A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy.

Heat shock protein 90, also known as Hsp90, is an extensively preserved molecular chaperone that performs a critical function in organizing various biological pathways and cellular operations. As a potential drug target, Hsp90 is closely linked to cancer. Hsp90 inhibitors are a class of drugs that have been extensively studied in preclinical models and have shown promise in a variety of diseases, especially cancer. However, Hsp90 inhibitors have encountered several challenges in clinical development, such as low efficacy, toxicity, or drug resistance, few Hsp90 small molecule inhibitors have been approved worldwide. Nonetheless, combining Hsp90 inhibitors with other tumor inhibitors, such as HDAC inhibitors, tubulin inhibitors, and Topo II inhibitors, has been shown to have synergistic antitumor effects. Consequently, the development of Hsp90 dual-target inhibitors is an effective strategy in cancer treatment, as it enhances potency while reducing drug resistance. This article provides an overview of Hsp90's domain structure and biological functions, as well as a discussion of the design, discovery, and structure-activity relationships of Hsp90 dual inhibitors, aiming to provide insights into clinical drug research from a medicinal chemistry perspective and discover novel Hsp90 dual inhibitors.

Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives.

Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.

Selective C-S Bond Constructions Using Inorganic Sulfurs via Photoinduced Electron Donor-Acceptor Activation.

By complementing traditional transition metal catalysis, photoinduced catalysis has emerged as a versatile and sustainable way to achieve carbon-heteroatom bond formation. This work discloses a visible-light-induced reaction for the formation of a C-S bond from aryl halides and inorganic sulfuration agents via electron donor-acceptor (EDA) complex photocatalysis. Divergent formations of organic sulfide and disulfide have been demonstrated under mild conditions. Preliminary mechanistic studies suggest that visible-light-induced intracomplex charge transfer within the monosulfide-anion-containing EDA complex permits the C-S bond construction reactivity.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry.

The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Bioinspired and Ligand-Regulated Unnatural Prenylation and Geranylation of Oxindoles with Isoprene under Pd Catalysis.

In nature, prenylation and geranylation are two important metabolic processes for the creation of hemiterpenoids and monoterpenoids under enzyme catalysis. Herein, we have demonstrated bioinspired unnatural prenylation and geranylation of oxindoles using the basic industrial feedstock isoprene through ligand regulation under Pd catalysis. Pentenylated oxindoles (with C5 added) were attained with high selectivity when using a bisphosphine ligand, whereas upon switching to a monophosphine ligand, selectivity toward geranylated oxindoles (with C10 added) was achieved. Moreover, the head-to-head product could be further isomerized to an internal skipped diene under Pd-H catalysis. No stoichiometric by-product was formed in the process.

Redox-Divergent Construction of (Dihydro)thiophenes with DMSO.

Thiophene-based rings are one of the most widely used building blocks for the synthesis of sulfur-containing molecules. Inspired by the redox diversity of these features in nature, we demonstrate herein a redox-divergent construction of dihydrothiophenes, thiophenes, and bromothiophenes from the respective readily available allylic alcohols, dimethyl sulfoxide (DMSO), and HBr. The redox-divergent selectivity could be manipulated mainly by controlling the dosage of DMSO and HBr. Mechanistic studies suggest that DMSO simultaneously acts as an oxidant and a sulfur donor. The synthetic potentials of the products as platform molecules were also demonstrated by various derivatizations, including the preparation of bioactive and functional molecules.

Design and synthesis of novel spirooxindole-indenoquinoxaline derivatives as novel tryptophanyl-tRNA synthetase inhibitors.

In the current study, we used an integrated approach combining bioinformatics, rational drug design, one-pot synthesis, and biological experiments in vitro for the potential discovery of novel tryptophanyl-tRNA synthetase (TrpRS) inhibitors. Atom economic and diastereoselective syntheses were used to generate several Spirooxindole-indenoquinoxaline derivatives in situ from isatin and amino acids viz. proline, phenylglycine, and sarcosine through targeting the 1,3-dipolar cycloaddition of azomethine ylides. These compounds were assayed by biochemical TrpRS inhibition, using in vitro experiments to test against various gram-positive and gram-negative strains, and using diffuse large B cell lymphoma (DLBCL) cell lines. Compound 6e was found to be the most active in vitro with IC50 values of 225 and 74 nM for tests against hmTrpRS and ecTrpRS, respectively. We also found a MIC90 value of 4 µg/mL for tests against S. aureus and IC50 values which ranged from 2.9 to 4.8 µM for tests against proliferation of DLBCL cell lines. Moreover, compound 6e was remarkably good at inducing bacterial autolysis in MRSA strains. Our results suggested that such an integrated approach could be an attractive and viable strategy for the discovery of novel TrpRS inhibitors as potential lead compounds for antibiotics and as novel anticancer agents. Discovery of novel spirooxindole-indenoquinoxaline TrpRS inhibitors as potential lead compounds with antibacterial and antitumor activities.

Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes.

Acne vulgaris is a prevalent cutaneous disease characterized by a multifactorial pathogenic process including hyperseborrhea, inflammation, over-keratinization of follicular keratinocytes and Propionibacterium acnes (P acnes) overgrowth. Salicylic acid (SA), a beta-hydroxy acid, is frequently used in the treatment of acne. SA has been found to decrease skin lipids and to possess anti-inflammatory properties. However, few studies have elucidated the mechanisms and pathways involved in such treatment of acne. In this study, we initially investigated the anti-acne properties of SA in human SEB-1 sebocytes. Treatment with SA decreased sebocyte lipogenesis by downregulating the adenosine monophosphate-activated protein kinase (AMPK)/sterol response element-binding protein-1 (SREBP-1) pathway and reduced inflammation by suppressing the NF-κB pathway in these cells. Salicylic acid also decreased the cell viability of SEB-1 by increasing apoptosis via the death signal receptor pathway. Subsequently, histopathological analysis of a rabbit ear acne model after application of SA for three weeks confirmed that SA suppressed the levels of cytokines and major pathogenic proteins around acne lesions, which supports the mechanisms suggested by our in vitro experiments. These results initially clarified that therapeutic activities of SA in acne vulgaris treatment could be associated with the regulation of SREBP-1 pathway and NF-κB pathway in human SEB-1 sebocytes.

Stereoselective Assembly of Multifunctional Spirocyclohexene Pyrazolones That Induce Autophagy-Dependent Apoptosis in Colorectal Cancer Cells.

Enantio- and diastereoselective synthesis of multifunctional spiropyrazolone scaffolds has been achieved using secondary amine-catalyzed [4 + 2] annulations of α,ß,γ,δ-unsaturated pyrazolones with aldehydes. The pyrazolone substrates serve as C4 synthons to produce 6-membered, carbocycle-based, chiral spiropyrazolone derivatives. The synthesized chiral compounds showed potent toxicity against a panel of cancer cell lines. The most potent compound 3h-induced cell cycle arrest and macroautophagy in HCT116 colorectal cancer cells, triggering autophagy-dependent apoptotic cell death.

Design, synthesis and biological evaluation of 4-aniline-thieno[2,3-d]pyrimidine derivatives as MNK1 inhibitors against renal cell carcinoma and nasopharyngeal carcinoma.

MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1) play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and protein levels. Based on the crystallographic structure of MNK1 protein and binding modes analysis of known MNK inhibitors, we have designed and synthesized a series of 4-aniline-thieno[2,3-d]pyrimidine derivatives as potential MNK1 inhibitors. These synthetic compounds are tested in biochemical and cell proliferation assays, and six of them display potent inhibitory capacity against MNK1 kinase and cancer cell lines. Compound 12dj with strongest inhibitory capacity is transferred to molecular mechanism studies, and the results indicated that 12dj remarkably suppresses the phosphorylation of EIF4E, a substrate of MNK1. And the expression levels of MNK1, ERK1/2 and pERK1/2 are not affected by compound 12dj incubation in SUNE-1 and 786-O cells. In summary, our works suggested that these novel 4-aniline-thieno[2,3-d]pyrimidine based MNK1 inhibitors might be attractive lead compounds for targeted therapy of renal cell carcinoma and nasopharyngeal carcinoma.

Design, synthesis and molecular mechanisms of novel dual inhibitors of heat shock protein 90/phosphoinositide 3-kinase alpha (Hsp90/PI3Kα) against cutaneous melanoma.

Overexpression of heat shock protein 90 (Hsp90) is common in various types of cancer. In cutaneous melanoma, a cancer with one of the high levels of Hsp90 overexpression, such expression was correlated with a panel of protein kinases, thus offering an opportunity to identify Hsp90-based multi-kinase inhibitors for novel cancer therapies. Towards this goal, we utilized a 2,4-dihydroxy-5-isopropylbenzate-based Hsp90 inhibitor scaffold and thieno[2,3-d]pyrimidine-based kinase inhibitor scaffold to develop a Hsp90-inhibiting compound library. Our inhibitory compound named 8m inhibited Hsp90 and PI3Kα with an IC50 value of 38.6 nM and 48.4 nM, respectively; it displayed improved cellular activity which could effectively induce cell cycle arrest and apoptosis in melanoma cells and lead to the inhibition of cell proliferation, colony formation, migration and invasion. Our results demonstrated 8m to be a promising lead compound for further therapeutic potential assessment of Hsp90/PI3Kα dual inhibitors in melanoma targeted therapy.

