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A series of biologically unexplored substituted 1,3,4-subtituted-pyrrolo[3,2-c]quinoline derivatives (PQs) was evaluated against a panel of about 60 tumor cells (NCI). Based on the preliminary antiproliferative data, the optimizations efforts permitted us to design and synthesize a new series of derivatives allowing us to individuate a promising hit (4g). The insertion of a 4-benzo[d] [1,3]dioxol-5-yl moiety on increased and extended the activity towards five panel tumor cell lines such as leukemia, CNS, melanoma, renal and breast cancer, reaching IG 50 in the low μM range. Replacement of this latter with a 4-(OH-di-Cl-Ph) group (4i) or introduction a Cl-propyl chain in position 1 (5), selectively addressed the activity against the entire leukemia sub-panel (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). Preliminary biological assays on MCF-7 such as cell cycle, clonogenic assay, ROS content test alongside a comparison of viability between MCF-7 and non-tumorigenic MCF-10 were investigated. Among the main anticancer targets involved in breast cancer, HSP90 and ER receptors were selected for in silico studies. Docking analysis revealed a valuable affinity for HSP90 providing structural insights on the binding mode, and useful features for optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDIT online web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2- c ]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC 50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

CDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell growth reduction. Inhibitors with a dual target mechanism of action could arrest cancer progression by simultaneously blocking the DNA repair mechanism and cell cycle, resulting in advantageous monotherapy. To this aim, in the present work, we identified compound 645656 with a significant affinity for both CDK-1 and PARP-1 by a mixed ligand- and structure-based virtual screening protocol. The Biotarget Predictor Tool was used at first in a Multitarget mode to filter the large National Cancer Institute (NCI) database. Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins' (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound 645656 in complex with both PARP-1 and CDK-1.

The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series' of small molecules with a significant affinity for SARS-CoV-2 M PRO , by a hybrid virtual screening protocol, combining ligand- and structure-based approaches with multivariate statistical analysis. The Biotarget Predictor Tool was used to filter a large in-house structural database and select a set of benzo[ b ]thiophene and benzo[ b ]furan derivatives. ADME properties were investigated, and induced fit docking studies were performed to confirm the DRUDIT prediction. Principal component analysis and docking protocol at the SARS-CoV-2 M PRO dimerization site enable the identification of compounds 1b , c , i , l and 2i , l as promising drug molecules, showing favorable dual binding site affinity on SARS-CoV-2 M PRO .

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2-4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (T m s). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the T m s, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.

This work aims to fill the gap in the present knowledge about the structure of pectin from Opuntia ficus-indica. The water-soluble pectin (WSP) fraction, extracted with the Microwave Assisted Extraction (MAE), was further deproteinated (dWSP) and analyzed through several biophysical and biochemical techniques. HPSEC, light scattering and FTIR data showed that dWSP is low methylated high molecular weight pectin. The biochemical structure of dWSP, after methanolysis, silylation, carboxyl reduction showed that dWSP belongs to rhamnogalacturonan I class. Then, dWSP was heat-modified (HM) to obtain small-molecular weight deproteinated fraction (HM-dWSP). Both species, dWSP and HM-dWSP, were tested in LAN5 and NIH 3T3 model cells to study their biological effect. Results indicated that both dWSP and HM-dWSP exerted cytotoxic activity affecting selectively LAN5 cancer cells, without any effect on NIH 3T3 normal cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, in silico studies have been achieved to better understand the chemical space of the interactions. Interestingly some meaningful structural features, useful for further developments, were found. The 8,9-di-Cl substituted derivative revealed as the most effective in the intercalative process, as well as on the inhibition of catalytic activity of topoisomerase II. Predicted ADME studies confirm that PBTs are promising as potential drug candidates., (© 2017 John Wiley & Sons A/S.)

A new series of 3-benzoylamino-5-(1H-imidazol-4-yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration-dependent antiproliferative activity against HeLa and MCF-7 cancer cell lines, exhibiting GI 50 values in the low micromolar range. In most cases, insertion of a methyl substituent on the imidazole moiety improved the antiproliferative activity. Therefore, methyl-imidazolyl-benzo[b]furans compounds were tested in cell cycle perturbation experiments, producing cell cycle arrest with proapoptotic effects. Their core similarity to known colchicine binding site binders led us to further study the structure features as antitubulin agents by in silico protocols., (© 2017 John Wiley & Sons A/S.)

A new series of 3-benzoylamino-5-imidazol-5-yl-benzo[b]thiophenes and the parent amino derivatives were synthesized and screened as antitumor agents. All tested compounds showed concentration-dependent antiproliferative activity profile against HeLa cell line, exhibiting GI50 values in the low micromolar range. The most active compounds were tested in cell cycle perturbation experiments. A rapid accumulation of cells in the G2/M phase, with a concomitant reduction of cells in both the S and G0/G1 phases, was observed, suggesting that cell exposure to selected derivatives produces mitotic failure. To rationalize the biological results, the 3-benzoylamino-benzo[b]thiophenes were analyzed through the in silico VLAK protocol. Compounds presenting the 3,4,5-trimethoxy-benzoyl moiety were in silico classified as potential antimitotic agents or topoisomerase II inhibitors, in good agreement with the biological studies., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

