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Design and Synthesis of Organic Molecules as Antineoplastic Agents

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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 45442

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Prof. Dr. Carla Boga

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Department of Industrial Chemistry “Toso Montanari”, Alma Mater Studiorum - University of Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
Interests: organic synthesis; bioorganic chemistry; NMR spectroscopy; small molecule synthesis; mechanism elucidation
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Dr. Gabriele Micheletti

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Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
Interests: organic synthesis; organophosphorus chemistry; heterocyclic chemistry; NMR spectroscopy
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Dear Colleagues,

The fight against cancer can be dealt with, among different approaches, by synthetizing new compounds with high effectiveness and selectivity to the targeting cancer cells by concomitantly reducing side effects.

In this context, synthetic organic chemistry plays a key role and constitutes a flexible tool since it gives access to a great number of compounds, including antitumoral molecules present in nature, but which are not readily available, as well as novel drugs exhibiting anticancer actions. Through the variation of functional groups or motifs within the organic architecture, it is possible to find and modulate structure–activity relationships and, once the molecular target has been identified, to design new molecules or structural hybrids. Original articles, as well as reviews, regarding recent advancements in the design and synthesis of organic molecules of interest as antineoplastic agents are greatly welcome for inclusion in this Special Issue of Molecules.

Prof. Dr. Carla Boga
Dr. Gabriele Micheletti
Guest Editors

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Keywords

antineoplastic
cancer
organic compounds
organic synthesis
drug design
biochemistry
medicinal chemistry
biological activity

Published Papers (13 papers)

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Editorial

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3 pages, 412 KiB

Open AccessEditorial

Design and Synthesis of Organic Molecules as Antineoplastic Agents

by Carla Boga and Gabriele Micheletti

Molecules 2020, 25(12), 2808; https://doi.org/10.3390/molecules25122808 - 18 Jun 2020

Cited by 1 | Viewed by 1878

Abstract

The fight against cancer is one of the most challenging tasks currently for lots of researchers in many fields, such as pharmaceuticals, medicine, and chemicals [...] Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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Research

Jump to: Editorial

14 pages, 1953 KiB

Open AccessArticle

3-Aryl-4-nitrobenzothiochromans S,S-dioxide: From Calcium-Channel Modulators Properties to Multidrug-Resistance Reverting Activity

by Matteo Micucci, Maurizio Viale, Alberto Chiarini, Domenico Spinelli, Maria Frosini, Cinzia Tavani, Massimo Maccagno, Lara Bianchi, Rosaria Gangemi and Roberta Budriesi

Molecules 2020, 25(5), 1056; https://doi.org/10.3390/molecules25051056 - 27 Feb 2020

Cited by 7 | Viewed by 2503

Abstract

Our research groups have been involved for many years in studies aimed at identifying new active organic compounds endowed with pharmacological properties. In this work, we focused our attention on the evaluation of cardiovascular and molecular drug resistance (MDR) reverting activities of some nitrosubstituted sulphur-containing heterocycles. Firstly, we have examined the effects of 4-nitro-3-(4-methylphenyl)-3,6-dihydro-2H-thiopyran S,S-dioxide 5, and have observed no activity. Then we have extended our investigation to the 3-aryl-4-nitrobenzothiochromans S,S-dioxide 6 and 7, and have observed an interesting biological profile. Cardiovascular activities were assessed for all compounds using ex vivo studies, while the MDR reverting effect was evaluated only for selected compounds using tumor cell lines. All compounds were shown to affect cardiovascular parameters. Compound 7i exerted the most effect on negative inotropic activity, while 6d and 6f could be interesting molecules for the development of more active ABCB1 inhibitors. Both 6 and 7 represent structures of large possible biological interest, providing a scaffold for the identification of new ABCB1 inhibitors. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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17 pages, 4222 KiB

Open AccessArticle

Synthesis of Novel Structural Hybrids between Aza-Heterocycles and Azelaic Acid Moiety with a Specific Activity on Osteosarcoma Cells

by Gabriele Micheletti, Natalia Calonghi, Giovanna Farruggia, Elena Strocchi, Vincenzo Palmacci, Dario Telese, Silvia Bordoni, Giulia Frisco and Carla Boga

Molecules 2020, 25(2), 404; https://doi.org/10.3390/molecules25020404 - 18 Jan 2020

Cited by 13 | Viewed by 3401

Abstract

Nine compounds bearing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups bound to an azelayl moiety through an amide bond were synthesized. The structural analogy with some histone deacetylase inhibitors inspired their syntheses, seeking new selective histone deacetylase inhibitors (HDACi). The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as a molecular target. Azelayl derivatives bound to a benzothiazolyl moiety further proved to be active as HDACi. The novel compounds were tested on a panel of both normal and tumor cell lines. Non-specific induction of cytotoxicity was observed in the normal cell line, while three of them induced a biological effect only on the osteosarcoma (U2OS) cell line. One of them induced a change in nuclear shape and size. Cell-cycle alterations are associated with post-transcriptional modification of both H2/H3 and H4 histones. In line with recent studies, revealing unexpected HDAC7 function in osteoclasts, molecular docking studies on the active molecules predicted their proneness to interact with HDAC7. By reducing side effects associated with the action of the first-generation inhibitors, the herein reported compounds, thus, sound promising as selective HDACi. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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12 pages, 1169 KiB

