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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 21575

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Special Issue Editors

Dr. Ana Paula Francisco

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Faculty of Pharmacy, University of Lisbon, Avenida Prof. Gama Pinto, 1649-019 Lisbon, Portugal
Interests: drug design; anticancer compounds; prodrug chemistry; drug delivery systems
Special Issues, Collections and Topics in MDPI journals

Dr. Noelia Duarte

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Guest Editor

iMed.ULisboa—Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Avenida Prof. Gama Pinto, 1649-019 Lisbon, Portugal
Interests: natural products; bioactive compounds; terpenes; phenolics; plant derived compounds; medicinal plants; natural products chemistry; mass spectrometry; multidrug resistance; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to the World Health Organization, cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2020. Cancer burden can be reduced by avoiding several risk factors, through appropriate screening and early detection and through the clinical treatment of neoplastic diseases. Chemotherapy remains a cornerstone among the several approaches for treatment, even though intrinsic or acquired resistance and metastasis are still major obstacles to a successful cure. In the last two decades, outstanding progress in genetics and molecular biology has prompted the discovery of novel molecular targets. Moreover, major advances in computational and in silico methods, combinatorial chemistry, chemical synthesis and natural products chemistry have provided new leads for the development of new anticancer drugs. Nevertheless, and despite the vast number of compounds that have reached the stage of preclinical and clinical studies, the research and development of new anticancer agents and therapeutic strategies must be an everlasting process and constitutes the main subject of this Special Issue of Pharmaceutics. We welcome original or review articles concerning the discovery and development of new anticancer agents obtained from either synthesis or natural sources, and topics such as drug targeting, drug design, pharmacokinetics, computer-aided drug design, in silico studies, drug repurposing, pharmacodynamics and drug delivery are greatly encouraged.

We look forward to receiving your contributions.

Dr. Ana Paula Francisco
Dr. Noelia Duarte
Guest Editors

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Keywords

synthetic/natural anticancer agents
drug design
targeted therapies
hybrid compounds
metastasis
multidrug resistance

Published Papers (10 papers)

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Research

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19 pages, 4059 KiB

Open AccessArticle

QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency

by Guohui Sun, Peiying Bai, Tengjiao Fan, Lijiao Zhao, Rugang Zhong, R. Stanley McElhinney, T. Brian H. McMurry, Dorothy J. Donnelly, Joan E. McCormick, Jane Kelly and Geoffrey P. Margison

Pharmaceutics 2023, 15(8), 2170; https://doi.org/10.3390/pharmaceutics15082170 - 21 Aug 2023

Cited by 8 | Viewed by 1604

Abstract

O⁶-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O⁶-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [³H]-methylated-DNA-based MGMT inactivation assays and calculated the IC₅₀ values. Using the results of 370 compounds, we performed quantitative structure–activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC₅₀ values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R²_pr = 0.7474, Q²_Fn = 0.7375–0.7437, CCC_pr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R²_pr = 0.7528, Q²_Fn = 0.7387–0.7449, CCC_pr = 0.8560). The prediction quality of 66 true external compounds was checked using the “Prediction Reliability Indicator” tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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18 pages, 3839 KiB

Open AccessArticle

Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma

by Farhat Jubeen, Ishrat Jabeen, Usman Aftab, Sadia Noor, Mah e Hareem, Misbah Sultan and Mohsin Kazi

Pharmaceutics 2023, 15(7), 1929; https://doi.org/10.3390/pharmaceutics15071929 - 11 Jul 2023

Cited by 2 | Viewed by 1541

Abstract

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm⁻¹) and carbonyl groups (1662.38 cm⁻¹) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC₅₀ (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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34 pages, 8047 KiB

Open AccessArticle

Potent and Selective Benzothiazole-Based Antimitotics with Improved Water Solubility: Design, Synthesis, and Evaluation as Novel Anticancer Agents

by Laura Gallego-Yerga, Valentín Ceña and Rafael Peláez

Pharmaceutics 2023, 15(6), 1698; https://doi.org/10.3390/pharmaceutics15061698 - 9 Jun 2023

Cited by 3 | Viewed by 1438

Abstract

The design of colchicine site ligands on tubulin has proven to be a successful strategy to develop potent antiproliferative drugs against cancer cells. However, the structural requirements of the binding site endow the ligands with low aqueous solubility. In this work, the benzothiazole scaffold is used to design, synthesize, and evaluate a new family of colchicine site ligands exhibiting high water solubility. The compounds exerted antiproliferative activity against several human cancer cell lines, due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HEK-293 cells, as evidenced by MTT and LDH assays. The most potent derivatives, containing a pyridine moiety and ethylurea or formamide functionalities, displayed IC₅₀ values in the nanomolar range even in the difficult-to-treat glioblastoma cells. Flow cytometry experiments on HeLa, MCF7, and U87MG cells showed that they arrest the cell cycle at the G2/M phases at an early time point (24 h), followed by apoptotic cell death 72 h after the treatment. Tubulin binding was confirmed by microtubule network disruption observed via confocal microscopy. Docking studies support favorable interaction of the synthesized ligands at the colchicine binding site. These results validate the proposed strategy to develop potent anticancer colchicine ligands with improved water solubility. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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15 pages, 7605 KiB