In order to investigate their anticancer potential, four new pyrazolo[1,2-a]benzo[1,2,3,4]tetrazinone derivatives, designed through the chemometric protocol VLAK, and three of the most active compounds of the previous series have been evaluated on some cellular events including proliferation, apoptosis induction, and cell cycle. The NCI one dose (10 μM) screening revealed that the 8,9-di-methyl derivative showed activity against Leukemia (CCRF-CEM) and Colon cancer cell line (COLO 205), reaching 81% and 45% of growth inhibition (GI), respectively. Replacement of the two methyl groups with two chlorine atoms maintained the activity toward Leukemia cell (CCRF-CEM, GI 77%) and selectively enhanced the activity against COLO 205 attaining a LD50 in the μM range and against SW-620 a GI of 77%. Interestingly, an appreciable growth inhibition of 47% against therapeutically "refractory" Non-Small Cell Lung Cancer (NCI-H522) was observed. Moreover, the apoptosis induction, based on mitochondrial membrane depolarization, was found in the range EC50 3-5 μM on HeLa cell, evidencing a well defined relationship with the related in vitro cell growth inhibitory assays (MTT) performed against other selected tumor cell lines not included in the NCI tumor panel (HeLa, cervix; H292, lung; LAN-5, CNS; CaCo-2, colon; 16HBE, normal human cell lung) and against MCF-7 tumor cell line (breast). Only for the most active compounds, further cell cycle tests on HeLa displayed a cell arrest on S phase. Thus, a promising new class of anticancer candidates, acting as valuable apoptotic inductors, is proposed., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-beta in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-beta inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 inhibitors included in the Binding Database. In order to overcome the difficulty due to the lack of crystallographic data for IKK-beta, a homology model of this protein has been built and validated. The results allowed to study in depth the structural bases for the interaction of each family of inhibitors and provided clues for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting this enzyme.

1-Methylpyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones 4, synthesized in good to excellent yields, were designed as novel alkylating agents because of their peculiar chemical behavior. All derivatives showed antiproliferative activity against more than 50 types of tumor cell lines with GI(50) reaching sub-micromolar values. SAR studies revealed that the presence of a chlorine atom is well-tolerated in both positions 8 and 9, whereas in the case of the methyl group, switching from the 8 to the 9 position gives rise to the most active compound of the series, 4g, either for the number of cell lines inhibited and for selectivity against leukaemia and renal cancer subpanels. COMPARE and 3D-MIND computations indicate, for compounds 4, an activity profile analogous to rifamycins and cytidine analogues.

The pyrrolo[1,2-f]phenanthridines 8-22 and the corresponding non-rigid analogues 23-41 were synthesised and their ability to inhibit the replication of HIV-1 was tested. Only the polycyclic derivatives 10, 11, and 13 showed a weak anti-HIV activity, whereas several pyrrolo-phenanthridines (8, 10, 16-18) were found to stimulate the multiplication of MT-4 cells at low concentrations. Derivative 10 demonstrated to possess the unique property of stimulating the multiplication of lymphocytes joined to HIV inhibition.

A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a-g (7b-f) were synthesized and tested for antibacterial and antifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C. neoformans. 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively. None of the compounds was active against bacteria. Preliminary structure-activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.

The new of 1-(2-hydroxyethoxy)methylindole derivatives 3a-i were prepared in good yields. None of them showed any significant anti-HIV activity and therefore the benzocondensation between the 2 and 3 positions of the pyrrole ring definitely reduced the weak activity found in the analogues 1a-c.

Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1 replication at concentrations that were very close to those cytotoxic for MT-4 cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations slightly below those cytotoxic for Vero cells. However for this series of glycosidopyrroles some relationship between calculated log P values and the observed cytotoxicity was found.

The series of 1-(1,3-dihydroxy-2-propoxy)methylpyrroles 2a-o were prepared in good overall yields according to Scheme I. When evaluated for antiviral activity against HIV-1, only compounds of the triphenyl series (R3 = NH2, N3, Br) were found to inhibit the HIV-1 replication at concentrations that were very not cytotoxic for MT-4 cells, with selectivity index 1.5-9.3. None of these compounds showed antibacterial or antifungal activity.

Acyclic glycosidopyrroles of type 3 were synthetized in good overall yields, according to the Scheme. When evaluated for antiviral activity against DNA and RNA viruses, only compound in which R1 = R2 = Ph, R3 = NH2 was found to inhibit the HIV-1 replication at concentrations that were not cytotoxic for MT-4 cells.

3-Diazopyrroles, a class of compounds particularly interesting from a chemical and biological point of view, were assayed for their ability to induce gene mutations employing back mutation (his+ reversion) test in the philamentous bacterium Streptomyces coelicolor at various time during life cycle. Our results suggest that in evaluating the mutagenicity and toxicity of chemicals in Streptomyces system it is important to consider factors such as growth phase. Furthermore in this series of diazopyrroles a relationship between toxicity, mutagenicity and chemical structure was found. The observed mutagenic activity can be the molecular basis for the appearance of antitumor activity.

Indolo[3,2-c]cinnolines of type 5, variously substituted either in the indole and in the cinnoline moieties, were prepared in good overall yields, by intramolecular cyclization of indolo derivatives 4. Compounds 5a-d showed a good cytotoxic activity against FLC and K562 leukemic cell lines, both sensitive and multi-drug resistant.

Pyrrolo-, pyrazolo- and triazolo-phenanthridines were synthetized by using a Pschorrtype cyclization reaction or an intramolecular cyclization of arylnitrenium ions. By using these synthetic methods several azolo-phenanthridines, variously functionalized either in the azolo ring and in the phenanthridine moiety, were prepared. The title compounds, tested against murine leukemia cell lines, sensible and multidrug resistant, showed moderate activity with IC50 in the range 5-50 microM.