Recent advances in small molecules for improving mitochondrial disorders.

Mitochondrial disorders are observed in various human diseases, including rare genetic disorders and complex acquired pathologies. Recent advances in molecular biological techniques have dramatically expanded the understanding of multiple pathomechanisms involving mitochondrial disorders. However, the therapeutic methods for mitochondrial disorders are limited. For this reason, there is increasing interest in identifying safe and effective strategies to mitigate mitochondrial impairments. Small-molecule therapies hold promise for improving mitochondrial performance. This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.

Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity.

The higher prevalence of metabolic syndrome (MetS) in women after menopause is associated with a decrease in circulating 17ß-oestradiol. To explore novel treatments for MetS in women with oestrogen deficiency, we studied the effect of exogenous butyrate on diet-induced obesity and metabolic dysfunctions using ovariectomized (OVX) mice as a menopause model. Oral administration of sodium butyrate (NaB) reduced the body fat content and blood lipids, increased whole-body energy expenditure, and improved insulin sensitivity. Additionally, NaB induced oestrogen receptor alpha (ERα) expression, activated the phosphorylation of AMPK and PGC1α, and improved mitochondrial aerobic respiration in cultured skeletal muscle cells. In conclusion, oral NaB improves metabolic parameters in OVX mice with diet-induced obesity. Oral supplementation with NaB might provide a novel therapeutic approach to treating MetS in women with menopause. Video Abstract.

Novel construction of multifunctional photo-responsive and nucleic acid-triggered doxorubicin-releasing liposomes for cancer therapy.

All-in-one nano theranostics integrating accurate diagnosis and combined therapy is promising for high-efficacy tumor treatment and receiving significant attention. In this study, we develop photo-controlled release liposomes with nucleic acid-triggered fluorescence and photoactivity for tumor imaging and synergistic antitumor therapy. Copper phthalocyanine as a photothermal agent is fused into lipid layers to prepare liposomes encapsulating cationic zinc phthalocyanine ZnPc(TAP)412+ and doxorubicin, followed by the modification of RGD peptide on the surface to obtain the final product RGD-CuPc:ZnPc(TAP)412+:DOX@LiPOs (RCZDL). RCZDL possesses favorable stability, significant photothermal effect, and photo-controlled release function through the characterization of physicochemical properties. It is shown that the fluorescence and ROS generation could be turned on by intracellular nucleic acid after illumination. RCZDL exhibits synergistic cytotoxicity, increased apoptosis, and significantly promoted cell uptake. Subcellular localization analysis indicates that ZnPc(TAP)412+ tends to be distributed in the mitochondria of HepG2 cells treated with RCZDL after exposure to light. The results of experiments in vivo on H22 tumor-bearing mice demonstrate that RCZDL had excellent tumor targeting, a prominent photothermal effect at the tumor sites, and synergistic antitumor efficiency. More importantly, little RCZDL has been found to be accumulated in the liver, and most were quickly metabolized by the liver. The results confirm that the proposed new intelligent liposomes provide a simple and cost-effective way for tumor imaging and combinatorial anticancer therapy.

Recent progress toward developing axial chirality bioactive compounds.

Atropisomers are stereoisomers with axial chirality arising from restricted rotation around a single bond. Lots of representatives of this class of axially chiral compounds exhibit remarkable biological properties for protein targets. This time-dependent chirality shows great potential for drug development. Herein, we comprehensively review axial chirality bioactive compounds, including C-C bonded atropisomers, C-N bonded atropisomers, and N-N bonded atropisomers. Examples of each are provided along with their biological activity. This review highlights the development of various examples of atropisomerism encountered in bioactive compounds, which is beneficial for medicinal chemists to advance atropisomeric drug molecules.

Design, synthesis, and biological evaluation of novel 7-substituted 10,11-methylenedioxy-camptothecin derivatives against drug-resistant small-cell lung cancer in vitro and in vivo.

