Current Medicinal Chemistry - Volume 30, Issue 24, 2023

The in-depth intersection between nanoscience and oncology comes from the fact that nanomaterials are in a similar dimension to basic biomolecules. Drug delivery systems (DDSs), which are either targeted to a particular site or intended for the controlled release in a particular position, have been studied extensively at the nanoscale and are, by far, the most advanced technology in the area of nanoparticle applications. This, consequently lead to the improvement and development of convenient administration routes, lower toxicity, fewer side effects, and extended drug life cycle. Carbon nanomaterials (CNMs) with favorable size and unique fluorescence properties, which was considered an ideal candidate to transport or deliver therapeutic drugs to specific targets in a controlled manner. The development of DDSs based on them constitutes an interesting topic in highly effective and universal therapies to achieve better therapeutic outcomes and reduce the side effects of malignancies. In this review, the cutting-edge progress of CNMs in DDSs was comprehensively summarized. Additionally, the emphasis was placed on the applications of CNMs including fullerene, graphene, carbon nanotubes (CNTs), carbon dots (CDs), and nano-diamonds (NDs) in drug delivering. Further, we gave some insights into the future direction and foreseeable challenges of DDSs based on CNMs used in cancer therapy, which we hope these inspirations in DDSs associated with anti-cancer therapy will provide perspectives in designing new drugs for further tumor treatment.

Lead optimization as a bottleneck in the process of drug discovery is conducted to tackle problems associated with poor pharmacokinetics, continuous emergence of drugresistance, adverse side effects and drug-drug interactions of known pharmaceuticals. Due to the intensive application of multi-targeted tyrosine kinase inhibitors (MTKI) in various pathological conditions, optimization of their structures has always been the focus of intensive medicinal chemistry research efforts. The current review portrays the application of scaffold hopping, bioisosterism, structure-based, and hybrid-based drug design methods in the optimization of lead compounds aiming to enhance their usefulness as novel drugs. Then, the review proceeds with examples of structural modifications carried out, particularly on multi-targeted drugs already available on the market. The demonstrated examples cover structural modifications on 7 well-known drugs during the last twenty years. The application of the above-mentioned strategies has led to the generation of 52 new multitargeted tyrosine kinase inhibitors. Most of the optimized compounds showed improved properties compared to their parent lead compound. The rationales behind the applied modifications and the achieved outcomes were discussed to present practical examples to the researchers engaged in the area.

Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and nonhistone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus producing adverse issues, causing therapeutic resistance, and they have poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDAC inhibitor is generally accomplished on the basis of systematic highthroughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, or linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target. The objective of this review is to elucidate the potential targets' design strategies, biological activity, and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates the designing strategies of the potential target along with biological activity and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is important for overcoming side effects, drug resistance, and effective cancer control.

Background: Alzheimer's disease (AD) is one of the most common diseases in the elderly, with a high incidence of dementia. The pathogenesis of AD is complex, and there is no unified conclusion and effective treatment in the clinic. In recent years, with the development of traditional Chinese medicine (TCM), researchers put forward the idea of prevention and treatment of AD based on TCM according to the characteristics of multi- target of TCM. Ferulic acid (FA), also known as 3-methoxy-4-hydroxycinnamic acid, is an active ingredient in TCM that inhibits β-amyloid (Aβ) aggregation and has antioxidant and anti-inflammatory effects. FA derivatives have been reported to have low toxicity, high biological activity, and high blood-brain barrier permeability. However, the multitarget of FA in the treatment of AD has not been systematically elucidated.

Objectives: In this systematic review, we aimed to comprehensively assess the neuroprotective effects of FA and its derivatives on in vitro and in vivo AD models.

Methods: We searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Baidu Academic, and Wanfang databases for relevant pre-clinical studies until November 2021.

Results: We identified studies that evaluated the efficacy of FA and its derivatives using relevant keywords. 864 studies were included, of which 129 were found in PubMed, 111 in CNKI, 454 in Baidu Academic, and 170 in Wanfang. Due to duplication between databases, and after applying the exclusion and inclusion criteria, 43 articles were selected. Thereafter, the abstracts of the 43 articles were reviewed. Finally, 21 articles were included in this review, including 11 in vivo, 5 in vitro, and 5 in vivo and in vitro studies.

Conclusion: Previous studies have shown that FA or its derivatives have multiple therapeutic effects on AD models and can improve the symptoms of AD and resistance of AD cell models. FA and its derivatives have anti-Aβ aggregation, antioxidant, antiinflammatory, and other effects and are potential drugs for the multi-targeted treatment of AD. The result of our study showed that FA and its derivatives have significant therapeutic effects on animal and cell models of AD, suggesting that they may be potential therapeutic drugs for patients with AD.