Antiproliferative Activities and SwissADME Predictions of Physicochemical Properties of Carbonyl Group-Modified Rotenone Analogues.

Rotenone is a naturally occurring compound shown to exhibit antiproliferative activity against various cancer cell lines, indicating its potential as a lead anticancer agent. However, its toxicity against normal cells has prompted further investigation and chemical modifications. In this study, a library of carbonyl group-modified rotenone derivatives was synthesized and evaluated for their antiproliferative activities against MCF-7 breast cancer cells, A549 human lung carcinoma cells, and HCT116 human colorectal cancer cells using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results showed several promising compounds that inhibited cell proliferation. Specifically, the oxime and alcohol rotenone derivatives exhibited antiproliferative activities against all 3 cancer cell lines, while the ethoxy, carbamate, and alkene derivatives are selective against MCF-7 (IC50 =5.72 µM), HCT116 (IC50 =8.86 µM), and A549 (IC50 =0.11 µM), respectively. SwissADME analysis showed that the physicochemical properties and drug-likeness of the synthesized rotenone derivatives were within the set limits, suggesting the favorable characteristics of these compounds for drug development. The findings obtained in this work highlight the potential of rotenone derivatives as promising chemotherapeutic candidates.

Mechanistic analysis and optimization of the copper-catalyzed enantioselective intramolecular alkene aminooxygenation.

The catalytic asymmetric aminooxygenation of alkenes provides an efficient and straightforward approach to prepare chiral vicinal amino alcohols. We have reported a copper(II)-catalyzed enantioselective intramolecular alkene aminooxygenation, using (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as the oxygen source, which results in the synthesis of chiral indolines and pyrrolidines. Herein we disclose that kinetics studies indicate the reaction is first order both in substrate and the [Cu(R,R)-Ph-bis(oxazoline)]OTf(2) catalyst and zero order in TEMPO. Furthermore, kinetic isotope effect studies support that the cis-aminocupration step, the addition of N-Cu across the alkene, is the rate-limiting step. Subsequent formation of a carbon radical intermediate and direct carbon radical trapping with TEMPO is the indicated mechanism for the C-O bond formation as suggested by a deuterium labeling experiment. A ligand screen revealed that C(4)-phenyl substitution on the bis(oxazoline) is optimal for high asymmetric induction. The size of the substrate's N-sulfonyl group also influences the enantioselectivity of the reaction. The preparative-scale catalytic aminooxygenation reaction (gram scale) was demonstrated, and an unexpected dependence on reaction temperature was uncovered on the larger scale reaction.

Inhibitory Effects of B-, C-, and E-Ring-Truncated Deguelin Derivatives Against A549, HCT116, and MCF-7 Cancer Cells.

Deguelin has been extensively studied for its anticancer properties; however, its clinical application has been hindered by concerns about in vivo toxicity. Structural modifications of deguelin including ring truncation have been explored to enhance its pharmacological properties. In this study, the design and straightforward synthesis of a series of B, C, and E (BCE)-ring-truncated deguelin analogues with deoxybenzoin backbone were described. The structure-activity relationships (SARs) were established by evaluation of their inhibitory activities against three cancer cell lines, A549 (adenocarcinomic human alveolar basal epithelial cells), HCT116 (human colorectal cancer cells), and MCF-7 (breast cancer cells). Six derivatives demonstrated significant and selective inhibitory activities. The ketone derivative 3a showed potency against A549 (IC50 = 6.62 µM) while the oxime analogue 6a and D-ring-benzylated ketone analogue 8d exhibited activity against HCT116 (IC50 = 3.43 and 6.96 µM, respectively). Moreover, the D-ring alkylated derivatives 8c and 8e-f were active against MCF-7 cells (IC50 < 10 µM). The potential suitability of the BCE-ring-truncated deguelin derivatives for drug development was further supported by the favorable in silico prediction of their physicochemical properties, druglikeness, and toxicity. This study could provide valuable insights for the further development of novel anticancer agents.

Evidence for alkene cis-aminocupration, an aminooxygenation case study: kinetics, EPR spectroscopy, and DFT calculations.

Alkene difunctionalization reactions are important in organic synthesis. We have recently shown that copper(II) complexes can promote and catalyze intramolecular alkene aminooxygenation, carboamination, and diamination reactions. In this contribution, we report a combined experimental and theoretical examination of the mechanism of the copper(II)-promoted olefin aminooxygenation reaction. Kinetics experiments revealed a mechanistic pathway involving an equilibrium reaction between a copper(II) carboxylate complex and the γ-alkenyl sulfonamide substrate and a rate-limiting intramolecular cis-addition of N-Cu across the olefin. Kinetic isotope effect studies support that the cis-aminocupration is the rate-determining step. UV/Vis spectra support a role for the base in the break-up of copper(II) carboxylate dimer to monomeric species. Electron paramagnetic resonance (EPR) spectra provide evidence for a kinetically competent N-Cu intermediate with a Cu(II) oxidation state. Due to the highly similar stereochemical and reactivity trends among the Cu(II)-promoted and catalyzed alkene difunctionalization reactions we have developed, the cis-aminocupration mechanism can reasonably be generalized across the reaction class. The methods and findings disclosed in this report should also prove valuable to the mechanism analysis and optimization of other copper(II) carboxylate promoted reactions, especially those that take place in aprotic organic solvents.

