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We have developed a study on the factors that influence the intrasite interactions in the cross-metathesis on solid support. When such interactions are possible, the outcome of the intrasite by-product depends on the non-immobilized olefin and the precatalyst used. The comparatively poor reactivity of first generation Grubbs precatalyst makes the easier intrasite coupling to succeed. [ABSTRACT FROM AUTHOR]

The application of the reagent-based diversification strategy for generation of libraries of biologically promising β-lactam derivatives is described. Key features are the versatility of the linker used and the cross-metathesis functionalization at the cleavage step. From an immobilized primary library, diversity was expanded by applying different cleavage conditions, leading to a series of cholesterol absorption inhibitor analogues together with interesting hybrid compounds through incorporation of a chalcone moiety. [ABSTRACT FROM AUTHOR]

In methyl 4-(5-amino-3-phenyl-1 H-pyrazol-1-yl)-3-nitrobenzoate, C17H14N4O4, the molecules are linked into complex sheets by a combination of N—H...N, N—H...O and C—H...O hydrogen bonds. In the isomeric methyl 3-nitro-4-[(5-phenyl-1 H-pyrazol-3-yl)amino]benzoate, molecules exhibit a polarized molecular–electronic structure and are linked into chains of edge-fused rings by a combination of N—H...O and C—H...O hydrogen bonds. [ABSTRACT FROM AUTHOR]

The mol­ecules of ethyl 4-(5-amino-3-methyl-1 H-pyrazol-1-yl)­benzoate, C13H15N3O2, are linked by two independent N—H⋯O hydrogen bonds into a chain of edge-fused and alternating R42(8) and R22(20) rings. A combination of N—H⋯N and N—H⋯O hydrogen bonds links the mol­ecules of methyl 4-(5-amino-3- tert-butyl-1 H-pyrazol-1-yl)benzoate, C15H19N3O2, into sheets of alternating R22(20) and R66(32) rings. In 4-(5-amino-3-methyl-1 H-pyrazol-1-yl)benzoic acid monohydrate, C11H11N3O2·H2O, the mol­ecular components are linked into a three-dimensional framework structure by a combination of five independent hydrogen bonds, two of O—H⋯N type and one each of O—H⋯O, N—H⋯O and N—H⋯N types. [ABSTRACT FROM AUTHOR]

Mol­ecules of methyl 4-[(5-methyl-1 H-pyrazol-3-yl)amino]-3-nitro­benzoate, C12H12N4O4, (I), exhibit a polarized (charge-separated) structure in the nitro­aniline portion. The mol­ecules are linked into chains of edge-fused R22(16) and R22(22) rings by a combination of N—H⋯O(carbon­yl) and C—H⋯O(nitro) hydrogen bonds. Methyl 1-(5-methyl-1 H-pyrazol-3-yl)-1 H-benzimidazole-5-carboxyl­ate, C13H12N4O2, (II), which is readily formed from (I) by reduction followed by ring formation, crystallizes with Z′ = 2 in the space group P . Each of the two independent mol­ecular types is linked into sheets of R44(28) rings by a combination of N—H⋯N and C—H⋯O(carbon­yl) hydrogen bonds. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of TAP7f, a penicillin derivative previously characterized as a potent antitumor agent that promotes ER stress and apoptosis, in combination with thapsigargin, an ER stress inducer, on melanoma cells. Methods: The synergistic antiproliferative effect of TAP7f in combination with thapsigargin was studied in vitro in murine B16-F0 melanoma cells, and in human A375 and SB2 melanoma cells. In vivo assays were performed with C57BL/6J mice challenged with B16-F0 cells. Immunofluorescence and Western blot assays were carried out to characterize the induction of ER stress and apoptosis. Necrotic tumor areas and the potential toxicity of the combined therapy were examined by histological analysis of tissue sections after hematoxylin-eosin staining. Results: In vitro, the combination of TAP7f with thapsigargin synergistically inhibited the proliferation of murine B16-F0, and human A375 and SB2 melanoma cells. When non-inhibitory doses of each drug were simultaneously administered to C57BL/6J mice challenged with B16-F0 cells, a 50% reduction in tumor volumes was obtained in the combined group. An apoptotic response characterized by higher expression levels of Baxenhanced PARP-1 cleavage and the presence of active caspase 3 was observed in tumors from the combined treatment. In addition, higher expression levels of GADD153/CHOP and ATF4 were found in tumors of mice treated with both drugs with respect to each drug used alone, indicating the induction of an ER stress response. No signs of tissue toxicity were observed in histological sections of different organs extracted from mice receiving the combination. Conclusion: The synergistic and effective antitumor action of TAP7f in combination with thapsigargin could be considered as a potential therapeutic strategy for melanoma treatment. [ABSTRACT FROM AUTHOR]

