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Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 14313

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Special Issue Editor

Prof. Dr. Maria- João R. P. Queiroz

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Guest Editor

Department/ Centre of Chemistry of Universidade do Minho, 4710-057 Braga, Portugal
Interests: metal-catalyzed reactions (C–C and C–X cross-couplings, C–H activation, carbonylation; CuAAC); nucleophilic aromatic substitution(SNAr); heterocycles of N and/or S with antitumor and/or antiangiogenic (tyrosine kinase inhibitors of VEGFR2) properties
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Dear Colleagues,

Heterocyclic compounds, monocyclic and fused ring systems, represent the largest and most diverse family of organic compounds with biological active properties, namely antitumor and/or antiangiogenic activities. The ability to bind via hydrogen bonding or hydrophobic interactions seems to be an important factor in the development of target-based molecular designs using docking studies. Pharmacokinetics (absorption, distribution, metabolism, excretion, toxicity or ADMET) may also be predicted by in silico studies and confirmed afterwards. The synthesis of novel heterocyclic compounds with antitumor and/or antiangiogenic properties using different methodologies, including those that are more sustainable (green), continues to interest many researchers around the world. The evaluation of their antitumor/antiangiogenic properties and toxicity remains essential in the search for compounds with better efficacy and fewer side effects than the ones currently in use to treat different types of cancer. Researchers in the field are cordially invited to submit relevant manuscripts for the Special Issue of Molecules, “Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds”.

Prof. Dr. Maria- João R. P. Queiroz
Guest Editor

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Keywords

heterocycles
synthetic methodologies including green chemistry
antitumor evaluation
structure–activity relationships
target-based design
docking studies
pharmacokinetics (ADMET)

Related Special Issue

Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds, 2nd Edition in Molecules

Published Papers (5 papers)

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Research

14 pages, 4365 KiB

Open AccessFeature PaperArticle

Synthesis of Novel Methyl 7-[(Hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates and Antitumor Activity Evaluation: Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Toxicity in Non-Tumor Cells

by Juliana M. Rodrigues, Ricardo C. Calhelha, António Nogueira, Isabel C. F. R. Ferreira, Lillian Barros and Maria-João R. P. Queiroz

Molecules 2021, 26(16), 4823; https://doi.org/10.3390/molecules26164823 - 10 Aug 2021

Cited by 2 | Viewed by 2013

Abstract

Several novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI₅₀ ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI₅₀ values. The effects of the methoxylated compounds 2b (2-OMeC₆H₄), 2f and 2g (3,4- or 3,5-diOMeC₆H₃, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI₅₀ = 7.8 µM) and selective compound (2g) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds)

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16 pages, 17609 KiB

Open AccessArticle

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles

by Ozvaldo Linares-Anaya, Alcives Avila-Sorrosa, Francisco Díaz-Cedillo, Luis Ángel Gil-Ruiz, José Correa-Basurto, Domingo Salazar-Mendoza, Adrian L. Orjuela, Jorge Alí-Torres, María Teresa Ramírez-Apan and David Morales-Morales

Molecules 2021, 26(9), 2780; https://doi.org/10.3390/molecules26092780 - 08 May 2021

Cited by 1 | Viewed by 2707

Abstract

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds)

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15 pages, 4446 KiB

Open AccessArticle

Synthesis of Novel Methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates and Antitumor Activity Evaluation: Studies In Vitro and In Ovo Grafts of Chick Chorioallantoic Membrane (CAM) with a Triple Negative Breast Cancer Cell Line

by Bruna R. Silva, Rita Rebelo, Juliana M. Rodrigues, Cristina P. R. Xavier, M. Helena Vasconcelos and Maria-João R. P. Queiroz

Molecules 2021, 26(6), 1594; https://doi.org/10.3390/molecules26061594 - 13 Mar 2021

Cited by 6 | Viewed by 2385

Abstract

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI₅₀ concentration of compound 2e (13 μM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds)

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13 pages, 2815 KiB

Open AccessArticle

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment

by Manvendra Kumar, Gaurav Joshi, Sahil Arora, Tashvinder Singh, Sajal Biswas, Nisha Sharma, Zahid Rafiq Bhat, Kulbhushan Tikoo, Sandeep Singh and Raj Kumar

Molecules 2021, 26(5), 1490; https://doi.org/10.3390/molecules26051490 - 09 Mar 2021

Cited by 14 | Viewed by 3396

Abstract

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFR^WT inhibitors with IC₅₀ values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFR^WT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFR^L858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC₅₀ = 3.65 μM) as compared to gefitinib (IC₅₀ > 20 μM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds)

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19 pages, 3269 KiB

Open AccessArticle

Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity

by Abdel Haleem M. Hussein, Ahmed A. Khames, Abu-Bakr A. El-Adasy, Ahmed A. Atalla, Mohamed Abdel-Rady, Mohamed I. A. Hassan, Mahrous A. Abou-Salim, Yaseen A. M. M. Elshaier and Assem Barakat

Molecules 2021, 26(4), 902; https://doi.org/10.3390/molecules26040902 - 09 Feb 2021

Cited by 3 | Viewed by 3183

Abstract

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Heterocyclic Antitumor Compounds)

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