Review
Biochemistry & Molecular Biology
Francesca Serena Abatematteo, Mauro Niso, Marialessandra Contino, Marcello Leopoldo, Carmen Abate
Summary: The sigma-1 receptor is a pluripotent chaperone protein that interacts with several client proteins at the mitochondria-endoplasmic reticulum membrane interfaces. Developing multifunctional ligands targeting sigma-1 receptors may be a successful strategy in overcoming pharmacokinetic issues associated with the administration of diverse drugs. The evidence of unintentional binding between some clinically used drugs and sigma-1 protein supports the potential of targeting sigma-1 receptors with MTDLs for the treatment of multifactorial pathologies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Francesca Gado, Rebecca Ferrisi, Beatrice Polini, Kawthar A. Mohamed, Caterina Ricardi, Elena Lucarini, Sara Carpi, Federica Domenichini, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Paola Nieri, Gabriella Ortore, Roger G. Pertwee, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Grazia Chiellini, Robert B. Laprairie, Clementina Manera
Summary: The design and synthesis of dualsteric/bitopic agents that can interact with both orthosteric and allosteric binding sites presents a novel approach in medicinal chemistry. In this study, we designed and characterized the first CB2R heterobivalent bitopic ligands, which displayed selective targeting of CB2R and functional selectivity for the cAMP signaling pathway. Additionally, the most promising bitopic ligand FD-22a showed anti-inflammatory and antinociceptive activity in in vitro and in vivo models, respectively. Computational studies further confirmed the bitopic nature of these compounds.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yan Lu, Qi Gu, Stephen F. Martin
Summary: The sigma 2 receptor is a potential therapeutic target in neuroscience, and new compounds with high affinity and selectivity have been identified.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Denise Lovison, Dario Alessi, Lorenzo Allegri, Federica Baldan, Maurizio Ballico, Giuseppe Damante, Marilisa Galasso, Daniele Guardavaccaro, Silvia Ruggieri, Andrea Melchior, Daniele Veclani, Chiara Nardon, Walter Baratta
Summary: The paper describes a chiral ruthenium complex with high cytotoxic activity against various cell lines, particularly showing strong inhibition against the anaplastic thyroid cancer cell line 8505 C.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Evangelia Sereti, Chrisiida Tsimplouli, Elisavet Kalaitsidou, Nikos Sakellaridis, Konstantinos Dimas
Summary: This study aimed to investigate the expression levels of both sigma receptor subtypes in several human cancer cell lines and study their relationship with the activity of sigma ligands. Through in vitro experiments and the NCI60 COMPARE algorithm, the cytotoxic mechanism of action of the selected sigma ligands studied herein was further elucidated.
Article
Chemistry, Multidisciplinary
Qiyuan Zhou, Shu Chen, Zoufeng Xu, Gongyuan Liu, Shuyuan Zhang, Zhigang Wang, Man-Kit Tse, Shek-Man Yiu, Guangyu Zhu
Summary: This study reports the synthesis of Pt-IV complexes bearing axial pyridines through ligand exchange reactions. It was discovered that these axial pyridines can be quickly released after reduction, indicating their potential as axial leaving groups. Two multitargeted Pt-IV prodrugs containing bioactive pyridinyl ligands, a PARP inhibitor and an EGFR tyrosine kinase inhibitor, were successfully obtained using this method. These conjugates show great potential for overcoming drug resistance, with the latter inhibiting the growth of Pt-resistant tumor in vivo. This research expands the synthetic methods for Pt-IV prodrugs and increases the range of bioactive axial ligands that can be conjugated to a Pt-IV center.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Ekaterina Yu Rybalkina, Natalia Moiseeva, Aida F. Karamysheva, Daria Eroshenko, Anastasia Konysheva, Alexei Nazarov, Victoria V. Grishko
Summary: The semi-synthetic A-cycle modified triterpenic derivatives showed cytotoxicity against tumor cells and were similar to classical inhibitors in their action mechanism. Combining the modified triterpenic derivatives with doxorubicin improved the cytotoxic effect of the therapeutic drug against resistant tumor cells.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Biochemistry & Molecular Biology
Paula Morales, Chante Muller, Nadine Jagerovic, Patricia H. Reggio
Summary: Both CB1, CB2, and TRPV1 receptors play important roles in neurological disorders. Selective activation of CB2 receptors without affecting CB1 receptors offers optimized pharmacology without psychoactive effects. Simultaneous activation of CB2 and TRPV1 receptors presents a promising polypharmacological strategy for pain relief and neuroprotection.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Lu Liu, Wei Li, Le Yang, Zi-tao Guo, Hao Xue, Ning-jie Xie, Xiao-yan Chen
Summary: Almonertinib, a novel EGFR tyrosine kinase inhibitor, is metabolized by CYP3A, with the major active metabolite being N-desmethyl almonertinib (HAS-719). Co-administration with itraconazole increased almonertinib levels but reduced HAS-719 levels, while rifampicin decreased levels of both almonertinib and HAS-719. Further metabolism of HAS-719 may contribute to its altered pharmacokinetics when combined with rifampicin.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Biochemistry & Molecular Biology
Francesca Paoletti, Franci Merzel, Alberto Cassetta, Iza Ogris, Sonia Covaceuszach, Joze Grdadolnik, Doriano Lamba, Simona Golic Grdadolnik
Summary: NGF plays a crucial role in the maintenance and growth of neuronal populations, with interactions with ATP impacting the binding to specific receptors. The study suggests that ATP may serve as a transient molecular modulator of NGF signaling in health and disease states.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Chemistry, Medicinal
