The Design of α/β‐Peptides: Study on Three‐Residue Turn Motifs and the Influence of Achiral Glycine on Helix and Turn

Novel three‐residue helix‐turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have ‘β‐Caa‐L ‐Ala‐L ‐Ala,’ ‘β‐Caa‐L ‐Ala‐γ‐Caa,’ and ‘β‐Caa‐L ‐Ala‐δ‐Caa’ (in which β‐Caa is C‐linked carbo‐β‐amino acid, γ‐Caa is C‐linked carbo‐γ‐amino acid, and δ‐Caa is C‐linked carbo‐δ‐amino acid) at the C terminus. These turn structures are stabilized by 12‐, 14‐, and 15‐membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7‐mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β‐peptides were designed and synthesized with alternating glycine (Gly) and (S)‐β‐Caa to study the influence of an achiral α‐residue on the helix and helix‐turn structures. In contrast to previous results, the three ‘β–α–β’ residues at the C terminus (α‐residue being Gly) are stabilized by only a 13‐mr forward hydrogen bond, which resembles an α‐turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed.     

Chiral allene-containing phosphines in asymmetric catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands.     

Microwave-assisted synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and pyrano[4,3-b]pyrans catalyzed by L-glutamine functionalized magnetic nanoparticles in water:ethanol mixture

In this work, we report an effective, one-pot syntheses of benzo[4,5]imidazo[1,2-a]pyrimidine and pyrano[4,3-b]pyran derivatives using L-glutamine functionalized nanoparticles (Fe₃O₄@SiO₂@L-glutamine NPs) under microwave irradiation. The organo-nanocatalyst underwent characterization through diverse techniques, including FT-IR, p-XRD, SEM, TEM, EDX, XPS, TGA, and VSM. Microwave irradiation and multicomponent reactions synergistically yield excellent product yields (≈80%–95%) in shorter reaction times (≈6–15 min) with a broader substrate scope. The organo-nanocatalyst displays notable catalytic efficacy, evidenced by high turnover numbers (TON) and turnover frequencies (TOF) across syntheses. This innovative protocol showcases exceptional efficiency, cost-effectiveness, and environmental friendliness, with advantages like minimal reaction conditions, easy catalytic recovery, recyclability, operational simplicity, and the use of eco-friendly solvents.     

Remarkably flexible quinazolinones—synthesis and biological applications

Even though several quinazolinone derivatives have been synthesized, still there is a constant demand for designing and synthesis of new quinazolinone derivatives by fine-tuning the electronic and steric properties of substituents due to their interesting structure-based biological utilities and the versatile chemistry. While many of the synthetic routes are useful as building blocks in synthetic organic chemistry, the drawbacks of some of these methods like unsatisfactory or variable yields, prolonged reaction times, inadequate tolerance to other substrates, including the use of costly catalysts/reagents. This review article is mainly focused on various synthetic routes for the preparation of quinazolinones, their important properties and applications.     

Alkenyl complexes of platinum group metals: a platform for diverse reactivity patterns

Intermediates for many catalysis reactions reported in the literature are metal‐alkyl and metal‐alkenyl, including metallacycloalkane species. Synthesis and reactions of metal‐alkyl, alkenyl and metallacyle complexes have shown a great deal of development during the past few decades. This review summarizes the significant contributions reported on metal‐alkenyl compounds, specifically those containing at least a carbon chain with pendant alkene group [M―CH₂CH₂CH?CH₂]. Although metal‐alkenyl complexes are stable with strong chelating diphosphines and with a decrease in the ligand donor strength, the complexes can decompose without any ambiguity. For example, platinum‐dialkenyl complexes react readily via β‐hydrogen elimination and reductive elimination promoted by the nature of the ligand, solvent and length of carbon chains. These complexes can also undergo intramolecular irreversible isomerization and this leads to the selective catalytic isomerization of 1‐alkenes to 2‐alkenes in the presence of platinum‐dialkenyl complexes as catalysts. Perhaps the most striking manifestations of flexibility are the facile and complete intramolecular and intermolecular alkene metathesis to yield the corresponding metallacycloalkenes in the presence of Grubbs’ catalysts. The diverse chemical reactivity of these complexes demonstrates both the scope and complexity of metal‐alkenyl chemistry depending on the nature of ligand and metal. Copyright © 2014 John Wiley & Sons, Ltd.     

