Douglasashworth1076

The detailed picture of bonding patterns suggests that the OPA formation in the Wittig mechanism can be better understood in terms of a two-stage one-step mechanism beyond molecular orbital considerations behind the traditionally accepted [2+2] cycloaddition proposal.Eight new polyhydroxanthones, penicixanthones A-H (1-8), including four monomers (1-4) and four dimers (5-8), were isolated from solid cultures of Penicillium purpurogenum SC0070. Their structures were elucidated by extensive spectroscopic analysis, X-ray single-crystal diffraction, and theoretical computations of ECD spectra. Penicixanthone B (2) has a hexahydroxanthone structure featuring an unusual oxygen bridge between C-6 and C-8a. Penicixanthone D (4) is distinct from other penicixanthones in stereochemistry, and its biosynthetic mechanism was proposed based on theoretical simulations for the reaction pathway of C-10a epimerization. Penicixanthone G (6) exhibited the most potent cytotoxicity (IC50 0.3-0.6 μM) when tested against human carcinoma A549, HeLa, and HepG2 cells, whereas it was nontoxic to the normal Vero cells (IC50 > 50 μM). It also displayed the strongest antibacterial activity (MIC 0.4 μg/mL) against both Staphylococcus aureus and the methicillin-resistant strain MRSA.Bonds between sulfur atoms are prevalent in natural products, peptides, and proteins. Disulfide bonds have a distinct chromophore. The wavelength of their maximal absorbance varies widely, from 250 to 500 nm. Here, we demonstrate that this wavelength derives from stereoelectronic effects and is predictable using quantum chemistry. We also provide a sinusoidal equation, analogous to the Karplus equation, that relates the absorbance maximum and the C-S-S-C dihedral angle. These insights provide a facile means to characterize important attributes of disulfide bonds and to design disulfides with specified photophysical properties.The reaction of GeCl2·dioxane with 2 equiv of the thiolate LiSHyp [Hyp = Si(SiMe3)3] yields the germanide (12-crown-4)2Li[Ge(SHyp)3] (1). A small structural variation in the substituent leads to a completely different result because the reaction of GeCl2·dioxane with 2 equiv of the thiolate KSHypPh3 [HypPh3 = Si(SiMe3)2(SiPh3)] in toluene yields the unexpected compound [Ph3Si][Me3Si]Ge[(C6H5)Ph2SiSiMe32SiS]Si[SSiMe3] (2) in high yield. The reaction cascade to give 2 includes several rearrangement reactions and an intramolecular [2 + 4] cycloaddition of a phenyl ring. The syntheses and molecular structures of both compounds are presented, together with quantum-chemical calculations and NMR measurements, to enlighten the reaction mechanism behind the formation of 2.The majority of current drugs against diseases, such as cancer, can bind to one or more sites in a protein and inhibit its activity. There are, however, well-known limits on the number of druggable proteins, and complementary current drugs with compounds that could selectively target DNA or RNA would greatly enhance the availability of cellular probes and therapeutic progress. We are focusing on the design of sequence-specific DNA minor groove binders that, for example, target the promoter sites of transcription factors involved in a disease. We have started with AT-specific minor groove binders that are known to enter human cells and have entered clinical trials. To broaden the sequence-specific recognition of these compounds, several modules that have H-bond acceptors that strongly and specifically recognize G·C base pairs were identified. A lead module is a thiophene-N-alkyl-benzimidazole σ-hole-based system with terminal phenyl-amidines that have excellent affinity and selectivity for a G·C base pair in the minor groove. Efforts are now focused on optimizing this module. In this work, we are evaluating modifications to the compound aromatic system with the goal of improving GC selectivity and affinity. The lead compounds retain the thiophene-N-alkyl-BI module but have halogen substituents adjacent to an amidine group on the terminal phenyl-amidine. The optimum compounds must have strong affinity and specificity with a residence time of at least 100 s.Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain central to five azoles and additional dehydroamino acids. The pathway through which these large thiopeptide antibiotics are formed in Streptomyces viridochromogene remains elusive. Starting with the cloning of the biosynthetic gene cluster of sulfomycins, we here dissect a two-stage process in which an unusual dehydrogenase heterotrimer functions with two distinct YcaO proteins to install five azole heterocycles into the core peptide sequence of the precursor peptide. The first stage involves the activity of a typical cyclodehydratase complex composed of a didomain E1-YcaO protein and an F-protein partner to heterocyclize distant residues l-Cys2 and l-Thr9 and then the activity of the heterotrimeric dehydrogenase complex that converts the resulting azolines to azoles. In the second stage, this dehydrogenase complex associates with a discrete YcaO protein to form an atypical, four-component azole synthase complex, which is capable of sequentially converting residues l-Cys7, l-Thr5, and l-Ser12 to azoles in a distinct manner. During this process, an E1-like partner protein plays a critical role and functions through the two stages to mediate a variety of specific protein-protein interactions. This partner protein participates in the formation of the active dehydrogenase heterotrimer and the engagement of discrete YcaO activity to form the azole synthase heterotetramer. The findings in this study advance the understanding in the biosynthesis of different azole-containing RiPPs and set the stage for the discovery, engineering, and creation of new thiopeptides using genome mining and synthetic biology approaches.Transition metal complexes are ubiquitous in biology and chemical catalysis, yet they remain difficult to accurately describe with ab initio methods due to the presence of a large degree of dynamic electron correlation, and, in some cases, strong static correlation which results from a manifold of low-lying states. Progress has been hindered by a scarcity of high quality gas-phase experimental data, while exact ab initio predictions are usually computationally unaffordable due to the large size of the relevant complexes. In this work, we present a data set of 34 tetrahedral, square planar, and octahedral 3d metal-containing complexes with gas-phase ligand-dissociation energies that have reported uncertainties of ≤ 2 kcal/mol. SGI-1776 supplier We perform all-electron phaseless auxiliary-field quantum Monte Carlo (ph-AFQMC) calculations utilizing multi-determinant trial wavefunctions selected by a blackbox procedure. We compare the results with those from density functional theory (DFT) with the B3LYP, B97, M06, PBE0, ωB97X-V, and DSD-PBEP86/2013 functionals, and a localized orbital variant of coupled cluster theory with single, double, and perturbative triple excitations (DLPNO-CCSD(T)).