ChemMedChem

Wound healing is a complex process and has been the subject of intense research for a long time. The recent emergence of nanotechnology has provided a new therapeutic modality in silver nanoparticles for use in burn wounds. Nonetheless, the beneficial effects of silver nanoparticles on wound healing remain unknown. We investigated the wound‐healing properties of silver nanoparticles in an animal model and found that rapid healing and improved cosmetic appearance occur in a dose‐dependent manner. Furthermore, through quantitative PCR, immunohistochemistry, and proteomic studies, we showed that silver nanoparticles exert positive effects through their antimicrobial properties, reduction in wound inflammation, and modulation of fibrogenic cytokines. These results have given insight into the actions of silver and have provided a novel therapeutic direction for wound treatment in clinical practice.

The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor‐specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor‐specific characteristics such as low pH or the expression of tumor‐associated enzymes. Furthermore, other strategies such as ADEPT (antibody‐directed enzyme prodrug therapy) and the design of self‐eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.

Bài tổng quan này mô tả một số phương pháp và kỹ thuật hiện đang được sử dụng để đưa ra các mô hình in silico nhằm dự đoán các thuộc tính ADMET. Bài báo cũng thảo luận một số yêu cầu cơ bản đối với việc tạo ra các mối quan hệ ADMET có tính toán học có cơ sở thống kê và dự đoán, cũng như một số cạm bẫy và vấn đề đã gặp phải trong các nghiên cứu này. Ý định của các tác giả là giúp người đọc nhận thức rõ hơn về một số thách thức liên quan đến việc phát triển các mô hình in silico ADMET có ích cho quá trình phát triển thuốc.

Curcumin binds to the amyloid β peptide (Aβ) and inhibits or modulates amyloid precursor protein (APP) metabolism. Therefore, curcumin‐derived isoxazoles and pyrazoles were synthesized to minimize the metal chelation properties of curcumin. The decreased rotational freedom and absence of stereoisomers was predicted to enhance affinity toward Aβ₄₂ aggregates. Accordingly, replacement of the 1,3‐dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Aβ₄₂ aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.

Infectious diseases continue to be one of the major contributors to human morbidity. The rapid rate at which pathogenic microorganisms have developed resistance against frontline antimicrobials has compelled scientists to look for new alternatives. Given their vast antimicrobial repertoire, substantial research effort has been dedicated toward the development of antimicrobial peptides (AMPs) as alternative drugs. However, inherent limitations of AMPs have driven substantial efforts worldwide to develop synthetic mimics of AMPs. This review focuses on the progress that has been made toward the development of small molecules that emulate the properties of AMPs, both in terms of design and biological activity. Herein we provide an extensive discussion of the structural features of various designs and we examine biological properties that have been exploited. Furthermore, we raise a number of questions for which the field has yet to provide solutions and discuss possible future research directions that remain either unexploited or underexploited.

Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole‐containing derivatives are endowed with a broad range of biological properties, including anti‐inflammatory, antimicrobial, anti‐HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure–activity relationships of these compounds.

Fourteen silver(I) complexes bearing N‐heterocyclic carbene (NHC) ligands were prepared and evaluated for anticancer activity. Some of these were found to exhibit potent antiproliferative activity toward several types of human cancer cell lines, including drug‐resistant cell lines, with IC₅₀ values in the nanomolar range. An initial investigation into the mechanism of cell death induced by this family of silver(I) complexes was carried out. Cell death was shown to result from the activation of apoptosis without involvement of primary necrosis. In HL60 cells, silver–NHCs induce depolarization of the mitochondrial membrane potential (ΔΨ_m) and likely allow the release of mitochondrial proteins to elicit early apoptosis. This effect is not related to the overproduction of reactive oxygen species (ROS). In addition, apoptosis is not associated with the activation of caspase‐3, but is triggered by the translocation of apoptosis‐inducing factor (AIF) and caspase‐12 from mitochondria and the endoplasmic reticulum, respectively, into the nucleus to promote DNA fragmentation and ultimately cell death. No modification in cell‐cycle distribution was observed, indicating that silver–NHCs are not genotoxic. Finally, the use of a fluorescent complex showed that silver–NHCs target mitochondria. Altogether, these results demonstrate that silver–NHCs induce cancer cell death independent of the caspase cascade via the mitochondrial AIF pathway.

The cellular protein lens epithelium‐derived growth factor, or transcriptional coactivator p75 (LEDGF/p75), plays a crucial role in HIV integration. The protein–protein interactions (PPIs) between HIV‐1 integrase (IN) and its cellular cofactor LEDGF/p75 may therefore serve as targets for the development of new anti‐HIV drugs. In this work, a structure‐based pharmacophore model for potential small‐molecule inhibitors of HIV‐1 IN–LEDGF/p75 interaction was developed using the LigandScout software. The 3D model obtained was used for virtual screening of our in‐house chemical database, CHIME, leading to the identification of compound CHIBA‐3002 as an interesting hit for further optimization. The rational design, synthesis and biological evaluation of four derivatives were then carried out. Our studies resulted in the discovery of a new and more potent small molecule (7, CHIBA‐3003) that is able to interfere with the HIV‐1 IN–LEDGF/p75 interaction at micromolar concentration, representing one of the first compounds to show activity against these specific PPIs. Docking simulations were subsequently performed in order to investigate the possible binding mode of our new lead compound to HIV‐1 IN. This study is a valid starting point for the identification of anti‐HIV agents with a different mechanism of action from currently available antiviral drugs.

As a result of the increasing application of structure‐based drug design, the visualization of protein–ligand complexes has become an important feature in medicinal chemistry. The large number of experimentally resolved complex structures and the further development of computer‐aided methods like docking or de novo design establishes new possibilities in this field. During lead finding and optimization, a manual investigation of many complexes and their interaction patterns is typically performed. We present an algorithm that automatically generates 2D‐protein–ligand diagrams as a possible solution for a transparent visualization of the contact partners in a complex and as a support for scientists in the evaluation of structure‐based design results. Running the software on representative test data sets, it generates collision free layouts for ∼76 % of the cases in the range of tenths of a second per complex. The success rate for complexes with ligands which have a molecular weight <500 Da is 87 %.