RESUMO
cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CHâ¯OîS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.
RESUMO
Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B1-400), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B1-400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a-15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b-37b). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.
Assuntos
Diabetes Mellitus Tipo 2 , Camundongos , Humanos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Estrutura-Atividade , Lactamas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismoRESUMO
In solution, the solvent determines the molecular conformation and the chemical reaction viability and selectivity. When solvent-solute and solvent-solvent interactions present similar strengths, explicit salvation is the best way to describe a system. The problem to solve is how big the explicit shell should be. In this paper, we want to answer one of the fundamental questions in the implementation of explicit solvation, exactly how many solvent molecules should be added and where they should be placed. Here we determine the first solvent sphere around a molecule and describe how it controls the conformation and selectivity of a selected reaction. NMR experiments were carried out to identify the number of solvent molecules around the solute that constitutes the first solvent sphere, and the interaction between this solvent sphere and the solute was detected using DFT and QTAIM calculations. A new approach to the solvation energy is presented. Finally, we established the role of solvent molecules in the conformation of the solute and in the transition states that produce the two possible products of the reaction.
RESUMO
The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX â π*CâO interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX â π*CâO interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-CâO interactions are through the nO â π*CâO electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.
RESUMO
Knowing the conformational properties of 1(10),4-cyclodecadiene gamma-lactones is important because of the biogenetic and evolutionary implications on the different groups of sesquiterpene lactones. Despite their importance, there are no physicochemical data on the conformational dynamic and the potential energy surface associated with the conformational changes of the cyclodecadiene ring. Fischer's biogenetic theory on the origin of ambrosanolides and helenanolides has support in the results presented since the conformers that yield two groups of sesquiterpene lactones coexist in solution as demonstrated by dynamic NMR experiments. These results are important on the basis of Fischer's proposal that states that the biosynthesis of each group of pseudoguaianolides requires a specific enzyme to select the right conformer to start the electrophilic cyclization. The germacra-1(10),4-dien-12,8alpha-olides can exist as a mixture of four different conformations, [(15)D(5),(1)D(14)], [(15)D(5),(1)D(14)], [(15)D(5),(1)D(14)], and [(15)D(5),(1)D(14)], and it is also proposed that the configuration of trans-annular cyclization depends on the conformation of the precursor. The results of the study presented herein show that 6-epi-desacetyllaurenobiolide exists in solution at room temperature as a mixture of two stable conformers, [(15)D(5),(1)D(14)] and [(15)D(5),(1)D(14)], which are more stable due to the diminishing of the so-called allylic strain. Analysis of the potential energy surface associated with the conformational interchange showed two other conformers that are intermediaries in the equilibria between [(15)D(5),(1)D(14)]/[(15)D(5),(1)D(14)] and [(15)D(5),(1)D(14)]/[(15)D(5),(1)D(14)]. This indicates the presence of six different conformers participating in the global process instead of the four that have been proposed. The experimental values of DeltaH(++), DeltaG(++), DeltaH(conf), and DeltaG(conf) of the conformational exchange and those calculated at the mPW1B95/6-31+G(d,p) level of theory are very similar, indicating that such level of theory is adequate for the description of this conformational equilibrium.