A series of novel 7-substituted 10,11-methylenedioxy-camptothecin (FL118) derivatives were designed, synthesized, and biologically evaluated. All the FL118 analogues showed significant cytotoxic activities in vitro with IC50 values in the nanomolar range and were more potent than topotecan. The most active compound 9c exhibited more significant anti-tumor activity against small-cell lung cancer (NCI-H446, H69, drug-resistant H69AR cells, drug-resistant NCI-H446/Irinotecan cells and drug-resistant NCI-H446/EP cells) in vitro. Additionally, 9c could also induce the expression of apoptosis proteins such as caspase-3, caspase-9, and PARP in small-cell lung cancer. Further studies showed that 9c induced apoptosis by inhibiting the expression of Mcl-1, Bcl-2, XIAP and survivin in small-cell lung cancer. In vivo9c also showed better anti-tumor efficacy, with the tumor growth inhibition rates were 40.4% (0.75 mg/kg), 73.7% (1.5 mg/kg), and 95.5% (3 mg/kg). It is noteworthy that 9c also demonstrated potent inhibition of drug-resistant tumor growth in NCI-H446/Irinotecan and NCI-H446/EP xenograft models, the tumor growth inhibition rates were 93.42% and 84.46%, respectively. Taken together, these findings indicated that compound 9c displays outstanding antitumor activity and drug-resistance in small-cell lung cancer both in vivo and in vitro, which could be worth further research as a novel anti-tumor drug against small-cell lung cancer.

From Center-to-Multilayer Chirality: Asymmetric Synthesis of Multilayer Targets with Electron-Rich Bridges.

Asymmetric synthesis of new atropisomerically multilayered chiral targets has been achieved by taking advantage of the strategy of center-to-multilayer chirality and double Suzuki-Miyaura couplings. Diastereomers were readily separated via flash column chromatography and well characterized. Absolute configuration assignment was determined by X-ray structural analysis. Five enantiomerically pure isomers possessing multilayer chirality were assembled utilizing anchors involving electron-rich aromatic connections. An overall yield of 0.69% of the final target with hydroxyl attachment was achieved over 11 steps from commercially available starting materials.

Multilayer 3D Chiral Folding Polymers and Their Asymmetric Catalytic Assembly.

A novel class of polymers and oligomers of chiral folding chirality has been designed and synthesized, showing structurally compacted triple-column/multiple-layer frameworks. Both uniformed and differentiated aromatic chromophoric units were successfully constructed between naphthyl piers of this framework. Screening monomers, catalysts, and catalytic systems led to the success of asymmetric catalytic Suzuki-Miyaura polycouplings. Enantio- and diastereochemistry were unambiguously determined by X-ray structural analysis and concurrently by comparison with a similar asymmetric induction by the same catalyst in the asymmetric synthesis of a chiral three-layered product. The resulting chiral polymers exhibit intense fluorescence activity in a solid form and solution under specific wavelength irradiation.

Asymmetric Catalytic Assembly of Triple-Columned and Multilayered Chiral Folding Polymers Showing Aggregation-Induced Emission (AIE).

Invited for the cover of this issue are Guigen Li's groups at Texas Tech University and Nanjing University. The cover artwork shows that chirality patterns exist from universal to molecular levels showing light emission properties. Read the full story of multilayer 3D chirality and its asymmetric catalytic synthesis at 10.1002/chem.202104102.

Asymmetric Catalytic Assembly of Triple-Columned and Multilayered Chiral Folding Polymers Showing Aggregation-Induced Emission (AIE).

Unprecedented chiral multilayer folding 3D polymers have been assembled and regulated by uniform and differentiated aromatic chromophore units between naphthyl piers. Screening catalysts, catalytic systems and monomers were proven to be crucial for asymmetric catalytic Suzuki-Miyaura polycouplings for this assembly. X-ray crystallography of the corresponding dimers and trimers revealed the absolute configuration and the intermolecular packing pattern. Up to 61 960 Mw /41 900 Mn and m/z 4317 for polymers and oligomers, as confirmed by gel permeation chromatography (GPC) and MALDI-TOF MS, indicated that these frameworks were composed of multiple stacked layers. The resulting multiple π-assemblies exhibited remarkable optical properties in aggregated states (photoluminescence in solids and aggregation-induced emission in solutions), as well as reversible redox properties in electrochemical performance.