Small-Molecule Inhibitors Targeting Protein SUMOylation as Novel Anticancer Compounds.

SUMOylation, one of post-translational modifications, is covalently modified on lysine residues of a target protein through an enzymatic cascade reaction similar to protein ubiquitination. Along with identification of many SUMOylated proteins, protein SUMOylation has been proven to regulate multiple biologic activities including transcription, cell cycle, DNA repair, and innate immunity. The dysregulation of protein SUMOylation and deSUMOylation modification is linked with carcinogenesis and tumor progression. The SUMOylation-associated enzymes are usually elevated in various cancers, which function as cancer biomarkers to relate to poor outcomes for patients. Considering the significance of protein SUMOylation in regulating diverse biologic functions in cancer progression, numerous small-molecule inhibitors targeting protein SUMOylation pathway are developed as potentially clinical anticancer therapeutics. Here, we systematically summarize the latest progresses of associations of small ubiquitin-like modifier (SUMO) enzymes with cancers and small-molecular inhibitors against human cancers by targeting SUMOylation enzymes. We also compared the pros and cons of several special anticancer inhibitors targeting SUMO pathway. As more efforts are invested in this field, small-molecule inhibitors targeting the SUMOylation modification pathway are promising for development into novel anticancer drugs.

Novel Self-Assembled Micelles Based on Cholesterol-Modified Antimicrobial Peptide (DP7) for Safe and Effective Systemic Administration in Animal Models of Bacterial Infection.

Owing to their broad-spectrum antibacterial properties, multitarget effects, and low drug resistance, antimicrobial peptides (AMPs) have played critical roles in the clinical therapy of drug-resistant bacterial infections. However, the potential hazard of hemolysis following systemic administration has greatly limited their application. Here, we developed a novel AMP derivative, DP7-C, by modifying a formerly identified highly active AMP (DP7) with cholesterol to form an amphiphilic conjugate. The prepared DP7-C easily self-assembled into stable nanomicelles in aqueous solution. The DP7-C micelles showed lower hemolytic activity than their unconjugated counterparts toward human red blood cells and a maximum tolerated dose of 80 mg/kg of body weight in mice via intravenous injection, thus demonstrating improved safety. Moreover, by eliciting specific immunomodulatory activities in immune cells, the DP7-C micelles exerted distinct therapeutic effects in zebrafish and mouse models of infection. In conclusion, DP7-C micelles may be an excellent candidate for the treatment of bacterial infections in the clinic.

Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives.

An efficient organocatalytic cascade reaction has been developed involving a Michael-hemiaminalization relay for the asymmetric synthesis of spiropiperidinone derivatives bearing adjacent quaternary and tertiary chiral centers via LUMO or HOMO activation. Importantly, this methodology demonstrates that applying distinct activation modes to different substrates in the same reaction can diverge diastereoselectivity. To our knowledge, this is also one of the few published cases of primary amine catalytic [3 + 3] cycloaddition reactions involving α-branched ß-ketoamides.

Viability and Biomechanics of Bare Diced Cartilage Grafts in Experimental Study.

OBJECTIVE: To assess the viability and biomechanics of bare diced cartilage grafts. METHODS: Cartilage samples were collected from 1 ear in 15 rabbits as well as costal cartilage. Each rabbit was inserted bare diced- and single-strip costal-cartilage grafts, respectively, into paraspinal subcutaneous pockets: after euthanasia at 2 months, specimens were weighed, with diced cartilage grafts examined histomorphologically by hematoxylin-eosin staining, masson trichrome staining, and immunohistochemistry. Finally, biomechanical properties of grafts were assessed. RESULTS: Bare diced cartilage grafts were connected into an integrated mass after 2 months, and inward growth of fibrous tissues and angiogenesis were observed. Mean wet weights of diced cartilage grafts were 1.603 ±â€Š0.278 and 1.662 ±â€Š0.204 g pre- and postoperation, respectively; those of costal cartilage grafts were 0.053 ±â€Š0.008 and 0.058 ±â€Š0.008 g, respectively. In compression assays, mean modulus values of elasticity at yield in diced- and costal-cartilage grafts were 7.65 ±â€Š0.59 and 22.30 ±â€Š1.15 MPa, respectively (P < 0.05); mean stress values were 4.07 ±â€Š0.38 and 12.50 ±â€Š1.15 MPa, respectively (P < 0.05). In the tensile test, mean modulus values of elasticity at yield of diced- and costal-cartilage grafts were 4.70 ±â€Š0.78 and 10.59 ±â€Š1.39 MPa, respectively (P < 0.05), mean stress values were 0.82 ±â€Š0.05 and 1.76 ±â€Š0.21 MPa, respectively (P < 0.05). CONCLUSIONS: Diced cartilage grafts had favorable viability and growth. Despite reduced elasticity and stress values, they still can be served as substitute for supportive filling materials.

