Diversity Oriented Synthesis of Novel Xanthones Reveal Potent Doxorubicin-Inspired Analogs
ChemMedChem. 2024 Feb 13:e202400055. doi: 10.1002/cmdc.202400055. Online ahead of print.ABSTRACTInspired by potent antiproliferative xanthone natural products and so far limited examples of derived bioactive agents, a structure activity study of architecturally novel types of xanthones is reported. Their preparation was enabled in a short and divergent manner by a modular chlorination in combination with optimized protocols for a polar condensation and a hetero-cyclization. Application of these procedures allowed for the synthesis of various polyhalogenated representatives (including mixed bromo/chloro xanthones) that were...
Source: ChemMedChem - February 14, 2024 Category: Chemistry Authors: Jonas W Meringdal Leon Bade Gerd Bendas Dirk Menche Source Type: research
Insights into the overcoming EGFR Del19/T790M/C797S mutation: A perspective on the 2-aryl-4-aminothienopyrimidine backbone
ChemMedChem. 2024 Feb 14:e202300634. doi: 10.1002/cmdc.202300634. Online ahead of print.ABSTRACTThe epithelial growth factor receptor signaling pathway has been proposed to benefit non-small cell lung cancer treatment. In this manuscript, we investigated the modification of 2-aryl-4-aminoquinazoline, the classical backbone of the fourth-generation EGFR inhibitors, in addition to obtaining a series of novel 2-aryl-4-aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. The bioactivity of these compounds was evaluated and it's suggested that compound A9 could ...
Source: ChemMedChem - February 14, 2024 Category: Chemistry Authors: Xuan Zhang Jie He Shidi Xu Li Fu Pengwu Zheng Shan Xu Qingshan Pan Wufu Zhu Source Type: research
Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects
ChemMedChem. 2024 Feb 14:e202300651. doi: 10.1002/cmdc.202300651. Online ahead of print.ABSTRACTIn this research work, a series of 16 quinazoline derivatives bearing ibuprofen and an amino acid were designed as inhibitors of epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) and cyclooxygenase-2 (COX-2) with the intention of presenting dual action in their biological behavior. The designed compounds were synthesized and assessed for cytotoxicity on epithelial cancer cells lines (AGS, A-431, MCF-7, MDA-MB-231) and epithelial non-tumorigenic cell line (HaCaT). From this evaluation, derivative 6 was observed t...
Source: ChemMedChem - February 14, 2024 Category: Chemistry Authors: Luis Roberto Gardu ño-Villavicencio Ulises Mart ínez-Ortega Elizabeth Ort íz-Sánchez Jos é Manuel Tinajero-Rodríguez Francisco Hern ández-Luis Source Type: research
A Structure-Activity Relationship Study of Amino Acid Derivatives of Pterostilbene Analogues Toward Human Breast Cancer
ChemMedChem. 2024 Feb 12:e202300727. doi: 10.1002/cmdc.202300727. Online ahead of print.ABSTRACTPterostilbene is the dimethylated analogue of Resveratrol, a compound with well-known biological activities, such as antioxidant, chemopreventive, anti-diabetic, anti-obesity, and cardioprotective. Despite many studies on the general effect of such polyphenolic molecules and their derivatives, a deep comprehension of their action and systematic structure-activity relationship studies are still rare. Herein, three different analogues of functionalizable Pterostilbene were efficiently synthesized and derivatized with a selected li...
Source: ChemMedChem - February 12, 2024 Category: Chemistry Authors: Fabiana Cordella Nicola Dragone Rosarita D'Orsi Concetta Saponaro Daniele Vergara Marco Lessi Gaetano Angelici Source Type: research
Neuroblastoma and its Targets Therapies: A Medicinal Chemistry Review
ChemMedChem. 2024 Feb 10:e202300535. doi: 10.1002/cmdc.202300535. Online ahead of print.ABSTRACTNeuroblastoma (NB) is a childhood malignant tumour belonging to a group of embryonic tumours originating from progenitor cells of the sympathoadrenal lineage. The heterogeneity of NB is reflected in the survival rates of those with low and intermediate risk diseases who have survival rates ranging from 85 to 90 %. However, for those identified with high-risk Stage 4 NB, the treatment options are much more limited. For this group, current treatment consists of immunotherapy (monoclonal antibodies) in combination with anti-cancer ...