Photo-Controlled [4+4] Cycloaddition of Anthryl-Polymer Systems: A Versatile Approach to Fabricate Functional Materials.

The reversible photo-induced [4+4] cycloaddition reaction of anthracene enables multiple cycles of dimerization and scission, allowing phototunable linkage of molecular fragments for the synthesis of polymer scaffolds. New functional materials ranging from hydrogels to shape-memory polymers were designed from anthryl-polymer systems because of their diverse photochemical reactivity and responsiveness. Light as an external stimulus allows for the remote and precise spatiotemporal control of materials without the need for additional reagents. Depending on how the photoreactive anthracene moieties were introduced, the interaction of anthryl-polymer systems with light results in various processes such as polymerization, cyclization, and cross-linking. Structural modifications of anthracene derivatives could shift their absorption from the ultraviolet to the visible light region, widening their range of applications including biologically relevant studies. These applications are further diversified and enhanced by the reversibility of the dimerization reaction using light and heat as stimuli. In this review, current developments in the synthesis and photodimerization of anthracene-containing polymers and their emerging applications in the fabrication of new materials are discussed.

Enhanced photo-reactivity of polyanthracene in the VIS region.

The wavelength-dependent photo-reactivity of polyanthracene was explored upon UV-C and VIS light irradiation. The material was prepared via one-pot chemical oxidation route using FeCl3 as oxidizing agent. A decrease in surface hydrophobicity of a polyanthracene-coated poly(methylmethacrylate) substrate from 109.11° to 60.82° was observed upon UV-C exposure for 48 hrs which was attributed to increase in oxygen content at the surface, as validated by energy dispersive X-ray spectroscopy. Upon exposure to ultraviolet-visible LEDs, photo-dimerization of polyanthracene in solution occurred and was monitored using UV-VIS spectroscopy. The photo-dimer product formation decreased from 381 nm to 468 nm and was found to be higher for the polyanthracene material compared to the monomer anthracene. At 381 nm, photo-dimerization of the material was found to be approx. 4x more efficient than the non-substituted monomer counterpart. Results obtained show that photo-dimerization of polyanthracene will proceed upon exposure with visible light LEDs with reduction in efficiency at longer wavelengths. To compensate, irradiation power of the light source and irradiation time were increased.

Self-assembled phenylethynylene bis-urea macrocycles facilitate the selective photodimerization of coumarin.

There is much interest in designing molecular sized containers that influence and facilitate chemical reactions within their nanocavities. On top of the advantages of improved yield and selectivity, the studies of reactions in confinement also give important clues that extend our basic understanding of chemical processes. We report here, the synthesis and self-assembly of an expanded bis-urea macrocycle to give crystals with columnar channels. Constructed from two C-shaped phenylethynylene units and two urea groups, the macrocycle affords a large pore with a diameter of ∼9 Å. Despite its increased size, the macrocycles assemble into columns with high fidelity to afford porous crystals. The porosity and accessibility of these channels have been demonstrated by gas adsorption studies and by the uptake of coumarin to afford solid inclusion complexes. Upon UV-irradiation, these inclusion complexes facilitate the conversion of coumarin to its anti-head-to-head (HH) photodimer with high selectivity. This is contrary to what is observed upon the solid-state irradiation of coumarin, which affords photodimers with low selectivity and conversion.

Stereoselective Copper-Catalyzed Intramolecular Alkene Aminooxygenation: Effects of Substrate and Ligand Structure on Selectivity.

A new protocol for diastereoselective copper-catalyzed intra-molecular alkene aminooxygenation, which provides methyleneoxy-functionalized disubstituted pyrrolidines and five-membered cyclic ureas from the corresponding γ-alkenyl sulfonamides and N-allylureas, is reported. In addition, some success was achieved in enantioselective desymmetrizations reactions. We discovered that the level of enantioselectivity and diastereoselectivity could be tuned by choice of copper(II) ligands and substrate N-substituent.

Robust scalable synthesis of a bis-urea derivative forming thixotropic and cytocompatible supramolecular hydrogels.

Synthetic hydrogels address a need for affordable, industrially scalable scaffolds for tissue engineering. Herein, a novel low molecular weight gelator is reported that forms self-healing supramolecular hydrogels. Its robust synthesis can be performed in a solvent-free manner using ball milling. Strikingly, encapsulated cells spread and proliferate without specific cell adhesion ligands in the nanofibrous material.

Diastereoselective pyrrolidine synthesis via copper promoted intramolecular aminooxygenation of alkenes: formal synthesis of (+)-monomorine.

The diastereoselectivity of the copper-promoted intramolecular aminooxygenation of various alkene substrates was investigated. Alpha-substituted 4-pentenyl sulfonamides favor the formation of 2,5-cis-pyrrolidines (dr >20:1) giving excellent yields which range from 76-97% while gamma-substituted substrates favor the 2,3-trans pyrrolidine adducts with moderate selectivity (ca. 3:1). A substrate whose N-substituent was directly tethered to the alpha-carbon exclusively yielded the 2,5-trans pyrrolidine. The synthetic utility of the method was demonstrated by a short and efficient formal synthesis of (+)-monomorine.