Publications by authors named "Margherita Brindisi"

83 Publications

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation.

ACS Med Chem Lett 2020 Nov 29;11(11):2268-2276. Epub 2020 Sep 29.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy.

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit . We identified compound as the most potent and selective HDAC6 inhibitor of the series. Biological investigation of compounds , , and demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. induced HDAC6-dependent pSTAT3 inhibition.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667836PMC
November 2020

Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation.

Eur J Med Chem 2021 Feb 7;212:112998. Epub 2020 Nov 7.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address:

In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
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http://dx.doi.org/10.1016/j.ejmech.2020.112998DOI Listing
February 2021

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis.

ChemMedChem 2020 Nov 10;15(21):1985-2003. Epub 2020 Sep 10.

Department of Excellence of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131, Naples, Italy.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system. At present, there is no definitive cure, and the few available disease-modifying options display either poor efficacy or life-threatening side effects. There is clear evidence that relapsing-remitting clinical attacks in MS are driven by inflammatory demyelination and that the subsequent disease steps, being irresponsive to immunotherapy, result from neurodegeneration. The endocannabinoid system (ECS) stands halfway between three key pathomechanisms underlying MS, namely inflammation, neurodegeneration and oxidative stress, thus representing a kingpin for the identification of novel therapeutic targets in MS. This review summarizes the current state of the art in the field of endocannabinoid metabolism modulators and their in vivo effects on relevant animal models. We also highlight key molecular underpinnings of their therapeutic efficacy as well as the potential to turn them into promising clinical candidates.
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http://dx.doi.org/10.1002/cmdc.202000310DOI Listing
November 2020

Drug Development and Medicinal Chemistry Efforts toward SARS-Coronavirus and Covid-19 Therapeutics.

ChemMedChem 2020 06 7;15(11):907-932. Epub 2020 May 7.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.

The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses.
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http://dx.doi.org/10.1002/cmdc.202000223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264561PMC
June 2020

Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials.

Curr Top Med Chem 2020 ;20(6):433-457

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy.

Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations.
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http://dx.doi.org/10.2174/1568026620666200102104930DOI Listing
December 2020

Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry.

J Med Chem 2020 03 2;63(6):2751-2788. Epub 2019 Dec 2.

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.

The urea functionality is inherent to numerous bioactive compounds, including a variety of clinically approved therapies. Urea containing compounds are increasingly used in medicinal chemistry and drug design in order to establish key drug-target interactions and fine-tune crucial drug-like properties. In this perspective, we highlight physicochemical and conformational properties of urea derivatives. We provide outlines of traditional reagents and chemical procedures for the preparation of ureas. Also, we discuss newly developed methodologies mainly aimed at overcoming safety issues associated with traditional synthesis. Finally, we provide a broad overview of urea-based medicinally relevant compounds, ranging from approved drugs to recent medicinal chemistry developments.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266097PMC
March 2020

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas.

Med Res Rev 2020 05 19;40(3):1002-1060. Epub 2019 Nov 19.

Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy.

Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.
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http://dx.doi.org/10.1002/med.21646DOI Listing
May 2020

Screening and Phenotypical Characterization of Histone Deacetylase 8 (HDAC8) Inhibitors as Multistage Antischistosomal Agents.

ACS Infect Dis 2020 01 12;6(1):100-113. Epub 2019 Nov 12.

Institute of Biochemistry and Cell Biology (IBBC) , National Research Council (CNR) , Campus A. Buzzati-Traverso, via E. Ramarini 32 , 00015 Monterotondo ( Rome ), Italy.

Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus . The disease is endemic in tropical and subtropical areas of the world where water is infested by the intermediate parasite host, the snail. More than 800 million people live in endemic areas and more than 200 million are infected and require treatment. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment and transmission control being safe and very effective against adult worms of all the clinically relevant species. Unfortunately, it is ineffective on immature, juvenile worms; therefore, it does not prevent reinfection. Moreover, the risk of development and spread of drug resistance because of the widespread use of a single drug in such a large population represents a serious threat. Therefore, research aimed at identifying novel drugs to be used alone or in combination with PZQ are needed. histone deacetylase 8 (HDAC8) is a class I zinc-dependent HDAC, which is abundantly expressed in all stages of its life cycle, thus representing an interesting target for drug discovery. Through virtual screening and phenotypical characterization of selected hits, we discovered two main chemical classes of compounds characterized by the presence of a hydroxamate-based metal binding group coupled to a spiroindoline or a tricyclic thieno[3,2-]indole core as capping groups. Some of the compounds of both classes were deeply investigated and showed to impair viability of larval, juvenile, and adult schistosomes, to impact egg production and/or to induce morphological alterations of the adult schistosome reproductive systems. Noteworthy, all of them inhibit the recombinant form of HDAC8 enzyme . Overall, we identified very interesting scaffolds, paving the way to the development of effective antischistosomal agents.
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http://dx.doi.org/10.1021/acsinfecdis.9b00224DOI Listing
January 2020

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Eur J Med Chem 2019 Dec 4;183:111674. Epub 2019 Sep 4.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D or D receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.
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http://dx.doi.org/10.1016/j.ejmech.2019.111674DOI Listing
December 2019

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using Structure-Based Combinatorial Library Design Approach.

Front Chem 2019 13;7:574. Epub 2019 Aug 13.

Department of Pharmacy, Department of Excellence 2018-2022, University of Naples Federico II, Naples, Italy.

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the tests along with no toxicity. Among them represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.
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http://dx.doi.org/10.3389/fchem.2019.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700280PMC
August 2019

Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.

J Med Chem 2020 01 27;63(1):23-39. Epub 2019 Aug 27.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy.

Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00924DOI Listing
January 2020

Bridged bicyclic 2,3-dioxabicyclo[3.3.1]nonanes as antiplasmodial agents: Synthesis, structure-activity relationships and studies on their biomimetic reaction with Fe(II).

Bioorg Chem 2019 08 31;89:103020. Epub 2019 May 31.

Department of Biotechnology, Chemistry and Pharmacy (DoE 2018-2022), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.
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http://dx.doi.org/10.1016/j.bioorg.2019.103020DOI Listing
August 2019

Raising the bar in anticancer therapy: recent advances in, and perspectives on, telomerase inhibitors.

Drug Discov Today 2019 07 25;24(7):1370-1388. Epub 2019 May 25.

University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100 Siena, Italy. Electronic address:

Telomerase is a ribonucleic reverse transcriptase enzyme that uses an integral RNA component as a template to add tandem telomeric DNA repeats, TTAGGG, at the 3' end of the chromosomes. 85-90% of human tumors and their derived cell lines predominantly express high levels of telomerase, therefore contributing to cancer cell development. However, in normal cells, telomerase activity is almost always absent except in germ cells and stem cells. This differential expression has been exploited to develop highly specific and potent cancer therapeutics. In this review, we outline recent advances in the development of telomerase inhibitors as anticancer agents.
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http://dx.doi.org/10.1016/j.drudis.2019.05.015DOI Listing
July 2019

A light in the dark: state of the art and perspectives in optogenetics and optopharmacology for restoring vision.

Future Med Chem 2019 03 25;11(5):463-487. Epub 2019 Mar 25.

Department of Biotechnology, Chemistry & Pharmacy, Department of Excellence 2018-2022, University of Siena, Via A. Moro 2, 53100 Siena, Italy.

In the last decade, innovative therapeutic strategies against inherited retinal degenerations (IRDs) have emerged. In particular, chemical- and opto-genetics approaches or a combination of them have been identified for modulating neuronal/optical activity in order to restore vision in blinding diseases. The 'chemical-genetics approach' (optopharmacology) uses small molecules (exogenous photoswitches) for restoring light sensitivity by activating ion channels. The 'opto-genetics approach' employs light-activated photosensitive proteins (exogenous opsins), introduced by viral vectors in injured tissues, to restore light response. These approaches offer control of neuronal activities with spatial precision and limited invasiveness, although with some drawbacks. Currently, a combined therapeutic strategy (optogenetic pharmacology) is emerging. This review describes the state of the art and provides an overview of the future perspectives in vision restoration.
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http://dx.doi.org/10.4155/fmc-2018-0315DOI Listing
March 2019

Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders.

