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European Journal of Medicinal Chemistry Mar 2024The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for... (Review)
Review
The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.
Topics: Immunoconjugates; Antibodies; Cell Membrane Permeability; Chemistry, Pharmaceutical; Molecular Weight; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 38387330
DOI: 10.1016/j.ejmech.2024.116216 -
Angewandte Chemie (International Ed. in... Nov 2023C-H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established... (Review)
Review
C-H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established cross-coupling methods, C-H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C-H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C-H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in-depth understanding of the challenges and potential of C-H activation methodologies in the production of pharmaceuticals.
Topics: Chemistry, Pharmaceutical; Pharmaceutical Preparations
PubMed: 37283078
DOI: 10.1002/anie.202306659 -
Archives of Pharmacal Research Dec 2023Chaenomeles plants belong to the Rosaceae family and include five species, Chaenomeles speciosa (Sweet) Nakai, Chaenomeles sinensis (Thouin) Koehne, Chaenomeles japonica... (Review)
Review
Chaenomeles plants belong to the Rosaceae family and include five species, Chaenomeles speciosa (Sweet) Nakai, Chaenomeles sinensis (Thouin) Koehne, Chaenomeles japonica (Thunb.) Lindl, Chaenomeles cathayensis (Hemsl.) Schneid and Chaenomeles thibetica Yu. Chaenomeles plants are found and cultivated in nearly every country worldwide. China serves as both the origin and distribution hub for the plants in the Chaenomeles genus, and all Chaenomeles species except for C. japonica are indigenous to China. Chaenomeles spp. is a type of edible medicinal plant that has been traditionally used in China to treat various ailments, such as rheumatism, cholera, dysentery, enteritis, beriberi, and scurvy. A variety of chemical constituents have been extracted from this genus, including terpenoids, phenolics, flavonoids, phenylpropanoids and their derivatives, benzoic acid derivatives, biphenyls, oxylipins, and alkaloids. The biological activity of some of these constituents has already been evaluated. Pharmacological investigations have demonstrated that the plants in the genus Chaenomeles exhibit anti-inflammatory, analgesic, antioxidant, antihyperglycemic, antihyperlipidemic, gastrointestinal protective, antitumor, immunomodulatory, antibacterial, antiviral, hepatoprotective, neuroprotective and other pharmacological activities. The objective of this review is to provide a comprehensive and up-to-date summary of the available information on the genus Chaenomeles to serve as a valuable reference for further investigations.
Topics: Rosaceae; Plant Extracts; Flavonoids; Antioxidants; Phenols; Phytochemicals; Ethnopharmacology; Phytotherapy
PubMed: 38062238
DOI: 10.1007/s12272-023-01475-w -
Annual Review of Pharmacology and... Jan 2024The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic... (Review)
Review
The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcase, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males.
Topics: Male; Humans; Female; Sexism; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37450899
DOI: 10.1146/annurev-pharmtox-030823-111731 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Dec 2023Since the emergence of the term "materia medica", scholars have proposed different opinions on its concept. This term has been used to refer to traditional...
Since the emergence of the term "materia medica", scholars have proposed different opinions on its concept. This term has been used to refer to traditional Chinese medicines, or medical books, or traditional pharmacology. Due to the differences in the concept of materia medica, scholars also have controversies about the concept of herbalism. Herbalism is usually understood as traditional Chinese pharmacology. After years of evolution, the term "herbalism" has now possessed the characteristics of an independent discipline, which can be defined as an applied basic discipline that comprehensively utilizes traditional and modern technological methods to study the formation, development, and changes of traditional pharmacology and reveal the basic theories and application laws of traditional medicine. At present, the research content of herbalism mainly includes three aspects: materia medica history, materia medica literature, and traditional pharmacology. This study explores the disciplinary concepts and main research content of herbalism based on a systematic review of the literature about the concepts of materia medica and herbalism, with the aim of attracting more attention to promote the establishment and development of the discipline of herbalism.
Topics: China; Drugs, Chinese Herbal; Herbal Medicine; Materia Medica; Medicine, Chinese Traditional; Technology
PubMed: 38212009
DOI: 10.19540/j.cnki.cjcmm.20230927.101 -
European Journal of Medicinal Chemistry Dec 2023Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.
