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Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijms23158271/s1., Cancer is still a challenging disease to treat, both in terms of harmful side effects and therapeutic efficiency of the available treatments. Herein, to develop new therapeutic molecules, we have investigated the anticancer activity of halogenated derivatives of different components of the bioluminescent system of marine Coelenterazine: Coelenterazine (Clz) itself, Coelenteramide (Clmd), and Coelenteramine (Clm). We have found that Clz derivatives possess variable anticancer activity toward gastric and lung cancer. Interestingly, we also found that both brominated Clmd (Br-Clmd) and Clm (Br-Clm) were the most potent anticancer compounds toward these cell lines, with this being the first report of the anticancer potential of these types of molecules. Interestingly, Br-Clm possessed some safety profile towards noncancer cells. Further evaluation revealed that the latter compound induced cell death via apoptosis, with evidence for crosstalk between intrinsic and extrinsic pathways. Finally, a thorough exploration of the chemical space of the studied Br-Clm helped identify the structural features responsible for its observed anticancer activity. In conclusion, a new type of compounds with anticancer activity toward gastric and lung cancer was reported and characterized, which showed interesting properties to be considered as a starting point for future optimizations towards obtaining suitable chemotherapeutic agents., The Portuguese “Fundação para a Ciência e Tecnologia“ (FCT) is acknowledged for funding project PTDC/QUI-QFI/2870/2020, the R&D Units CIQUP (UIDB/00081/2020), GreenUPorto (UIDB/05748/2020), LAQV/REQUIMTE (UIDB/50006/2020), and the Associated Laboratory IMS (LA/P/0056/2020). L. Pinto da Silva acknowledges funding from FCT under the Scientific Employ ment Stimulus (2021.00768.CEECIND). Patricia González-Berdullas acknowledges funding for her postdoctoral position in the framework of project PTDC/QUI/QFI/2870/2020. Carla Magalhães acknowledges FCT for her PhD grant (SRFH/BD/143211/2019). Renato B. Pereira acknowledges PRIMA Foundation (H2020- PRIMA 2018—Section 2, Project MILKQUA) and FCT (PTDC/QUI QFI/2870/2020) for the funding.

Neurodegenerative disorders of the central nervous system are a class of heterogeneous pathologies affecting millions of people worldwide and represent a global health burden in developed and developing countries. Without restorative treatments currently available, research on neuroprotective drugs is considered a health priority. In this study, new analogues of the glycyl-l-prolyl-l-glutamic acid (Glypromate) neuropeptide were designed, synthesized, and biologically evaluated using (1R,3S,4S)-2-azanorbornane-3-carboxylic acid as a hybrid construct of l-proline and l-pipecolic acid. Neuroprotection assays carried out in human neuroblastoma SH-SY5Y cells using 6-hydroxydopamine as a stress inducer showed great percentage of recovery (29.7-40.0%) at 100 μM. Among this series, [(1R,3S,4S)-2-glycyl-2-azanorbornane-3-carbonyl]-l-aspartic acid (2a) stands out with a remarkable percentage of recovery (40.0%, at 100 μM) and safe toxicological profile in SH-SY5Y and human adipose mesenchymal stem cells.

This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at dopamine D2 receptors (D2R). Methyl picolinoyl-l-valyl-l-alaninate (compound 6b) produced a statistically significant increase in the maximal [3H]-NPA response at 0.01 nM (11.9 ± 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 ± 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 ± 7.1% for 6b vs 15.4 ± 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of 6b show EC50 (0.33 ± 0.21 μM for 6b vs 0.17 ± 0.07 μM for MIF-1) and Emax (86.0 ± 5.4% for 6b vs 93.6 ± 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic 6b was tested for agonist activity at the human D2R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D2R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 μM. Conformational energy minimization for 6b shows that this peptidomimetic cannot adopt the postulated type-II β-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.

This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-l-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (18 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day-old Wistar-Kyoto rat embryos suggest that 6a displays no neurotoxicity up to 100 μM. Overall, the pharmacological and toxicological profile and the structural simplicity of 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological and biological data herein reported, along with >20â000 outcomes of preclinical assays, was used to seek a general model to predict the allosteric modulatory potential of molecular candidates for a myriad of target receptors, organisms, cell lines, and biological activity parameters based on perturbation theory (PT) ideas and machine learning (ML) techniques, abbreviated as ALLOPTML. By doing so, ALLOPTML shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. To the best of our knowledge, ALLOPTML is the first general-purpose chemoinformatic tool using a PTML-based model for the multioutput and multicondition prediction of allosteric compounds, which is expected to save both time and resources during the early drug discovery of allosteric modulators., This research was funded by Fundação para a Ciência e Tecnologia (FCT, Portugal), through grants UIDB/50006/2020 (to LAQV-REQUIMTE Research Unit) and for project grants PTDC/BIA-MIB/29059/2017 and PEst-OE/QUI/UI0674/2013. This work was also supported by the Collaborative Project of Genomic Data Integration (CICLOGEN)., The support of Ikerbasque, Basque Foundation for Science and the research grants from Ministry of Economy and Competitiveness, MINECO, Spain (FEDER CTQ2016–74881-P), and Basque government (IT1045–16) are also acknowledged. The financial support (ED431G 2019/02) from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund—ERDF) is gratefully acknowledged. I.E.S.-D. thanks FCT for the doctoral grant SFRH/BD/93632/2013. X.G.-M. thanks Xunta de Galicia for financial support (GPC2014/003).