Source: ChemMedChem - February 10, 2024 Category: Chemistry Authors: Amgad Gerges Una Canning Source Type: research
Challenges for the Discovery of non-covalent WRN Helicase inhibitors
ChemMedChem. 2024 Feb 9:e202300613. doi: 10.1002/cmdc.202300613. Online ahead of print.ABSTRACTThe Werner Syndrome RecQ helicase (WRN) is a synthetic lethal target of interest for the treatment of cancers with microsatellite instability (MSI). Different hit finding approaches were initially tested. The identification of WRN inhibitors proved challenging due to a high propensity for artefacts via protein interference, i.e., hits inhibiting WRN enzymatic activities through multiple, unspecific mechanisms. Previously published WRN Helicase inhibitors (ML216, NSC19630 or NSC617145) were characterized in an extensive set of bio...
Source: ChemMedChem - February 9, 2024 Category: Chemistry Authors: Alisa Heuser Wassim Abdul Rahman Elisabeth Bechter Jutta Blank Sylvia Buhr Dirk Erdmann Patrizia Fontana Fanny Mermet-Meillon Marco Meyerhofer Ross Strang Maxime Schrapp Catherine Zimmermann Marta Cortes-Cros Henrik M öbitz Jacques Hamon Source Type: research
The Therapeutic Potential in Cancer of Terpyridine-Based Metal Complexes Featuring Group 11 Elements
ChemMedChem. 2024 Feb 8:e202300645. doi: 10.1002/cmdc.202300645. Online ahead of print.ABSTRACTTerpyridine-based complexes with group 11 metals emerge as potent metallodrugs in cancer therapy. This comprehensive review focuses on the current landscape of anticancer examples, particularly highlighting the mechanisms of action. While Cu(II) complexes, featuring diverse ancillary ligands, dominate the field, exploration of silver and gold species remains limited. These complexes exhibit significant cytotoxicity against various cancer cell lines with a commendable selectivity for non-tumorigenic cells. DNA interactions, employ...
Source: ChemMedChem - February 8, 2024 Category: Chemistry Authors: Mar ía Gil-Moles M Concepci ón Gimeno Source Type: research
Hypoxia: Intriguing Feature in Cancer Cell Biology
ChemMedChem. 2024 Feb 8:e202300551. doi: 10.1002/cmdc.202300551. Online ahead of print.ABSTRACTHypoxia, a key aspect of the tumor microenvironment, plays a vital role in cell proliferation, angiogenesis, metabolism, and the immune response within tumors. These factors collectively promote tumor advancement, aggressiveness, metastasis and result in a poor prognosis. Hypoxia inducible factor 1α (HIF-1α), activated under low oxygen conditions, mediates many of these effects by altering drug target expression, metabolic regulation, and oxygen consumption. These changes promote cancer cell growth and survival. Hypoxic tumor c...
Source: ChemMedChem - February 8, 2024 Category: Chemistry Authors: Monalisa Chowdhury Prasanta Kumar Das Source Type: research
Synthesis and in vitro metabolic stability of sterically shielded antimycobacterial phenylalanine amides
ChemMedChem. 2024 Feb 8:e202300593. doi: 10.1002/cmdc.202300593. Online ahead of print.ABSTRACTNα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improve...
Source: ChemMedChem - February 8, 2024 Category: Chemistry Authors: Markus Lang Uday S Ganapathy Lea Mann R üdiger W Seidel Richard Goddard Frank Erdmann Thomas Dick Adrian Richter Source Type: research
Gaucher Disease: A Glance from a Medicinal Chemistry Perspective
ChemMedChem. 2024 Feb 8:e202300641. doi: 10.1002/cmdc.202300641. Online ahead of print.ABSTRACTRare diseases are particular pathological conditions affecting a limited number of people and few drugs are known to be effective as therapeutic treatment. Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, belongs to this class of disorders, and it is considered the most common among the Lysosomal Storage Diseases. The two main therapeutic approaches are the Enzyme Replacement Therapy (ERT) and the Substrate Reduction Therapy (SRT). ERT, consisting in replacing the defective enzyme by administeri...