Topics: Proteolysis Targeting Chimera; Chemistry, Pharmaceutical; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37708797
DOI: 10.1016/j.ejmech.2023.115793 -
Fitoterapia Jul 2023Kalopanax septemlobus is a traditional herbal medicine for multiple medicinal sites (root, stem bark, bark, leaves) in East Asia, and its bark has a significant curative... (Review)
Review
Kalopanax septemlobus is a traditional herbal medicine for multiple medicinal sites (root, stem bark, bark, leaves) in East Asia, and its bark has a significant curative effect on rheumatoid arthritis. In the past 13 years (2009-2022), the research literature accounted for 50% of the total, and it is becoming a research highlight of the relevant international scholars (ACS, ScienceDirect, PubMed, Springer, and Web of Science). This paper is the first comprehensive review of its chemistry, pharmacology, and toxicity for more than half a century (1966-2022), in which the chemical studies include triterpenoids & saponins (86 compounds), and phenylpropanoids (26 compounds), involving 46 new structures and one biomarker-triterpenoid saponin (Kalopanaxsaponin A); According to the number of literature, the pharmacological effects and mechanisms are systematically divided into five aspects, such as: anti-inflammatory, anti-tumor, antioxidant, antifungal and anti-diabetic, etc., covering its toxicological progress. To provide literature support for the exploration of new drugs against related diseases, such as rheumatoid arthritis, which are becoming younger nowadays.
Topics: Kalopanax; Molecular Structure; Plants, Medicinal; Medicine, Traditional; Arthritis, Rheumatoid; Phytochemicals; Ethnopharmacology; Medicine, Chinese Traditional; Plant Extracts
PubMed: 37290493
DOI: 10.1016/j.fitote.2023.105561 -
Chemistry & Biodiversity Sep 2023This review provides the first comprehensive appraisal of bioactive compounds and their biological activities in Persea species from 1950 to 2023. Relevant articles from... (Review)
Review
This review provides the first comprehensive appraisal of bioactive compounds and their biological activities in Persea species from 1950 to 2023. Relevant articles from reputable databases, including PubMed, Web of Science, Science Direct and Google Scholar were collected, leading to the isolation of about 141 metabolite compounds, mainly flavonoids, terpenoids, fatty alcohols, lignoids, and γ-lactone derivatives. These compounds exhibit diverse biological activities, including insecticidal, antifeedant, nematicidal, antibacterial, antifungal, antiviral, cytotoxic, anti-inflammatory, and antioxidant properties. The review emphasizes the significant chemical and pharmacological potential of different Persea species, encouraging further research in various fields and medicine. Valuable insights into potential applications of Persea plants are provided.
Topics: Ethnopharmacology; Plant Extracts; Persea; Anti-Inflammatory Agents; Antifungal Agents; Phytochemicals; Phytotherapy
PubMed: 37539983
DOI: 10.1002/cbdv.202300947 -
The American Journal of Medicine Mar 2024
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacogenetics
PubMed: 37423432
DOI: 10.1016/j.amjmed.2023.06.014 -
International Journal of Pharmaceutics Sep 2023The feasibility of co-amorphous systems to be wet granulated together with microcrystalline cellulose (MCC) was investigated. Solid state and molecular interactions were...
The feasibility of co-amorphous systems to be wet granulated together with microcrystalline cellulose (MCC) was investigated. Solid state and molecular interactions were analysed for various co-amorphous drug-amino acid formulations of indomethacin with tryptophan and arginine, respectively, via XRPD, DSC and FTIR. The co-amorphous binary systems were produced by ball-milling for 90 min at different molar ratios followed by wet granulation with MCC and water in a miniaturised scale. Tryptophan containing systems showed crystalline reflections in their XRPD diffractograms and endothermal events in their DSC analyses, and were therefore excluded from upscaling attempts. The systems containing arginine were found to be remain amorphous for at least ten months and were upscaled for production in a high-shear blender under application of two different parameter settings. Under the harsher instrument settings, a composition with a low MCC ratio experienced recrystallisation during wet granulation, while all other compositions could be successfully processed via wet granulation and stayed stable for a storage period of at least twelve weeks, indicating that wet granulation of co-amorphous systems can be feasible.
Topics: Indomethacin; Chemistry, Pharmaceutical; Powders; Calorimetry; Spectroscopy, Fourier Transform Infrared; Particle Size; Drug Stability
PubMed: 37586574
DOI: 10.1016/j.ijpharm.2023.123318