily applied to other relevant biomolecular systems.

SN- and NS-puckered sugar conformers are precursors of the (6-4) photoproduct in thymine dinucleotide.

Some amount of furanose in a southern conformation, possibly in both, but certainly in one of the two adjacent nucleotides of a dipyrimidine site, is necessary for (6-4) photoproduct formation in oligonucleotides. To explore the necessity, role, and most favorable location of each South sugar conformer in the formation of the (6-4) adduct in the thymine dinucleotide TpT, the photochemical behavior of two synthetic analogues, in which the South sugar conformation is prohibited for one of their two sugars, has been examined. Herein, we experimentally demonstrate that the presence of one sugar presenting some amount of South puckering, at any of the extremities, is sufficient to trigger (6-4) adduct formation. Nonetheless, the photochemical behavior of the dinucleotide with a South-puckered conformation at the 5'-end, mimics more closely that of TpT. In addition, using the 5' North 3' South-dilocked dinucleotide, we demonstrate that the flexibility of the South pucker at the 3'-end has little influence on the (6-4) adduct formation.

Anti Regiospecificity in the Photosensitized Cycloaddition of 4-Tetrazolouracil Nucleoside.

The [2 + 2] photocycloaddition of natural pyrimidine nucleobases is devoid of regioselectivity. Although modified pyrimidines have been developed to selectively obtain syn-cyclobutane isomers, the targeted formation of anti-cyclobutane isomers has not been addressed yet. Herein, using NMR analyses and DFT calculations, we demonstrate that the acetone photosensitized excitation of the 4-tetrazolouracil motif in the nucleoside series specifically provides anti-cyclobutane photoproducts in 51% yield. In addition, the cis stereomer formation is preferred over the trans-cyclobutane formation (71:29).

Intramolecular OH/π versus C-H/O H-Bond-Dependent Conformational Control about Aryl-C(sp3) Bonds in Cannabidiol Derivatives.

Conformational control in cannabidiol derivatives has been studied by NMR, XRD, and DFT. The stabilization of their axial M and P conformations about the aryl-C(sp3) bond is an effect of competing intramolecular OH/π and CH/O H-bonds. In a nonpolar solvent and in the solid state, the OH/π bond is a determinant of the M conformation. In polar solvents, the CH/O H-bond shifts the equilibrium toward the P conformer because of the breaking of the OH/π bond.

C2'-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level.

Fluorine configuration at C2' of the bis(2'-fluorothymidine) dinucleotide is demonstrated to drive intramolecular base stacking. 2'-ß F-Configuration drastically reduces stacking compared to the 2'-α series. Hence, base stacking emerges as being tunable by the C2'-F stereoconfiguration through dramatic puckering variations scrutinized by NMR and natural bond orbital analysis. Accordingly, 2'-ß F-isomer photoreactivity is significantly reduced compared to that of the 2'-α F-isomer.

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series.

Two successive original routes leading to two novel families of polyheterocycles starting from the versatile chromone-based Michael acceptors platform are reported herein. The major aspect of this work is the selective access to these frameworks by changing the course of the domino process involved in their formation. First, enaminochromanones were selectively accessed under uncommon kinetic control. In this study, we showed that the tuning of the selectivity toward the kinetic product could be achieved by key structural modifications of the different reaction partners involved in the domino process. Once selectivity was efficiently controlled, enaminochromanones were ultimately transformed into a more complex family of polyheterocycles containing the pyrrolo-oxazinone framework. Here, the modulation of the domino sequence toward these particularly scarce structures was enabled by a pivotal switch in reactivity induced by aryl-λ3-iodanes.

Original Mitsunobu-Triggered Sequence Involved in a One-Pot Domino Process toward Tetracyclic Systems Bearing a Bis-N,O-acetal Junction.

Herein is reported an efficient, one-pot domino process through a 1,6-aza-Michael addition-triggered sequence and an original Mitsunobu-type concerted sequence for the synthesis of tetracyclic systems containing a bis-N,O-acetal junction. This methodology led to the construction of four new bonds, the cleavage of three C-O bonds, and the generation of an asymmetric center. Mitsunobu activation afforded final ring closure involving the creation of two bonds, which remains unprecedented among reported Mitsunobu-type sequences. The latter occurred in a regioselective fashion at the challenging C6-position of 2-pyridone intermediates. In the case of adequately substituted enantiopure amino alcohols, up to 95:5 of diastereoisomeric excess was achieved. Computational studies allowed the discrimination of a favored pathway for Mitsunobu sequence and supported the regioselectivity as well as the diastereoselectivity observed for this step.