Open AccessArticle

Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents

by Irene Conforti, Andrea Benzi, Irene Caffa, Santina Bruzzone, Alessio Nencioni and Alberto Marra

Pharmaceutics 2023, 15(5), 1472; https://doi.org/10.3390/pharmaceutics15051472 - 11 May 2023

Cited by 1 | Viewed by 1589

Abstract

The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task. We synthesized ten β-d-iminoribofuranosides bearing various heterocycle-based chains carbon-linked to the anomeric position starting from non-carbohydrate derivatives. They were then submitted to NAMPT inhibition assays, as well as to pancreatic tumor cells viability and intracellular NAD⁺ depletion evaluation. The biological activity of the compounds was compared to that of the corresponding analogues lacking the carbohydrate unit to assess, for the first time, the contribution of the iminosugar moiety to the properties of these potential antitumor agents. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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18 pages, 2725 KiB

Open AccessArticle

Discovery of New 1,4,6-Trisubstituted-1H-pyrazolo[3,4-b]pyridines with Anti-Tumor Efficacy in Mouse Model of Breast Cancer

by Maria Georgiou, Nikolaos Lougiakis, Roxane Tenta, Katerina Gioti, Stavroula Baritaki, Lydia-Evangelia Gkaralea, Elisavet Deligianni, Panagiotis Marakos, Nicole Pouli and Dimitris Stellas

Pharmaceutics 2023, 15(3), 787; https://doi.org/10.3390/pharmaceutics15030787 - 27 Feb 2023

Cited by 2 | Viewed by 1653

Abstract

Purine analogues are important therapeutic tools due to their affinity to enzymes or receptors that are involved in critical biological processes. In this study, new 1,4,6-trisubstituted pyrazolo[3,4-b]pyridines were designed and synthesized, and their cytotoxic potential was been studied. The new derivatives were prepared through suitable arylhydrazines, and upon successive conversion first to aminopyrazoles, they were converted then to 1,6-disubstituted pyrazolo[3,4-b]pyridine-4-ones; this served as the starting point for the synthesis of the target compounds. The cytotoxic activity of the derivatives was evaluated against several human and murine cancer cell lines. Substantial structure activity relationships (SARs) could be extracted, mainly concerning the 4-alkylaminoethyl ethers, which showed potent in vitro antiproliferative activity in the low μM level (0.75–4.15 μΜ) without affecting the proliferation of normal cells. The most potent analogues underwent in vivo evaluation and were found to inhibit tumor growth in vivo in an orthotopic breast cancer mouse model. The novel compounds exhibited no systemic toxicity; they affected only the implanted tumors and did not interfere with the immune system of the animals. Our results revealed a very potent novel compound which could be an ideal lead for the discovery of promising anti-tumor agents, and could also be further explored for combination treatments with immunotherapeutic drugs. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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17 pages, 2679 KiB

Open AccessArticle

Novel Dimer Derivatives of PF-543 as Potential Antitumor Agents for the Treatment of Non-Small Cell Lung Cancer

by Su Bin Kim, Khem Raj Limbu, Yoon Sin Oh, Soo Lim Kim, Seung Ki Park, Dong Jae Baek and Eun-Young Park

Pharmaceutics 2022, 14(10), 2035; https://doi.org/10.3390/pharmaceutics14102035 - 24 Sep 2022

Cited by 3 | Viewed by 1448

Abstract

Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, and the incidence and mortality rate are continuously increasing. In many cases, lung cancer cannot be completely treated with surgery, so chemotherapy is used in parallel; however, the treatment often fails due to drug resistance. Therefore, it is necessary to develop a new therapeutic agent with a new target. The expression of sphingosine kinase promotes cancer cell growth and survival and induces resistance to chemotherapeutic agents. Sphingosine-1-phosphate (S1P), produced by sphingosine kinase (SK), has been shown to regulate cancer cell death and proliferation. PF-543, currently known as an SK inhibitor, has been reported to demonstrate low anticancer activity in several cancers. Therefore, in this study, a derivative of PF-543 capable of increasing anticancer activity was synthesized and its efficacy was evaluated by using an NSCLC cell line and xenograft animal model. Based on the cytotoxic activity of the synthesized compound on lung cancer cells, the piperidine forms (Compounds 2 and 4) were observed to exhibit superior anticancer activity than the pyrrolidine forms of the head group (Compounds 1 and 3). Compounds 2 and 4 showed inhibitory effects on SK1 and SK2 activity, and S1P produced by SK was reduced by both compounds. Compounds 2 and 4 demonstrated an increase in the cytotoxicity in the NSCLC cells through increased apoptosis. As a result of using an SK1 and SK2 siRNA model to determine whether the cytotoxic effects of Compounds 2 and 4 were due to SK1 and SK2 inhibition, it was found that the cytotoxic effect of the derivative was SK1 and SK2 dependent. The metabolic stability of Compounds 2 and 4 was superior compared to PF-543, and the xenograft experiment was performed using Compound 4, which had more excellent MS. Compound 4 demonstrated the inhibition of tumor formation. The results of this experiment suggest that the bulky tail structure of PF-543 derivatives is effective for mediating anticancer activity, and the results are expected to be applied to the treatment of NSCLC. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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27 pages, 5845 KiB