[Design, synthesis and evaluation of a novel MEK protein inhibitors].

This study was conducted to design and synthetize highly efficient, specific, non-resistant small MEK inhibitors. Based on active small molecules which have been reported, we studied the action mode with MEK protein using Autodock 4.2, generated innovative and feasible design method, designed novel small MEK protein inhibitors with a reference to molecular modeling and docking. The anti-tumor activities of four kinds of cells including MCF-7, PANC-1, SY5Y, A549 were tested with MTT method in vitro. The structure of 10 new small molecules has been determined with 1H NMR and 13C NMR. The compounds 4, 6, 7, 8, 10 had high antitumor activities, the compounds 1, 3, 5 also showed good activity, and the compounds 2, 9 showed cell selectivity in killing tumor.

Targeting Programmed Cell Death Using Small-Molecule Compounds to Improve Potential Cancer Therapy.

Evasion of cell death is one of the hallmarks of cancer cells, beginning with long-established apoptosis and extending to other new forms of cell death. An elaboration of cell death pathways thus will contribute to a better understanding of cancer pathogenesis and therapeutics. With the recent substantial biochemical and genetic explorations of cell death subroutines, their classification has switched from primarily morphological to more molecular definitions. According to their measurable biochemical features and intricate mechanisms, cell death subroutines can be divided into apoptosis, autophagic cell death, mitotic catastrophe, necroptosis, parthanatos, ferroptosis, pyroptosis, pyronecrosis, anoikis, cornification, entosis, and NETosis. Supportive evidence has gradually revealed the prime molecular mechanisms of each subroutine and thus providing series of possible targets in cancer therapy, while the intricate relationships between different cell death subroutines still remain to be clarified. Over the past decades, cancer drug discovery has significantly benefited from the use of small-molecule compounds to target classical modalities of cell death such as apoptosis, while newly identified cell death subroutines has also emerging their potential for cancer drug discovery in recent years. In this review, we comprehensively focus on summarizing 12 cell death subroutines and discussing their corresponding small-molecule compounds in potential cancer therapy. Together, these inspiring findings may provide more evidence to fill in the gaps between cell death subroutines and small-molecule compounds to better develop novel cancer therapeutic strategies.

Codelivery of a miR-124 Mimic and Obatoclax by Cholesterol-Penetratin Micelles Simultaneously Induces Apoptosis and Inhibits Autophagic Flux in Breast Cancer in Vitro and in Vivo.

Penetratin is a classical cell-penetrating peptide with the potential to assist in the transmembrane delivery of proteins or drugs. However, the synthesis and application of cholesterol-penetratin (Chol-P) conjugates as nonviral delivery systems for microRNAs or drugs have not previously been reported. In this study, the amphiphilic Chol-P was shown to self-assemble into micelles and efficiently deliver miR-124 and obatoclax. The codelivered miR-124-M-Oba had a homogeneous particle size and a positive zeta potential. Treatment with miR-124 mincreased cytotoxicity, and cell proliferation, was promoted by miR-124 inhibitor-loaded micelles in MCF-7 human breast cancer cells. Moreover, the inhibitory effects on cell proliferation, colony formation, and cell migration were increased in the miR-124-M-Oba group compared to the miR-124-M group. miR-124-M-Oba induced higher levels of mitochondrial apoptosis via Bax and caspase-9 activation. In addition, we found that the cationic Chol-P and miR-124-M could potently induce autophagy, and miR-124 was degraded in the corresponding autophagolysosomes. The obatoclax encapsulated in miR-124-M-Oba could inhibit the degradation of miR-124 and p62 in autophagolysosomes, which consequently maintained the concentration of miR-124 in breast cancer cells. Furthermore, miR-124-M-Oba potently inhibited tumor growth in subcutaneous xenograft breast cancer models. In summary, the miR-124-M-Oba prepared in this work showed improved apoptosis induction and autophagic flux inhibitory effects in MCF-7 cells, and miR-124-M-Oba may have potential applications in breast cancer therapy.