Atropisomerism about Aryl-C(sp(3)) Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution.

A catalytic hydrogenation of cannabidiol derivatives known as phenylcyclohexenes was used to prepare epimeric (1R,1S) and/or rotameric (M,P) phenylcyclohexanes. The reaction is diastereoselective, in favor of the 1S epimer, when large groups are attached to the phenyl ring. For each epimer, variable-temperature NMR experiments, including EXSY spectroscopy and DFT calculations, were used to determine the activation energies of the conformational exchange arising from the restricted rotation about the aryl-C(sp(3)) bond that led to two unequally populated rotamers. The conformational preference arises essentially from steric interactions between substituents vicinal to the pivot bond. The conformers of epimers (1S)-2e,f show high rotational barriers of up to 92 kJ mol(-1), unlike those of (1R)-2e,f and with much lower barriers of ∼72 kJ mol(-1). The height of the barriers not only depends on the substituents at the axis of chirality but also is influenced by the position of a methyl group on the monoterpene ring. The feature most favorable to high rotational barriers is when the methyl at C1 lies equatorially. This additional substituent effect, highlighted for the first time, seems fundamental to allowing atropisomerism in hindered ortho-substituted phenylcyclohexanes.

A minute amount of s-puckered sugars is sufficient for (6-4) photoproduct formation at the dinucleotide level.

The di-2'-α-fluoro analogue of thymidylyl(3',5')thymidine, synthesized to probe the effect of a minimum amount of S conformer on the photoreactivity of dinucleotides, is endowed with only 3% and 8% of S sugar conformation at its 5'- and 3'-end, respectively. This analogue gives rise to the (6-4) photoproduct as efficiently as the dithymine dinucleotide (74% and 66% at the 5'- and 3'-end, respectively) under 254 nm. Our results suggest that the 5'-N, 3'-S conformer gives rise to the (6-4) photoproduct.

Atropisomerism about aryl-Csp(3) bonds: the electronic and steric influence of ortho-substituents on conformational exchange in cannabidiol and linderatin derivatives.

Terpenylation reactions of substituted phenols were used to prepare cannabidiol and linderatin derivatives, and their structure and conformational behavior in solution were investigated by NMR and, for some representative examples, by DFT. VT-NMR spectra and DFT calculations were used to determine the activation energies of the conformational change arising from restricted rotation about the aryl-Csp(3) bond that lead to two unequally populated rotameric epimers. The NBO calculation was applied to explain the electronic stabilization of one conformer over another by donor-acceptor charge transfer interactions. Conformational control arises from a combination of stereoelectronic and steric effects between substituents in close contact with each other on the two rings of the endocyclic epoxide atropisomers. This study represents the first exploration of the stereoelectronic origins of atropisomerism around C(sp(2))-C(sp(3)) single bonds through theoretical calculations.

Regioselective synthesis of 3,4,5-trisubstituted 2-aminofurans.

Three series of methyl 5-substituted 2-aminofuran-4-keto-3-carboxylates have been prepared following a multicomponent reaction strategy by the addition of an isocyanide to 4-oxo-2-butynoate in the presence of an aldehyde. The cycloaddition regioselectivity is generally high (>95%) but decreases when an electron-rich substituent is located at the butynoate 4-position.

Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity.

A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.

Can fruit-form be a marker for argan oil production?

Deforestation is an important matter for the argan forest whose preservation necessitates planting trees. Macroscopic parameters are urgently needed to identify trees presenting good potential as oil producers. This study demonstrates that argan oil produced from kernels of apiculate fruit is richer in d-tocopherol, whereas oil produced from spherical fruit is richer in linoleic acid, and that produced from fusiform fruit is richer in oleic acid. Therefore, the use of fruit-form as a marker could permit an easy organic production of "naturally enriched" oils.