While photodynamic therapy is known for significant advantages over conventional cancer therapies, its dependence on light has limited it to treating tumors on or just under the skin or on the outer lining of organs/cavities. Herein, we have developed a single-molecule photosensitizer capable of intracellular self-activation and with potential tumor-selectivity due to a chemiluminescent reaction involving only a cancer marker. Thus, the photosensitizer is directly chemiexcited to a triplet excited state capable of generating singlet oxygen, without requiring either a light source or any catalyst/co-factor. Cytotoxicity assays involving the photosensitizer show significant toxicity toward tumor cells, even better than reference drugs, while not inducing toxicity toward normal cells. This work provides a proof-of-concept for a novel type of photosensitizer that eliminates the current restrictions that photodynamic therapy presents regarding tumor size and localization.

Alzheimers disease (AD) is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide, are hallmark neuropathological lesions in Alzheimers disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE-1 enzyme is essential for the generation of β-amyloid. BACE-1 knockout mice do not produce β-amyloid and are free from Alzheimers associated pathologies, including neuronal loss and certain memory deficits. The fact that BACE-1 initiates the formation of β-amyloid, and the observation that BACE-1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE-1 inhibition, thus reducing β-amyloid and its associated toxicities. In this sense, quantitative structure-activity relationships (QSAR) could play an important role in studying these β-secretase inhibitors. QSAR models are necessary in order to guide the β-secretase synthesis. This work is aimed at reviewing different design and synthesis and computational studies for a very large and heterogeneous series of β-secretase inhibitors. First, we review design, synthesis, and Biological assay of β-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find out the structural requirements. Next, we review QSAR studies using the method of Linear Discriminant Analysis (LDA) in order to understand the essential structural requirement for receptor binding for β- secretase inhibitors.

A new series of 9-deazaxanthine derivatives with various substituents at the heterocyclic system were synthesized and evaluated for their binding affinities for the four human recombinant adenosine receptors, A(1)-A(3) subtypes. A number of the 9-deazaxanthines derivatives 3a-m showed moderate-to-high affinity for hA(2B) receptors, with compound 3f showing a 32-fold selectivity for A(2B) over A(1) and a 2750-fold selectivity for A(2B) over A(2A).

cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels-Alder reaction from cyclopentadiene and appropriately protected 2-imidazolone--followed by dihydroxylation, glycol protection, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction--, was used to synthesize (+/-)-cis-([7-(6-chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazin-5-yl)methanol, a key intermediate for novel 1'-homocarbanucleosides based on a cyclopenta[b]pyrazine scaffold as shown by its conversion into several 6-substituted purinyl derivatives.

Exo-2-azabicyclo[2.2.1]hept-5-enes were obtained by cycloaddition reactions between cyclopentadiene and protonated (S)- and (R)-1-phenylethylimines of (1R,endo)-benzonorbornen-2-yl glyoxylate. The non-natural (1R,endo)-benzonorbornen-2-ol proved to be an efficient chiral auxiliary in these asymmetric aza-Diels–Alder reactions, which afforded only exo-cycloadducts with 1S : 1R diastereomeric ratios of 15 : 85 for (S)-(1-phenylethyl)imine and 93 : 7 for (R)-(1-phenylethyl)imine. The obtained diastereoisomers were effortlessly and efficiently isolated using a chromatographic column. The absolute configuration of all the formed adducts was unequivocally assigned through NMR, specific optical rotation and X-ray data.

1,3-Cycloaddition reactions between methyl glyoxylate oxime and alkenes in the presence of BF3·OEt2 provides isoxazolidines.

Cyclobutyl nucleoside analogues containing guanine and 8-azaguanine (compounds 5-10) were prepared from (1R,cis)-3-aminomethyl-2,2-dimethylcyclobutylmethanol (1). All were evaluated as antiviral and antitumoral agents in a variety of assay systems. Compounds 6 and 7 showed a noteworthy activity against a respiratory syncytial virus and compound 10 was moderately active against vaccinia virus. Only compound 5 showed some cytostatic activity.