An informatic pipeline for managing high-throughput screening experiments and analyzing data from stereochemically diverse libraries

Integration of flexible data-analysis tools with cheminformatics methods is a prerequisite for successful identification and validation of “hits” in high-throughput screening (HTS) campaigns. We have designed, developed, and implemented a suite of robust yet flexible cheminformatics tools to support HTS activities at the Broad Institute, three of which are described herein. The “hit-calling” tool allows a researcher to set a hit threshold that can be varied during downstream analysis. The results from the hit-calling exercise are reported to a database for record keeping and further data analysis. The “cherry-picking” tool enables creation of an optimized list of hits for confirmatory and follow-up assays from an HTS hit list. This tool allows filtering by computed chemical property and by substructure. In addition, similarity searches can be performed on hits of interest and sets of related compounds can be selected. The third tool, an “S/SAR viewer,” has been designed specifically for the Broad Institute’s diversity-oriented synthesis (DOS) collection. The compounds in this collection are rich in chiral centers and the full complement of all possible stereoisomers of a given compound are present in the collection. The S/SAR viewer allows rapid identification of both structure/activity relationships and stereo-structure/activity relationships present in HTS data from the DOS collection. Together, these tools enable the prioritization and analysis of hits from diverse compound collections, and enable informed decisions for follow-up biology and chemistry efforts.     

Ring expansion/homologation--aldehyde condensation cascade using tert-trihalomethylcarbinols

Treatment of cyclic tert-trihalomethylcarbinols with CrCl(2) in THF/HMPA in the presence of aryl or aliphatic aldehydes initiates a cascade sequence of one carbon ring expansion-olefination affording conjugated exocyclic ketones. Acyclic tert-trihalomethylcarbinols undergo a comparable cascade of one carbon homologation-olefination.     

Structural unit analysis identifies lead series and facilitates scaffold hopping in combinatorial chemistry

Combinatorial chemistry and high-throughput screening technologies produce huge amounts of data on a regular basis. Sieving through these libraries of compounds and their associated assay data to identify appropriate series for follow-up is a daunting task, which has created a need for computational techniques that can find coherent islands of structure-activity relationships in this sea. Structural unit analysis (SUA) examines an entire data set so as to identify the molecular substructures or fragments that distinguish compounds with high activity from those with average activity. The algorithm is iterative and follows set heuristics in order to generate the structural units. It produces graphs that represent a set of units, which become SUA rules. Finding all of the input structures that match these graphs generates clusters. The Apriori algorithm for association rule mining is adapted to explore all of the combinations of structural units that define useful series. User-defined constraints are applied toward series selection and the refinement of rules. The significance of a series is determined by applying statistical methods appropriate to each data set. Application to the NCI-H23 (DTP Human Tumor Cell Line Screen) database serves to illustrate the process by which structural series are identified. An application of the method to scaffold hopping is then discussed in connection with proprietary screening data from a lead optimization project directed toward the treatment of respiratory tract infections at Bayer Healthcare. SUA was able to successfully identify promising alternative core structures in addition to identifying compounds with above-average activity and selectivity.     

Three New ent‐Labdane Diterpenoids from the Wood of Excoecaria agallocha Linn.

An extensive study of metabolites present in Excoecaria agallocha Linn . led to the isolation of three new ent‐labdane‐type diterpenoids, named agallochaexcoerins A–C ( 1 – 3 ), besides three known compounds. The skeleton present in compound 1 is rather unusual, containing of a seven‐membered lactone. The structures were elucidated on the basis of spectroscopic studies and comparison with known related compounds. The isolated compounds 1 – 6 were not active against Raw 264.7 (macrophage‐like), K 562 (leukemia), and COLO 205 (colon) human carcinoma cell lines.