Transition metal‐catalyzed, C−C and C−N bond‐forming reactions have made an enormous impact in the way complex molecules are assembled. The benefits of solid‐phase chemistry soon made this type of reaction applicable to solid‐supported processes. In this review, we report the most recent applications and possibilities of this combination. Remarkably, the solid‐phase CuAAC and ring‐closing metathesis have demonstrated an important role in synthetic biology, alike more traditional Pd‐catalyzed reactions, such as Suzuki‐Miyaura, Heck, Sonogashira, which are valuable tools for accessing libraries of biologically relevant small molecules. Examples proved the validity of solid‐phase transition metal‐catalyzed reactions as a practical and fast strategy to cover the current organic chemistry demands. [ABSTRACT FROM AUTHOR]

We have prepared immobilized olefins as models for the cross metathesis using different olefin partners in the presence of second generation Grubbs and Hoveyda-Grubbs precatalysts. We have demonstrated that solid-phase cross metathesis is strongly dependent on the degree of homo-dimerization of the non-immobilized olefin and the reactivity of such a homodimer. As in the homogeneous phase, the Hoveyda-Grubbs precatalyst was better for immobilized α,β-unsaturated carbonyl compounds. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A novel mimetic peptide that inhibits Aβ cytotoxicity at submicromolar concentration is reported. • Antiaggregant activities were measured using different biophysical assays. • Complex formation and its dynamic behaviour was analysed using docking and enhanced sampling MD. • Docking posits compound 7 interacts with the CHC region implicated in Aβ oligomerization. • The mimetic peptide would act through the inhibition of the conformational transition of Aβ 42. Abstract A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ 42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ 42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ 42 aggregates. The early stage interaction between compound 7 and the Aβ 42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ 42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early "on-pathway" events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: A straightforward solid phase-based strategy for the rapid generation of two small libraries of trans 3-alkyl-substituted β-lactams is described. For the glycine-derived library, a controlled excess of nonactivated acid chlorides was used to prevent oxazinone formation. The second library involved the attachment of Fmoc-protected p-aminophenol to Wang resin for the preparation of structurally-closed analogues of known cholesterol absorption inhibitors. This strategy allowed us to introduce diversity in the three variable positions of the β-lactam ring. [Copyright &y& Elsevier]

An extended library of hybrids that combined a penicillin derivative with a peptoid moiety was designed and synthetized using either a solid-phase or a mixed solid-phase/solution-phase strategy. The library was further evaluated for antiproliferative activity. While none of the different synthesized compounds showed significant cytotoxicity against a normal cell line, tumor cell results drew several conclusions, when comparing with our reference, the highly active triazolylpeptidyl penicillin derivative, TAF7f. Thus, when the 1,2,3-triazole group was exchanged by its "retro-inverse" analogue, no change was noted in the activity of the hybrids; however, better performance was generally obtained if the triazole is replaced by a glycine moiety. Additionally, the absence of hydrogen bond donor groups decreased the compounds activity, which could explain that, in general, this set of derivatives were less active than their peptide-containing analogues. From this study, is indisputable that, regardless of the type of chain (peptide, peptoid or mixture) attached to penicillin, an isobutyl side chain placed in the position closest to penicillin and a benzyl in the next position are determinant for the activity., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

An efficient and novel synthetic strategy for the generation of different carbocyclic moieties by ring closing carbonyl-olefin metathesis is reported. Herein, we describe a sustainably attractive protocol for one of the most powerful carbon-carbon bond-forming reactions, based on solvent-reduction, use of InCl 3 catalyst, and microwave irradiation, affording target compounds with yields up to 96%.

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence. Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy -performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective ( in silico ) and prospective (experimentally confirmed) screening. Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC 50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC 50 = 0.12-20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC 50 7-45 μM). Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruatta, Prada Gori, Fló Díaz, Lorenzelli, Perelmuter, Alberca, Bellera, Medeiros, López, Ingold, Porcal, Dibello, Ihnatenko, Kunick, Incerti, Luzardo, Colobbio, Ramos, Manta, Minini, Lavaggi, Hernández, Šarlauskas, Huerta García, Castillo, Hernández-Campos, Ribaudo, Zagotto, Carlucci, Medrán, Labadie, Martinez-Amezaga, Delpiccolo, Mata, Scarone, Posada, Serra, Calogeropoulou, Prousis, Detsi, Cabrera, Alvarez, Aicardo, Araújo, Chavarría, Mašič, Gantner, Llanos, Rodríguez, Gavernet, Park, Heo, Lee, Paul Park, Bollati-Fogolín, Pritsch, Shum, Talevi and Comini.)

Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of β-catenin and integrin αVβ3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma. KEY MESSAGES: • TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells. • TAP7f downregulates VEGF receptor expression in endothelial cells. • TAP7f downregulates VEGF and PDGF expression in melanoma cells. • TAP7f inhibits angiogenesis in vivo., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We have previously examined the in vitro and in vivo antitumor action of TAP7f, a synthetic triazolylpeptidyl penicillin, on murine melanoma cells. In this work, we explored the signal transduction pathways modulated by TAP7f in murine B16-F0 and human A375 melanoma cells, and the contribution of some intracellular signals to the apoptotic cell death. TAP7f decreased ERK1/2 phosphorylation and increased phospho-p38, phospho-JNK and phospho-Akt levels. ERK1/2 blockage suppressed cell growth, while inhibition of p38, JNK and PI3K-I pathways reduced the antitumor effect of TAP7f. Pharmacological inhibition of p38 and JNK, or blockage of PI3K-I/Akt cascade with a dominant negative PI3K-I mutant diminished Bax expression levels and PARP-1 cleavage, indicating the involvement of these pathways in apoptosis. PI3K-I/Akt inhibition also favored an autophagic response, as evidenced by the higher expression levels of Beclin-1 and LC3-II detected in transfected cells exposed to TAP7f. However, although PI3K-I/Akt blockage promoted an autophagic survival response, this mechanism appears not to be critical for TAP7f antitumor action. It was also shown that TAP7f induced ER stress by enhancing the expression of ER stress-related genes and proteins. Downregulation of CHOP protein with specific siRNA increased cell growth and decreased cleavage of PARP-1, supporting its role in apoptosis. Furthermore, it was found that activation of p38, JNK and Akt occurred downstream ER perturbation. In summary, our results showed that TAP7f triggers an apoptotic cell death in melanoma cells through induction of ER stress and activation of p38, JNK and PI3K-I/Akt pathways., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development of hybrid compounds led to the discovery of new pharmacologically active agents for some of the most critical diseases, including cancer. Herein, we describe a new series of oxadiazole-containing structures designed by a molecular hybridization approach. Penicillin derivatives and amino acids were linked to amino acid and aromatic moieties through the formation of a 1,2,4-oxadiazole ring. Alternatively, condensation between amino acid-derived hydrazides and an activated penicillanic acid led to a series of 1,3,4-oxadiazole penicillin-containing hybrids and non-cyclized diacylhydrazides. From the cytotoxicity assays it is highlighted that two 1,2,4-oxadiazoles and one 1,3,4-oxadiazole connecting a penicillin and aliphatic amino acids displayed a high degree of cytotoxic selectivity, ranging between being three and four times more potent against tumor cells than normal cells. The results give a very interesting perspective suggesting that these hybrid compounds can offer a novel antitumor scaffold with promising cytotoxicity profiles., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: Encouraged by the antitumor activity exhibited by triazolylpeptidyl penicillins, we decided to synthesize and evaluate a library of peptoid analogs. Results: The replacement of the dipeptide unit of the reference compound, TAP7f, was investigated. In addition, the effect of the triazole linking group on the biological activity of these new derivatives was evaluated, exchanging it with a glycine spacer. The cytotoxic effect of the library compounds was determined in the B16-F0 cell line and compared with the effects on normal murine mammary gland cells. Conclusion: Among the tested compounds, peptoid 4e exhibited the highest antiproliferative activity.

Propargylamines have gained importance in the area of anticancer research. We synthesized 1-substituted propargylic tertiary amines using the A3-coupling as the key step. Both, solution and solid-phase protocols, were used to provide a library of 1-substituted propargylic tertiary amines with interesting structural diversity. The triple negative breast cancer subtype is the most aggressive and it lacks effective therapeutic options, while pancreatic cancer is one of the neoplasms with worse prognosis and limited therapeutic possibilities. The development of tumor-selective drugs has always been a major challenge in cancer treatment. From our library, two propargylamines displayed a high degree of cytotoxic selectivity. These levels of selectivity give a very interesting perspective for further development of 1-substituted propargylic tertiary amines as new potential chemotherapeutic antitumor agents.

Aim: According to the need for the development of new anticancer agents, we have synthetized novel bioactive compounds and aimed to determine their antitumor action., Materials & Methods: We describe in vitro studies evaluating the effect of 35 novel chemical compounds on two triple negative murine mammary adenocarcinoma tumors., Results & Conclusion: Three compounds were selected because of their high antitumor activity and their low toxicity to normal cells. Their effect on tumor cells apoptosis, clonogenicity and migratory capacity, were determined. We found that the selected compounds showed inhibition of viability and clonogenic capacity, and promotion of apoptosis. They also decreased the migratory capacity of tumor cells. The results obtained suggest the likelihood of their future use as antitumor and/or antimetastatic agents., Competing Interests: Financial & competing interests disclosure The work was supported by grants of Universidad Nacional de Rosario to MJR (1MED474). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Maria Jose Rico.)

An efficient solid-phase protocol for the rapid generation of libraries of biologically promising 1,2,4-benzotriazines, including amino acid-derived components, is described.

An efficient application of the Julia-Kocienski coupling for the olefination of aldehydes with resin-bound benzothiazol-2-yl and 1-phenyl-1H-tetrazol-5-yl sulfones is described. Olefins is generally obtained in high overall yield for the six-reaction steps.

[reaction: see text] An efficient cross-metathesis on solid support for the synthesis of beta-lactam analogues of cholesterol absorption inhibitors is described. The applied strategy allows the introduction of diversity in positions 3 and 4 of the beta-lactam ring with excellent 3,4-trans selectivity and complete E selectivity at the C-3 side chain.

Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.

Solid phase, solution, and hybrid approaches to the synthesis of small focused libraries of alpha,alpha-disubstituted-alpha-acylaminoketones have been explored. Solution and hybrid approaches that used support-bound reagents and scavenger resins were the most productive.

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.