Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5- hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl- 1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1‴R,2‴R,4‴S + 2R,1‴R,2‴R,4‴S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.Fil: Batista Junior, João Marcos. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Batista, Andrea N. L.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Kato, Massuo J.. Universidade de Sao Paulo; BrasilFil: Bolzani, Vanderlan S.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: López, Silvia Noelí. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Nafie, Laurence A.. Syracuse University; Estados UnidosFil: Furlan, Maysa. Universidade Estadual Paulista Julio de Mesquita Filho; Brasi

Vibrational circular dichroism in amino acids and peptides. 3. Solution- and solid-phase spectra of alanine and serine

Vibrational circular dichroism (VCD) in solution and solid phases is reported for alanine and serine in vibrational modes involving hydrogen and deuterium stretching motions. The quality of the solution-phase VCD spectra was significantly enhanced by on-line computer averaging techniques. Solid-phase spectra were obtained as mulls in halocarbon oil and this method promises to be a useful new sampling technique in VCD spectroscopy. VCD signals in the solid phase are considerablq larger than the solution spectra for the same molecules. The increased magnitude is attributed to such effects as conformational uniformity, local ordering, and crqstal lattice interactions between molecules. A neb vibrational assignment of solutionphase alanine in the carbon-hydrogen stretching region is presented as determined from the solid-phase Ranian spectra of alaninc-do and alanine-C*-dl. The basic features of the observed VCD spectra of alanine and serine are discussed in terms of their constituent normal modes and the chiral perturbation of locally symmetric groups

Effect of Conformational Variability on the Drug Resistance of Candida auris ERG11p and FKS1

Candida auris infection has been recognized as an urgent threat to antifungal drug resistance, and the Eagle effect of C. auris FKS1 (1,3-β-d-glucan synthase) wild-type isolates has also been noted. The Eagle effect, namely, where higher concentrations of antifungals reduce fungicidal activity relative to lower concentrations, is a confounding factor of apparent antifungal resistance, but the detailed mechanism remains unclear. Here, we present the conformational variability of mutation sites for ERG11p (lanosterol 14α-demethylase) and FKS1 from deep neural network-based prediction along with the reported X-ray crystallographic and cryo-electron microscopy (cryo-EM) structures of antifungals. The sequence variability maps provide valuable insights into the inconsistent correlation between azole resistance and the mysterious Eagle effect with the dispersion of minimal inhibitory concentration (MIC) for echinocandin resistance. The conformational variability prediction supports the hypothesis that mutations K143R of clade I, VF125AL of clade III, and Y132F of clade IV for C. auris ERG11p make the corresponding site variable and that an increased population of invisible variable conformations potentially contributes to triazole resistance. In contrast, the predicted rigid conformation by the S639F mutation of hot spot region 1 (HS1) for FKS1 suggests that caspofungin (CAS) is involved in an uncompetitive inhibition, and a decreased population of the CAS-bound state of FKS1 with Rho1 leads to drug resistance. The predicted variable HS1 region for FKS1 WT isolates and the rigid one for FKS1 S639F mutants support the in vivo drug response and the in vitro MIC dispersion. A plausible mechanism of the Eagle effect is hereby proposed, namely, that a high concentration of CAS with a high membrane affinity reduces the population of the CAS-bound state of FKS1 with Rho1, as well as accompanying events such as aggregation or association depending on the conformational variability of HS1

Simultaneous Resonance Raman Optical Activity Involving Two Electronic States

In the present work, the first observation of strong resonance Raman optical activity (RROA) involving more that one resonant electronic state is reported. The chiral transition metal complex bis-(trifluoroacetylcamphorato) copper­(II), abbreviated Cu­(tfc)₂, exhibits both resonance Raman (RR) and RROA spectra with laser excitation at 532 nm. Vibrational assignments for this complex were carried out by comparing the non-RR spectra of Cu­(tfc)₂ excited at 1024 nm to density functional theory (DFT) calculations. The theory of the single-electronic-state (SES) RROA is extended to the next simplest level of theory involving two resonant electronic states (TES) without interstate vibronic coupling as an aide to the interpretation of the observed TES-RROA spectra. Based on measured UV–vis electronic absorbance spectra and corresponding TD-DFT calculations, the most likely two states associated with the RROA spectra are identified