Quantitative structure-activity relationship models for the prediction of mode of toxic action (MOA) of 221 phenols to the ciliated protozoan Tetrahymena pyriformis using atom-based quadratic indices are reported. The phenols represent a variety of MOAs including polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Linear discriminant analysis (LDA), and four machine learning techniques (ML), namely k-nearest neighbours (k-NN), support vector machine (SVM), classification trees (CTs) and artificial neural networks (ANNs), have been used to develop several models with higher accuracies and predictive capabilities for distinguishing between four MOAs. Most of them showed global accuracy of over 90%, and false alarm rate values were below 2.9% for the training set. Cross-validation, complementary subsets and external test set were performed, with good behaviour in all cases. Our models compare favourably with other previously published models, and in general the models obtained with ML techniques show better results than those developed with linear techniques. We developed unsupervised and supervised consensus, and these results were better than our ML models, the results of rule-based approach and other ensemble models previously published. This investigation highlights the merits of ML-based techniques as an alternative to other more traditional methods for modelling MOA.

Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.

A series of novel 9-deazaxanthine derivatives with various substituents at the heterocyclic system is synthesized and evaluated for binding affinities for the four human recombinant adenosine receptors, A1—A3 subtypes.

Glyoxylates of three chiral alcohols were conveniently prepared by reaction of the alcohol with oxalyl chloride followed by reduction of the resulting alkoxy oxalyl chloride with tributyl- tin hydride. The products were isolated in 75-80% yield by straightforward flash chromatography.

Aminoalcohol precursor of carbocyclic analogues of nucleosides (±)-cis-3-aminomethyl-1-indanylmethanol was efficiently synthesized starting from benzonorbornadiene (5) previously prepared by addition of cyclopentadiene to 1-bromo-2-fluorobenzene.

Cyclobutyl nucleoside analogues containing guanine and 8-azaguanine (compounds 5-10) were prepared from (1R,cis)-3-aminomethyl-2,2-dimethylcyclobutylmethanol (1). All were evaluated as antiviral and antitumoral agents in a variety of assay systems. Compounds 6 and 7 showed a noteworthy activity against a respiratory syncytial virus and compound 10 was moderately active against vaccinia virus. Only compound 5 showed some cytostatic activity.

Seven new carbocyclic nucleosides derived from indan (1a-g) were efficiently prepared from 1,2-indanedimethanol via Mitsunobu reaction with 6-chloroadenine and subsequent introduction of the appropriate substituent.

A new series of 6-substituted purinylcarbonucleosides derivatives of indan, 8a-g and 10a-d, was synthesized from (′)-cis-1,3-indandimethanol acetate (5), which was prepared in three steps from benzonorbornadiene. 6-Chloropurine was introduced both by Mitsunobu reaction with 5 and by substitution of the mesylate 6, Suzuki-Miyaura reactions of the protected 6-chloropurine derivative 7 with substituted phenylboronic acids afforded 9a-d (protected purine derivatives with substituted phenyl rings at position 6); deprotection of the latter yielded the new series of purinylcarbonucleoside indan derivatives 10a-d. Treatment of compound 7 with R'H/NaOH afforded a parallel series 8a-g, with alkoxy or amino groups R' at position 6 instead of substituted phenyl rings.

Jose E. Rodriguez-Borges,* Sofia Goncalves, Maria Luisa do Vale, Xerardo Garcia-Mera, Alberto Coelho, and Eddy Sotelo CIQ-Departamento de Quimica, Faculdade de Ciencias, UniVersidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal, and Departamento de Quimica Organica and Instituto de Farmacia Industrial, Facultade de Farmacia, UniVersidade de Santiago de Compostela, Santiago de Compostela, 15782 Spain

A new and general method is described for the synthesis, in three steps and in good overall yields, of tetrasubstituted xanthines from an easily prepared imidazole precursor. The method is especially useful for the preparation in standardized conditions of series of xanthines combining a broad variety of primary or secondary alkyl, benzyl or aryl groups at N1 and of alkyl or arylmethyl groups at N3, that are not readily available by other methods.

Seven new carbocyclic nucleosides derived from indan (1a-g) were efficiently prepared from 1,2-indanedimethanol via Mitsunobu reaction with 6-chloroadenine and subsequent introduction of the appropriate substituent.

Six new carbocyclic nucleosides were prepared by constructing a purine base (in compounds 9-11) or pyrimidine base (in 6-8) on the amino groups of (+/-)-(1 beta,2 alpha,4 beta)-4-amino-1,2-cyclopentanedimethanol (4) and (+/-)-(1 beta,3 alpha,4 beta)-4-amino-1,3-cyclopentanedimethanol (5), and their activities against a variety of viruses and tumour cell lines were determined.