Volatile compound formation during argan kernel roasting.

Virgin edible argan oil is prepared by cold-pressing argan kernels previously roasted at 110 degrees C for up to 25 minutes. The concentration of 40 volatile compounds in virgin edible argan oil was determined as a function of argan kernel roasting time. Most of the volatile compounds begin to be formed after 15 to 25 minutes of roasting. This suggests that a strictly controlled roasting time should allow the modulation of argan oil taste and thus satisfy different types of consumers. This could be of major importance considering the present booming use of edible argan oil.

Argan oil and postmenopausal Moroccan women: impact on the vitamin E profile.

Vitamin E supplements could be beneficial for postmenopausal women. To evaluate the effect of edible argan oil consumption on the antioxidant status of postmenopausal women, the vitamin E serum level of 151 menopausal women consuming either olive or argan oil was determined. Serum level of vitamin E was increased in the argan oil consumer group. Therefore, an argan oil-enriched diet can be recommended to help prevent some postmenopausal disorders.

Therapeutic potential of argan oil: a review.

OBJECTIVES: The therapeutic benefits of argan oil consumption have been claimed by natives of Morocco and explorers for more than eight centuries. However, argan oil has remained unresearched for a long time. Traditionally, argan oil has been well known for its cardioprotective properties and it is also used in the treatment of skin infections. Argan oil is principally composed of mono-unsaturated (up to 80%) and saturated (up to 20%) fatty acids. As minor components, it contains polyphenols, tocopherols, sterols, squalene, and triterpene alcohols. Together with the mono-unsaturated fatty acids, these minor components are likely to be responsible for its beneficial effects. This review aims to present an overview of the known pharmacological properties of argan oil. KEY FINDINGS: Antiproliferative, antidiabetic, and cardiovascular-protective effects of argan oil have been particularly actively evaluated over the last 5 years in order to build on phytochemical studies that indicate the presence of large amounts of possibly pharmacologically active compounds. SUMMARY: This review shows that a lack of clinical data constitutes a serious weakness in our knowledge about argan oil, therefore it is difficult to correlate the reported pharmacological activities to any potential clinical relevance.

In silico study of MMP inhibition.

Lack of enzyme inhibition selectivity is frequently the major drawback preventing the development of enzyme inhibitors. Sulfonylhydrazides have recently been suggested to act as zinc ligands. Consequently, such derivatives potentially possess important industrial or therapeutic implications. DFT calculations (B3LYP/6-31G**+LANL2DZ theory level) of the binding modes and free energies of binding of a variety of N-acetyl-N'-sulfonylhydrazides in the presence of a Zn(2+) ion embedded in an MMP active site model show that protonated and deprotonated sulfonylhydrazides bind the Zn(2+) ion according to different modes. These results strongly suggest that sulfonylhydrazides can be developed as selective metalloprotease inhibitors, and the results of molecular docking computations fully support this hypothesis.

Simultaneous presence of unsaturation and long alkyl chain at P'1 of Ilomastat confers selectivity for gelatinase A (MMP-2) over gelatinase B (MMP-9) inhibition as shown by molecular modelling studies.

Structural analogues of Ilomastat (Galardin), containing unsaturation(s) and chain extension carrying bulky phenyl group or alkyl moieties at P'1 were synthesized and purified by centrifugal partition chromatography. They were analyzed for their inhibitory capacity towards MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14, main endopeptidases involved in tumour progression. Presence of unsaturation(s) decreased the inhibitory potency of compounds but, in turn increased their selectivity for gelatinases. 2b and 2d derivatives with a phenyl group inhibited preferentially MMP-9 with IC50 equal to 45 and 38 nM, respectively, but also display activity against MMP-2 (IC50 equal to 280 and 120 nM, respectively). Molecular docking computations confirmed affinity of these substances for both gelatinases. With aims to obtain a specific gelatinase A (MMP-2) inhibitor, P'1 of Ilomastat was modified to carry one unsaturation coupled to an alkyl chain with pentylidene group. Docking studies indicated that MMP-2, but not MMP-9, could accommodate such substitution; indeed 2a proved to inhibit MMP-2 (IC50=123 nM), while displaying no inhibitory capacity towards MMP-9.