Open AccessArticle

Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens

by Kiminori Ohta, Asako Kaise, Fumi Taguchi, Sayaka Aoto, Takumi Ogawa and Yasuyuki Endo

Molecules 2019, 24(21), 3966; https://doi.org/10.3390/molecules24213966 - 01 Nov 2019

Cited by 2 | Viewed by 3036

Abstract

Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC₅₀: 0.09 μM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur–π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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14 pages, 4204 KiB

Open AccessFeature PaperArticle

Synthesis, Antitumor Activity, and Docking Analysis of New Pyrido[3′,2′:4,5]furo(thieno)[3,2-d]pyrimidin-8-amines

by Samvel N. Sirakanyan, Domenico Spinelli, Athina Geronikaki, Elmira K. Hakobyan, Harutyun Sahakyan, Erik Arabyan, Hovakim Zakaryan, Lusine E. Nersesyan, Anahit S. Aharonyan, Irina S. Danielyan, Rafayel E. Muradyan and Anush A. Hovakimyan

Molecules 2019, 24(21), 3952; https://doi.org/10.3390/molecules24213952 - 31 Oct 2019

Cited by 19 | Viewed by 3050

Abstract

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3′,2′:4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2–e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure–activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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16 pages, 3955 KiB

Open AccessFeature PaperArticle

Synthesis of 9-Hydroxystearic Acid Derivatives and Their Antiproliferative Activity on HT 29 Cancer Cells

by Natalia Calonghi, Carla Boga, Dario Telese, Silvia Bordoni, Giorgio Sartor, Chiara Torsello and Gabriele Micheletti

Molecules 2019, 24(20), 3714; https://doi.org/10.3390/molecules24203714 - 15 Oct 2019

Cited by 10 | Viewed by 2816

Abstract

9-Hydroxystearic acid (9-HSA) is an endogenous cellular lipid that possesses antiproliferative and selective effects against cancer cells. A series of derivatives were synthesized in order to investigate the effect of the substituent in position 9 and on the methyl ester functionality on the biological activity. The two separate enantiomers of methyl 9-hydroxystearate and of methyl 9-aminostearate showed antiproliferative activity against the HT29 cell line. This indicates the importance of position 9 groups being able to make hydrogen bonding with the molecular target. Further, this effect must be preserved when the carboxy group of 9-HSA is esterified. The biological tests showed that the amines, contrarily to methyl esters, resulted in cytotoxicity. A deep investigation on the effect of methyl (R)-9-hydroxystearate on HT29 cells showed an antiproliferative effect acting through the CDKN1A and MYCBP gene expression. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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26 pages, 3386 KiB

Open AccessFeature PaperArticle

Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm Activity

by Andrey Smolobochkin, Almir Gazizov, Marina Sazykina, Nurgali Akylbekov, Elena Chugunova, Ivan Sazykin, Anastasiya Gildebrant, Julia Voronina, Alexander Burilov, Shorena Karchava, Maria Klimova, Alexandra Voloshina, Anastasia Sapunova, Elena Klimanova, Tatyana Sashenkova, Ugulzhan Allayarova, Anastasiya Balakina and Denis Mishchenko

Molecules 2019, 24(17), 3086; https://doi.org/10.3390/molecules24173086 - 25 Aug 2019

Cited by 21 | Viewed by 4085

Abstract

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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11 pages, 896 KiB

Open AccessArticle

Design, Synthesis and Cancer Cell Growth Inhibition Evaluation of New Aminoquinone Hybrid Molecules

by Andrea Defant and Ines Mancini

Molecules 2019, 24(12), 2224; https://doi.org/10.3390/molecules24122224 - 14 Jun 2019

Cited by 15 | Viewed by 3223

Abstract

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI₅₀ than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI₅₀ < 10 nM). Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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14 pages, 2928 KiB

Open AccessArticle

Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones

by Jacek Kędzia, Tomasz Bartosik, Joanna Drogosz, Anna Janecka, Urszula Krajewska and Tomasz Janecki

Molecules 2019, 24(10), 1868; https://doi.org/10.3390/molecules24101868 - 15 May 2019

Cited by 4 | Viewed by 2828

Abstract

In the search for new anticancer agents, a library of variously substituted 3-methylidenechroman-4-ones was synthesized using Horner–Wadsworth–Emmons methodology. Acylation of diethyl methylphosphonate with selected ethyl salicylates furnished 3-diethoxyphosphorylchromen-4-ones which were next used as Michael acceptors in the reaction with various Grignard reagents. The adducts were obtained as the mixtures of trans and cis diastereoisomers along with a small amount of enol forms. Their relative configuration and preferred conformation were established by NMR analysis. The adducts turned up to be effective Horner–Wadsworth–Emmons reagents giving 2-substituted 3-methylidenechroman-4-ones, which were then tested for their possible cytotoxic activity against two leukemia cell lines, HL-60 and NALM-6, and against MCF-7 breast cancer cell line. All new compounds (14a–o) were highly cytotoxic for the leukemic cells and showed a moderate or weak effect on MCF-7 cells. Analog 14d exhibited the highest growth inhibitory activity and was more potent than carboplatin against HL-60 (IC₅₀ = 1.46 ± 0.16 µM) and NALM-6 (IC₅₀ = 0.50 ± 0.05 µM) cells. Further tests showed that 14d induced apoptosis in NALM-6 cells, which was mediated mostly through the extrinsic pathway. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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25 pages, 7783 KiB