ACS Med Chem Lett 2019 Mar 23;10(3):228-236. Epub 2019 Jan 23.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100 Siena, Italy.

The allosteric targeting of ionotropic glutamate receptors (iGluRs) is a valuable approach for treating various central nervous system (CNS) disorders. In this frame, this Innovations provides a summary of the state-of-the art in the development of allosteric modulators for iGluRs and offers an outlook regarding innovative strategies for treating neurological diseases.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421537PMC
March 2019

Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies.

ChemMedChem 2019 03 5;14(5):545-560. Epub 2019 Feb 5.

Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA.

Herein we present the design, synthesis, and biological evaluation of potent and highly selective β-secretase 2 (memapsin 1, beta-site amyloid precursor protein cleaving enzyme 2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for type 2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2 a {N -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a-bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure-activity relationship study led to the identification of determinants of the inhibitors' potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N -methyl-N -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; K =0.031 nm, selectivity over BACE1: ≈174 000-fold] and 3 l [N -((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N ,5-dimethyl-N -((R)-1-phenylethyl)isophthalamide; K =1.6 nm, selectivity over BACE1: >500-fold] displayed outstanding potency and selectivity. Inhibitor 3 l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential.
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http://dx.doi.org/10.1002/cmdc.201800725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637425PMC
March 2019

Asymmetric Diels-Alder reaction of 3-(acyloxy) acryloyl oxazolidinones: optically active synthesis of a high-affinity ligand for potent HIV-1 protease inhibitors.

RSC Adv 2019 17;9(71):41755-41763. Epub 2019 Dec 17.

Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA.

We describe here our investigation of the asymmetric Diels-Alder reaction of chiral 3-(acyloxy)acryloyl oxazolidinones as dienophiles in various Lewis-acid promoted reactions with cyclopentadiene. The resulting highly functionalized cycloadducts are useful intermediates for the synthesis, particularly for the optically active synthesis of 6-5-5 tricyclic hexahydro-4-3,5-methanofuro[2,3-]pyranol () with five contiguous chiral centers. This stereochemically defined crown-like heterocyclic derivative is an important high affinity ligand for a variety of highly potent HIV-1 protease inhibitors. Among the various dienophiles and Lewis acid-mediated reactions surveyed, 3-(4-methoxybenzoyl)acryloyl oxazolidinone as the dienophile and diethylaluminum chloride as the Lewis-acid provided the desired product with excellent diastereoselectivity. The cycloaddition was carried out in multi-gram scale and the cycloadduct was efficiently converted to alcohol with high enantiomeric purity. The optically active ligand was then transformed into potent HIV-1 protease inhibitor .
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http://dx.doi.org/10.1039/c9ra10178kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351138PMC
December 2019

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents.

Eur J Med Chem 2019 Jan 3;162:290-320. Epub 2018 Nov 3.

European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy; Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131, Napoli, Italy.

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.
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http://dx.doi.org/10.1016/j.ejmech.2018.11.004DOI Listing
January 2019

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry.

ChemMedChem 2018 11 11;13(22):2351-2373. Epub 2018 Oct 11.

Department of Chemistry and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.

The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.
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http://dx.doi.org/10.1002/cmdc.201800518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604631PMC
November 2018

Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies.

Eur J Med Chem 2018 Sep 31;157:127-138. Epub 2018 Jul 31.

European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b, with a spiroindoline-based hydroxamate bearing a tert-butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.069DOI Listing
September 2018

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain.

ChemMedChem 2018 10 30;13(19):2090-2103. Epub 2018 Aug 30.

European Research Centre for Drug Discovery and Development (NatSynDrugs), Department of Biotechnology, Chemistry, and Pharmacy (DoE 2018-2020), University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.