Open AccessArticle

New Diarylamine K_V10.1 Inhibitors and Their Anticancer Potential

by Špela Gubič, Žan Toplak, Xiaoyi Shi, Jaka Dernovšek, Louise Antonia Hendrickx, Ernesto Lopes Pinheiro-Junior, Steve Peigneur, Jan Tytgat, Luis A. Pardo, Lucija Peterlin Mašič and Tihomir Tomašič

Pharmaceutics 2022, 14(9), 1963; https://doi.org/10.3390/pharmaceutics14091963 - 17 Sep 2022

Cited by 4 | Viewed by 1717

Abstract

Expression of the voltage-gated potassium channel K_V10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K_V10.1 inhibitors was prepared by structural optimisation and exploration of the structure–activity relationship of the previously published hit compound ZVS-08 (1) and its optimised analogue 2. The potency and selectivity of the new inhibitors between K_V10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K_V10.1 inhibitors, 17a and 18b, with improved nanomolar IC₅₀ values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC₅₀ values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K_V10.1-expressing cell line MCF-7 in two independent assays. In addition, 17a and 18b also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine K_V10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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Review

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33 pages, 1915 KiB

Open AccessReview

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies

by Carmelo Laface, Felicia Maria Maselli, Anna Natalizia Santoro, Maria Laura Iaia, Francesca Ambrogio, Marigia Laterza, Chiara Guarini, Pierluigi De Santis, Martina Perrone and Palma Fedele

Pharmaceutics 2023, 15(6), 1604; https://doi.org/10.3390/pharmaceutics15061604 - 27 May 2023

Cited by 5 | Viewed by 2790

Abstract

Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs’ resistance. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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23 pages, 4648 KiB

Open AccessReview

Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges?

by Marcin Cieślak and Marta Słowianek

Pharmaceutics 2023, 15(3), 812; https://doi.org/10.3390/pharmaceutics15030812 - 2 Mar 2023

Cited by 8 | Viewed by 4293

Abstract

The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug approach. This limitation has been overcome by PROTACs, bifunctional molecules that are able to bind the protein of interest and the E3 ubiquitin ligase complex. This interaction results in the ubiquitination of POI and subsequent proteolysis in the cellular proteasome. Out of hundreds of proteins serving as substrate receptors in E3 ubiquitin ligase complexes, current PROTACs recruit only a few of them, including CRBN, cIAP1, VHL or MDM-2. This review will focus on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis, such as transcription factors, kinases, cytokines, enzymes, anti-apoptotic proteins and cellular receptors. The structure of several PROTACs, their chemical and pharmacokinetic properties, target affinity and biological activity in vitro and in vivo, will be discussed. We will also highlight cellular mechanisms that may affect the efficacy of PROTACs and pose a challenge for the future development of PROTACs. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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45 pages, 15725 KiB

Open AccessReview

Halophyte Plants as Potential Sources of Anticancer Agents: A Comprehensive Review

by Luísa Custodio, Pedro Garcia-Caparros, Catarina Guerreiro Pereira and Pedro Castelo-Branco

Pharmaceutics 2022, 14(11), 2406; https://doi.org/10.3390/pharmaceutics14112406 - 8 Nov 2022

Cited by 4 | Viewed by 2188

Abstract

Salt-tolerant plants (halophytes) are widely distributed worldwide in several environments such as coastal salt marshes, sand dunes, and inland deserts. To cope with the harsh conditions that characterize those habitats, which include high salinity and radiation levels, such plants have developed morphological and physiological traits, the latter including the synthesis and accumulation of important secondary metabolites such as alkaloids and polyphenols. While essential in maintaining plant homeostasis, these compounds are highly valued in the medical field for the treatment of several human diseases, including cancer. Cancer is one of the most life-threatening disorders worldwide, which accentuates the need to improve current cancer therapies and minimize potential adverse secondary side-effects. In this context, the pharmacological evaluation of natural compounds has attracted growing interest since nature has already provided some important anti-cancer drugs. This review compiles, for the first time, research regarding the anticancer activity of halophytes from different families, including, whenever possible, the bioactive molecules involved in such therapeutical properties along with possible mechanisms of action. The introduction section provides some pertinent information regarding cancer and a summary of the most important characteristics of halophytes. The next section gives information regarding the in vitro and in vivo cytotoxic properties of several halophyte species, grouped by families, including contents in bioactive metabolites and proposed modes of action, if possible. Lastly, the conclusion presents the most relevant metabolites and/or promising species and extracts that could be further explored in anticancer drug research. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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