Asymmetric Catalytic Approach to Multilayer 3D Chirality.

Invited for the cover of this issue is Guigen Li and co-workers at Texas Tech University and Nanjing University. The cover artwork shows that chirality phenomena exists in the universe and in nature, including at micro and molecular levels. Read the full text of the article at 10.1002/chem.202100700.

Asymmetric Catalytic Approach to Multilayer 3D Chirality.

The first asymmetric catalytic approach to multilayer 3D chirality has been achieved by using Suzuki-Miyaura cross-couplings. New chiral catalysts were designed and screened under various catalytic systems that proved chiral amide-phosphines to be more efficient ligands than other candidates. The multilayer 3D framework was unambiguously determined by X-ray structural analysis showing a parallel pattern of three layers consisting of top, middle and bottom aromatic rings. The X-ray structure of a catalyst complex, dichloride complex of Pd-phosphine amide, was obtained revealing an interesting asymmetric environment nearby the Pd metal center. Three rings of multilayer 3D products can be readily changed by varying aromatic ring-anchored starting materials. The resulting multilayer products displayed strong luminescence under UV irradiation and strong aggregation-induced emission (AIE). In the future, this work would benefit not only the field of asymmetric synthesis but also materials science, in particular polarized organic electronics, optoelectronics and photovoltaics.

Triple-Columned and Multiple-Layered 3D Polymers: Design, Synthesis, Aggregation-Induced Emission (AIE), and Computational Study.

Conjugated polymers and oligomers have great potentials in various fields, especially in materials and biological sciences because of their intriguing electronic and optoelectronic properties. In recent years, the through-space conjugation system has emerged as a new assembled pattern of multidimensional polymers. Here, a novel series of structurally condensed multicolumn/multilayer 3D polymers and oligomers have been designed and synthesized through one-pot Suzuki polycondensation (SPC). The intramolecularly stacked arrangement of polymers can be supported by either X-ray structural analysis or computational analysis. In all cases, polymers were obtained with modest to good yields, as determined by GPC and 1H-NMR. MALDI-TOF analysis has proven the speculation of the step-growth process of this polymerization. The computational study of ab initio and DFT calculations based on trimer and pentamer models gives details of the structures and the electronic transition. Experimental results of optical and AIE research confirmed by calculation indicates that the present work would facilitate the research and applications in materials.

Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20S)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives.

A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.

Self-assembling nanoparticles of dually hydrophobic prodrugs constructed from camptothecin analogue for cancer therapy.

Nanomedicines have shown success in cancer therapy in recent years because of their excellent solubility in aqueous solution and drug accumulation through controlled release in tumor tissues, but the preparation of most nanomedicines still requires ionic materials, surfactants or the amphiphilic structure to maintain nanoparticle stability and function. In this study, we developed a couple of novel dually hydrophobic prodrugs (DHPs) by combining two hydrophobic compounds through different linkers and elaborated their self-assembly mechanisms by virtue of computational simulation. Importantly, without using any excipients, FL-2 NPs exhibited significantly prolonged retention in blood circulation and displayed a remarkable anti-tumor effect at very low concentration in vivo. Both DHPs consisted of camptothecin structural analogue(FL118) and a marine natural product (ES-285). Comparative experiments proved that these compounds could quickly form nanoparticles by way of simple preparation and remained relatively stable for long periods in PBS. FL-2 NPs linked with a disulphide bond could rapidly release bioactive FL118 after being triggered by endogenous reductive stimulus to exert anti-cancer effects. Overall, this study provides a new strategy for design of therapeutic nanomedicines consisting of dually hydrophobic molecules for cancer therapy.

Synthesis of Diastereoenriched α-Aminomethyl Enaminones via a Brønsted Acid-Catalyzed Asymmetric aza-Baylis-Hillman Reaction of Chiral N-Phosphonyl Imines.

An effective chiral GAP methodology for preparing α-aminomethyl enaminones through a (R)-CSA-catalyzed asymmetric aza-Baylis-Hillman reaction is reported. Excellent yields and high diastereoselectivity could be obtained under mild conditions and convenient GAP techniques. The confirmations of the absolute configuration of N-phosphonyl imine and chiral enaminone by X-ray diffraction provides an explicit explanation of the chirality mechanism for GAP chemistry.