Open AccessFeature PaperArticle

4,5-Diaryl 3(2H)Furanones: Anti-Inflammatory Activity and Influence on Cancer Growth

by Dmitrii Semenok, Jury Medvedev, Lefki-P. Giassafaki, Iason Lavdas, Ioannis S. Vizirianakis, Phaedra Eleftheriou, Antonis Gavalas, Anthi Petrou and Athina Geronikaki

Molecules 2019, 24(9), 1751; https://doi.org/10.3390/molecules24091751 - 06 May 2019

Cited by 13 | Viewed by 3445

Abstract

Apart from their anti-inflammatory action, COX inhibitors have gathered the interest of many scientists due to their potential use for the treatment and prevention of cancer. It has been shown that cyclooxygenase inhibitors restrict cancer cell growth and are able to interact with known antitumor drugs, enhancing their in vitro and in vivo cytotoxicity. The permutation of hydrophilic and hydrophobic aryl groups in COX inhibitors leads to cardinal changes in the biological activity of the compounds. In the present study, thirteen heterocyclic coxib-like 4,5-diarylfuran-3(2H)-ones and their annelated derivatives—phenanthro[9,10-b]furan-3-ones—were synthesized and studied for anti-inflammatory and COX-1/2 inhibitory action and for their cytotoxic activity on the breast cancer (MCF-7) and squamous cell carcinoma (HSC-3) cell lines. The F-derivative of the –SOMe substituted furan-3(2H)-ones exhibited the best activity (COX-1 IC₅₀ = 2.8 μM, anti-inflammatory activity (by carrageenan paw edema model) of 54% (dose 0.01 mmol/kg), and MCF-7 and HSC-3 cytotoxicity with IC₅₀ values of 10 μM and 7.5 μM, respectively). A cytotoxic effect related to the COX-1 inhibitory action was observed and a synergistic effect with the anti-neoplastic drugs gefitinib and 5-fluorouracil was found. A phenanthrene derivative exhibited the best synergistic effect with gefitinib. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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9 pages, 919 KiB

Open AccessArticle

Synthesis of Novel Pyrazole Derivatives and Their Tumor Cell Growth Inhibitory Activity

by Ying-Jie Cui, Long-Qian Tang, Cheng-Mei Zhang and Zhao-Peng Liu

Molecules 2019, 24(2), 279; https://doi.org/10.3390/molecules24020279 - 13 Jan 2019

Cited by 16 | Viewed by 4409

Abstract

To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a–e as well as the unexpected pyrazole derivatives 5a–e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI₅₀ = 0.26 μM) and lung tumor A549 cells (GI₅₀ = 0.19 μM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a–e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI₅₀ values of 0.021 and 0.69 μM, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC₅₀ of 7.30 μM. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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22 pages, 1608 KiB

Open AccessArticle

Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives

by Anna Spivak, Rezeda Khalitova, Darya Nedopekina, Lilya Dzhemileva, Milyausha Yunusbaeva, Victor Odinokov, Vladimir D’yakonov and Usein Dzhemilev

Molecules 2018, 23(11), 3000; https://doi.org/10.3390/molecules23113000 - 16 Nov 2018

Cited by 23 | Viewed by 4599

Abstract

Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4–7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b–12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis. Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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12 pages, 6818 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel 4-Substituted Coumarin Derivatives as Antitumor Agents

by Ran An, Zhuang Hou, Jian-Teng Li, Hao-Nan Yu, Yan-Hua Mou and Chun Guo

Molecules 2018, 23(9), 2281; https://doi.org/10.3390/molecules23092281 - 06 Sep 2018

Cited by 41 | Viewed by 4530

Abstract

Herein, fifteen new compounds containing coumarin, 1,2,3-triazole and benzoyl- substituted arylamine moieties were designed, synthesized and tested in vitro for their anticancer activity. The results showed that all tested compounds had moderate antiproliferative activity against MDA-MB-231, a human breast cancer cell line, under both normoxic and hypoxic conditions. Furthermore, the 4-substituted coumarin linked with benzoyl 3,4-dimethoxyaniline through 1,2,3-triazole (compound 5e) displayed the most prominent antiproliferative activities with an IC₅₀ value of 0.03 μM, about 5000 times stronger than 4-hydroxycoumarin (IC₅₀ > 100 μM) and 20 times stronger than doxorubicin (IC₅₀ = 0.60 μM). Meanwhile, almost all compounds revealed general enhancement of proliferation-inhibiting activity under hypoxia, contrasted with normoxia. A docking analysis showed that compound 5e had potential to inhibit carbonic anhydrase IX (CA IX). Full article

(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)

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