Source: ChemMedChem - February 8, 2024 Category: Chemistry Authors: Filippo Prencipe Chiara Barzan Chiara Savian Giampiero Spalluto Emanuele Carosati Marco De Amici Giorgio Mosconi Teresa Gianferrara Stephanie Federico Tatiana Da Ros Source Type: research
Current Small Molecules-Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics
ChemMedChem. 2024 Feb 8:e202300705. doi: 10.1002/cmdc.202300705. Online ahead of print.ABSTRACTNeurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule-based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Considering the highly complex nature...
Source: ChemMedChem - February 8, 2024 Category: Chemistry Authors: Nitesh Sanghai Billy Vuong Ahmet Burak Berk Muhammad Shaharyar K Afridi Geoffrey K Tranmer Source Type: research
Effective Anticancer Potential of a New Sulfonamide as a Carbonic Anhydrase IX Inhibitor Against Aggressive Tumors
This study examines efficiency of a newly synthesized sulfonamide derivative 2-bromo-N-(4-sulfamoylphenyl)propanamide (MMH-1) on the inhibition of Carbonic Anhydrase IX, which is overexpressed in many solid tumors including breast cancer. The inhibitory potential of MMH-1 compound against hCA I, II, IX, and XII, was evaluated. To this context, the cytotoxic effect of MMH-1 on cancer and normal cells was tested and found to selectively affect MDA-MB-231 cells. MMH-1 reduced cell proliferation by holding cells in the G0/G1 phase (72%) and slowed the cells' wound healing capacity. MMH-1 inhibited CA IX under both hypoxic and ...
Source: ChemMedChem - February 7, 2024 Category: Chemistry Authors: Ismail Koyuncu Ebru Temiz Eray Metin G üler Mustafa Durgun Ozg ür Yuksekdag Simone Giovannuzzi Claudiu T Supuran Source Type: research
Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities
ChemMedChem. 2024 Feb 7:e202300667. doi: 10.1002/cmdc.202300667. Online ahead of print.ABSTRACTNagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potenci...
Source: ChemMedChem - February 7, 2024 Category: Chemistry Authors: Kgothatso A Chirwa Karol R Francisco Phelelisiwe S Dube Hayoung Park Lesetja J Legoabe Thaiz Rodrigues Teixeira Conor R Caffrey Richard Beteck Source Type: research
Targeting peptide based therapeutics: Integrated computational and experimental studies of autophagic regulation in host-parasite interaction
ChemMedChem. 2024 Feb 5:e202300679. doi: 10.1002/cmdc.202300679. Online ahead of print.ABSTRACTCutaneous leishmaniasis caused by the intracellular parasite Leishmania major, exhibits significant public health challenge worldwide. Present study manifests the crucial role of ATG8 protein as a potential target for combating L. major infection. Using bioinformatics analysis, we identified non-conserved motifs within the ATG8 in L. major. Subsequently, a peptide library was generated based on these motifs, and three peptides were selected for further investigation through molecular docking and molecular dynamics simulations. Su...
Source: ChemMedChem - February 6, 2024 Category: Chemistry Authors: Vrushali Guhe Shailza Singh Source Type: research
Pinpointing Acidic Residues in Proteins
ChemMedChem. 2024 Feb 2:e202300623. doi: 10.1002/cmdc.202300623. Online ahead of print.ABSTRACTIt is of great importance to pinpoint specific residues or sites of a protein in biological contexts to enable desired mechanism of action for small molecules or to precisely control protein function. In this regard, acidic residues including aspartic acid (Asp) and glutamic acid (Glu) hold great potential due to their great prevalence and unique function. To unlock the largely untapped potential, great efforts have been made recently by synthetic chemists, chemical biologists and pharmacologists. Herein, we would like to highlig...
Source: ChemMedChem - February 2, 2024 Category: Chemistry Authors: Weimin Xuan Jun-An Ma Source Type: research