Enantioselective assembly of multi-layer 3D chirality.

The first enantioselective assembly of sandwich-shaped organo molecules has been achieved by conducting dual asymmetric Suzuki-Miyaura couplings and nine other reactions. This work also presents the first fully C-C anchored multi-layer 3D chirality with optically pure enantiomers. As confirmed by X-ray diffraction analysis that this chiral framework is featured by a unique C2 -symmetry in which a nearly parallel fashion consisting of three layers: top, middle and bottom aromatic rings. Unlike the documented planar or axial chirality, the present chirality shows its top and bottom layers restrict each other from free rotation, i.e., this multi-layer 3D chirality would not exist if either top or bottom layer is removed. Nearly all multi-layered compounds showed strong luminescence of different colors under UV irradiation, and several randomly selected samples displayed aggregation-induced emission (AIE) properties. This work is believed to have broad impacts on chemical, medicinal and material sciences including optoelectronic materials in future.

Multilayer 3D Chirality and Its Synthetic Assembly.

3D chirality of sandwich type of organic molecules has been discovered. The key element of this chirality is characterized by three layers of structures that are arranged nearly in parallel fashion with one on top and one down from the center plane. Individual enantiomers of these molecules have been fully characterized by spectroscopies with their enantiomeric purity measured by chiral HPLC. The absolute configuration was unambiguously assigned by X-ray diffraction analysis. This is the first multilayer 3D chirality reported and is anticipated to lead to a new research area of asymmetric synthesis and catalysis and to have a broad impact on chemical, medicinal, and material sciences in future.

Synthesis of novel 10,11-methylenedioxy-camptothecin glycoside derivatives and investigation of their anti-tumor effects in vivo.

10,11-Methylenedioxy-camptothecin (FL118) is a novel camptothecin analogue that possesses exceptional antitumor efficacy in human tumor xenograft models. The aim of the current study was to develop novel 20-substituted FL118 derivatives coupled with glycosyl-succinic acid esters with improved antitumor efficacy. These FL118 glycoside derivatives were designed, synthesized and their cytotoxicity evaluated in three tumor cell lines (A-549, MDA-MB-231 and RM-1). All of the derivatives showed superior in vitro cytotoxic activity and were more potent than irinotecan in A549 and MDA-MB-231 cells. In mouse prostate cancer cells RM-1, 10,11-methylenedioxy-camptothecin rhamnoside 11b displayed significant activities with IC50 of 48.27 nM. Western blot analysis demonstrated that 11b inhibited survivin expression and induced cancer cells apoptosis. Further cell cycle analyses clearly showed 11b induced G2/M phase cell cycle arrest. Molecule docking studies suggested that the binding mode of 11b was different from that of the crystal complex of ligand topotecan in Top1/DNA. Importantly, 11b showed high in vivo antitumor efficacy in the RM-1 mouse model with transplantation of prostate cancer (TGI = 44.9%) at dose of 9 mg kg-1 without apparent toxicity.

Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor.

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

Exploring the Relationship between Nicotinic Acetylcholine Receptor Ligand Size, Efficiency, Efficacy, and C-Loop Opening.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fundamental physiological activities in the nervous system and have become important targets for drug design. For a long time, the acetylcholine binding protein (AChBP) has been used as a surrogate to study the nAChR structure-function. Taking advantage of more than 100 AChBP crystal structures in the Protein DataBank (PDB), we explored the relationship between the size, efficiency, and efficacy of nAChR ligands and the C-loop movement. We found that the size of the ligand is correlated with the opening of the C-loop, which can be used in selecting AChBP crystal structures with appropriate C-loop opening to be used for nAChR ligand docking. Ligand size and C-loop opening are reversely correlated with the ligand efficiency rather than the binding affinity. Ligand efficiency could be accurately predicted using simple computational docking, giving a correlation coefficients (R2) up to 0.73. The efficacy of nAChR ligands might be related to ligand size, C-loop opening, and ligand efficiency. Results from this study are useful for engineering the binding affinity and efficacy of nAChR ligands.