Laura Braconi, Silvia Dei, Marialessandra Contino, Chiara Riganti, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Maria Grazia Perrone, Nicola Antonio Colabufo, Stefano Guglielmo, Elisabetta Teodori
Summary: New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized and studied as MDR reversers, showing potent inhibitory effects on P-gp transport activity and increasing the antiproliferative effect of doxorubicin in MDR cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yan Zhang, Zhenzhi Cai, Julia Struwe, Chanchan Ma, Wangyu Zeng, Xinyi Liao, Min Xu, Lutz Ackermann
Summary: In this study, a versatile strategy for constructing challenging seven-membered rings using a 7-endo-trig cyclization initiated by a phosphorus-centered radical is reported. This approach allows for the efficient synthesis of a wide range of phosphorylated dibenzocycloheptanones in a step-economical manner. Additionally, a traceless addition/exchange strategy was devised for the preparation of dephosphorylated products at room temperature with excellent yields, enabling concise synthesis of biorelevant allocochicine derivatives.
Article
Chemistry, Multidisciplinary
Naveen J. Roy, Shreyada N. Save, Virender Kumar Sharma, Benchamin Abraham, Abhijith Kuttanamkuzhi, Shilpy Sharma, Mayurika Lahiri, Pinaki Talukdar
Summary: NQO1, a detoxifying enzyme overexpressed in tumors, can protect cancer cells against oxidative stress. The activation of 'protransporter' systems in cancer cells has been achieved using NQO1 activatable quinones, leading to cell apoptosis. The ion transport activity of salicylamides was effectively inhibited by caging the OH group with NQO1-activatable quinones. Activation of the trapped 'protransporters' following reduction by NQO1 was verified. Both the transporters and trapped protransporters exhibited significant toxicity towards MCF-7 breast cancer cells, mediated through oxidative stress, mitochondrial membrane depolarization, and lysosomal deacidification. Induction of cell death via the intrinsic apoptotic pathway was confirmed by monitoring PARP1 cleavage.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Medicinal
Rong Zeng, Xiu-Ming Yang, Xue Li, Yu Guan, Tao Yu, Peng Yan, Wen Yuan, Sheng-Li Niu, Jing Gu, Ying-Chun Chen, Qin Ouyang
Summary: In this study, a simplified compound OY-101 was developed as a specific and efficient P-gp inhibitor with high reversal activity and low cytotoxicity. The OY-101 showed excellent synergistic anti-cancer effect with vincristine against drug-resistant cells without obvious toxicity, suggesting its potential as an anti-tumor chemotherapy sensitizer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Saibin Zhu, Yeji Wang, Zhongqing Wen, Yanwen Duan, Yong Huang
Summary: The study revealed that Huanglongmycin congener 14 exhibited stronger cytotoxicity against tested cancer cells, and highlighted the critical role of the C-7 ethyl group of 14 in its binding to the DNA-topoisomerase I complex.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Enza Lacivita, Mauro Niso, Margherita Mastromarino, Andrea Garcia Silva, Cibell Resch, Andre Zeug, Maria Loza, Marian Castro, Evgeni Ponimaskin, Marcello Leopoldo
Summary: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with no effective treatments currently available. Studies show that targeting the brain serotonin system may help treat core symptoms of ASD and associated intellectual disabilities. New compounds with 5-HT receptor properties have been synthesized and show promise for future ASD treatments.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Eduardo Penna, Mauro Niso, Sabina Podlewska, Floriana Volpicelli, Marianna Crispino, Carla Perrone-Capano, Andrzej J. Bojarski, Enza Lacivita, Marcello Leopoldo
Summary: The kinetics of drug-target interaction has been a topic of increasing interest in the field of pharmacology. Previous studies have shown the importance of the lipophilicity of a molecule in this process, but there has been limited research on the 5-HT7 receptor (5-HT7R), a GPCR involved in neurodevelopmental and neuropsychiatric disorders. In this study, the researchers explored the structure-kinetics relationships of a specific class of ligands for the 5-HT7R and found that the position of polar groups within the molecule, rather than overall lipophilicity, influenced the interaction kinetics. Additionally, molecular docking and dynamics simulations were used to gain further insights into the relationship between structure and kinetics.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Francesca S. Abatematteo, Philip D. Mosier, Mauro Niso, Leonardo Brunetti, Francesco Berardi, Fulvio Loiodice, Marialessandra Contino, Benjamin Delprat, Tangui Maurice, Antonio Laghezza, Carmen Abate
Summary: The sigma-1 receptor is important in physiological and pathological processes, and the phenoxyalkylpiperidine compounds show potential as high-affinity agonists. Compound 1a, in particular, exhibits strong activity and warrants further investigation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Margherita Mastromarino, Mauro Niso, Carmen Abate, Ewgenij Proschak, Mariam Dubiel, Holger Stark, Marian Castro, Enza Lacivita, Marcello Leopoldo
Summary: Long-chain arylpiperazine scaffold is a versatile template for designing CNS drugs targeting serotonin and dopamine receptors. This study synthesized and evaluated ten new arylpiperazine derivatives with affinity profiles at serotonin and dopamine receptors, aiming to treat ASD or psychosis. The new compounds incorporated antioxidant fragments to counteract oxidative stress. Compound 12a showed an affinity profile compatible with antipsychotic activity, while compound 9b had an affinity profile consistent with ASD studies. Both compounds also had antioxidant properties.