The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
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http://dx.doi.org/10.1002/cmdc.201800397DOI Listing
October 2018

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors.

Asian J Org Chem 2018 Aug 8;7(8):1448-1466. Epub 2018 Jun 8.

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907 (USA).

We have developed a conceptually new generation of non-peptidic HIV-1 protease inhibitors incorporating novel structural templates inspired by nature. This has resulted in protease inhibitors with exceptional potency and excellent pharmacological and drug-resistance profiles. The design of a stereochemically defined -tetrahydrofuran (-THF) scaffold followed by modifications to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease led to darunavir, the first clinically approved drug for treatment of drug resistant HIV. Subsequent X-ray crystal structure-based design efforts led us to create a range of exceptionally potent inhibitors incorporating other intriguing molecular templates possessing fused ring polycyclic ethers with multiple stereocenters. These structural templates are critical to inhibitors' exceptional potency and drug-like properties. Herein, we will highlight the synthetic strategies that provided access to these complex scaffolds in a stereoselective and optically active form, enabling our medicinal chemistry and drug development efforts.
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http://dx.doi.org/10.1002/ajoc.201800255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781882PMC
August 2018

Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand.

Bioorg Med Chem Lett 2018 08 26;28(15):2605-2610. Epub 2018 Jun 26.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biochemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K value of 10.9 nM and EC of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.
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http://dx.doi.org/10.1016/j.bmcl.2018.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085084PMC
August 2018

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.

J Med Chem 2018 05 15;61(10):4561-4577. Epub 2018 May 15.

Departments of Infectious Diseases and Hematology , Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556 , Japan.

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044451PMC
May 2018

iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome.

Exp Cell Res 2018 07 4;368(2):225-235. Epub 2018 May 4.

Medical Genetics, University of Siena, Strada delle Scotte 4, 53100, Siena, Italy.

Mutations in MECP2 gene have been identified in more than 95% of patients with classic Rett syndrome, one of the most common neurodevelopmental disorders in females. Taking advantage of the breakthrough technology of genetic reprogramming, we investigated transcriptome changes in neurons differentiated from induced Pluripotent Stem Cells (iPSCs) derived from patients with different mutations. Profiling by RNA-seq in terminally differentiated neurons revealed a prominent GABAergic circuit disruption along with a perturbation of cytoskeleton dynamics. In particular, in mutated neurons we identified a significant decrease of acetylated α-tubulin which can be reverted by treatment with selective inhibitors of HDAC6, the main α-tubulin deacetylase. These findings contribute to shed light on Rett pathogenic mechanisms and provide hints for the treatment of Rett-associated epileptic behavior as well as for the definition of new therapeutic strategies for Rett syndrome.
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http://dx.doi.org/10.1016/j.yexcr.2018.05.001DOI Listing
July 2018

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

Eur J Med Chem 2018 Apr 10;150:698-718. Epub 2018 Mar 10.

Department of Biotechnology, Chemistry and Pharmacy, Dipartimento di Eccellenza 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba current through Ca1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902032PMC
April 2018

The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses.

Org Biomol Chem 2018 03 26;16(12):2006-2027. Epub 2018 Feb 26.

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.

The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivatives including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivatives. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomolecules. In this review, we present mechanistic studies, chemical methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivatives, and their applications in the synthesis of bioactive natural products and their congeners.
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http://dx.doi.org/10.1039/c8ob00138cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864567PMC
March 2018

( S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation.

J Med Chem 2018 03 26;61(5):2124-2130. Epub 2018 Feb 26.

Department of Drug Design and Pharmacology , University of Copenhagen , Jagtvej 162 , DK-2100 Copenhagen , Denmark.

Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
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http://dx.doi.org/10.1021/acs.jmedchem.8b00099DOI Listing
March 2018

Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants.

ChemMedChem 2018 04 15;13(8):803-815. Epub 2018 Mar 15.

Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan.

Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.
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http://dx.doi.org/10.1002/cmdc.201700824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912973PMC
April 2018