Article
Chemistry, Medicinal
Robert W. Garvey, Enza Lacivita, Mauro Niso, Beata Duszynska, Paul E. Harris, Marcello Leopoldo
Summary: This study reports the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. One of the probes has the ability to selectively label the 5-HT1A receptor in pancreatic islet cells and shows useful properties for further characterization of this receptor's role.
Article
Chemistry, Medicinal
Margherita Mastromarino, Maria Favia, Igor A. Schepetkin, Lylia N. Kirpotina, Ewa Trojan, Mauro Niso, Antonio Carrieri, Monika Leskiewicz, Magdalena Regulska, Massimiliano Darida, Francesco Rossignolo, Stefano Fontana, Mark T. Quinn, Agnieszka Basta-Kaim, Marcello Leopoldo, Enza Lacivita
Summary: Formyl peptide receptor 2 (FPR2) agonists, including the newly identified ureidopropanamide derivatives, show promising potential in resolving inflammation and treating neurodegenerative disorders with underlying chronic neuroinflammation. Computational studies provide insights into the interactions between these compounds and FPR2. In vitro and in vivo experiments demonstrate the anti-inflammatory effects and improved mitochondrial function of selected compounds.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Dario P. Anobile, Mauro Niso, Adrian Puerta, Stephanie M. Fraga Rodrigues, Francesca S. Abatematteo, Amir Avan, Carmen Abate, Chiara Riganti, Elisa Giovannetti
Summary: A new sigma-2 receptor ligand FA4 was synthesized and evaluated for its anti-proliferative, pro-apoptotic, and anti-migratory activity on PDAC primary cell cultures. The results showed that FA4 effectively inhibited the aggressive and chemoresistant behavior of PDAC, with significant antiproliferative and antimigratory effects.
Article
Biochemistry & Molecular Biology
Bashar M. Thejer, Vittoria Infantino, Anna Santarsiero, Ilaria Pappalardo, Francesca S. Abatematteo, Sarah Teakel, Ashleigh Van Oosterum, Robert H. Mach, Nunzio Denora, Byung Chul Lee, Nicoletta Resta, Rosanna Bagnulo, Mauro Niso, Marialessandra Contino, Bianca Montsch, Petra Heffeter, Carmen Abate, Michael A. Cahill
Summary: Sigma-2 receptor (S2R) is functionally associated with both transmembrane protein TMEM97 and translocator protein (TSPO). This study provides evidence of the interaction between S2R and TSPO, as well as the physical colocalization of TMEM97 and TSPO in certain cancer cells. Additionally, the role of S2R-interacting partner PGRMC1 was clarified. This is the first suggestion of a functional interaction between TSPO and TMEM97, which can be influenced by S2R ligands.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Giovanni Graziano, Angela Stefanachi, Marialessandra Contino, Ruben Prieto-Diaz, Alessia Ligresti, Poulami Kumar, Antonio Scilimati, Eddy Sotelo, Francesco Leonetti
Summary: Multicomponent reactions (MCRs) are widely used in synthetic organic chemistry for drug discovery and development due to their flexibility in forming complex products with high efficiency. They are considered as an exploratory and evolutionary tool in medicinal chemistry, enabling sustainable and rapid synthesis of biologically active molecules. This review provides an overview of the approaches and applications of MCRs in the development of new anticancer drugs, showcasing their extensive use in this field.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Francesca Serena Abatematteo, Maria Majellaro, Bianca Montsch, Ruben Prieto-Diaz, Mauro Niso, Marialessandra Contino, Angela Stefanachi, Chiara Riganti, Giuseppe Felice Mangiatordi, Pietro Delre, Petra Heffeter, Eddy Sotelo, Carmen Abate
Summary: Sigma receptor subtypes, sigma 1 and sigma 2, are potential targets for cancer and Alzheimer's disease therapy. Novel specific fluorescent ligands have been developed, including compounds 19 (sigma pan affinity) and 29 (sigma 2 selective), which show specificity for sigma 2 receptors and can be used as powerful tools for studying these receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Biochemistry & Molecular Biology
Carmen Abate, Tangui Maurice
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)