Development and Advances of Drugs for Cancer Theranostics – PART-IV

Cancer, a highly heterogeneous disease at intra/inter patient levels, is one of the most serious threats to human health across the world [1, 2]. Notwithstanding the noteworthy advances in its treat-ment, the morbidity and mortality of cancer are projected to grow for a long period, and the global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020 [3]. Accordingly, there is a constant need to explore novel anticancer agents. <p> There are several strategies to discover novel anticancer candidates: (1) new lead hits or candidates from natural resources [4] whichexhibit various biological properties and are a rich source of com-pounds in drug discovery due to the structural and mechanistic diversity, and more than 60% anti-cancer agents can be traced to a natural product; (2) Molecular hybridization is one of the most prom-ising strategies for the discovery of novel anticancer drug candidates since hybrid molecules have the potential to bind multiple targets or to enhance the effect through acting with another bio-target or to counterbalance the side effects caused by the other part of the hybrid [5]; (3) Dimerization is a useful tool to develop novel anticancer drug candidates with enhanced biological activity, reduced side effects and improved pharmacokinetic profiles [6]; (4) Drug repurposing strategy is is an attractive strategy and has been approved, along with non-anticancer macrolide drugs for the treatment of cancer, for anticancer drug discovery since toxicity and pharmacokinetic profiles have already been estab-lished [7]. <p> Heterocycles coumarin, β-lactone, macrolide and triazole are useful anticancer pharmacophores since their derivatives could exert the anticancer activity through diverse mechanisms, inclusive of inhibition of aromatase, carbonic anhydrase, ki-nase, P-glycoprotein, sulfatase, telomerase, vascular endothelial growth factor receptor 2 and tubulin [8-11]. In particular, nat-ural-derived coumarin, β-lactone and macrolide derivatives are important sources of new anticancer lead hits/candidates; mac-rolide repurposed drugs can circumvent high cost and long-time associated with traditional drug discovery strategies; couma-rin, β-lactone and macrolide hybrids as well as bis-triazole compounds have the potential to enhance the anticancer activity, overcome drug resistance, reduce the side effects and improve pharmacokinetic profiles.

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Cytotoxic Agents of the Crinane Series of Amaryllidaceae Alkaloids

Natural Product Communications ◽

10.1177/1934578x1200701234 ◽

2012 ◽

Vol 7 (12) ◽

pp. 1934578X1200701 ◽

Cited By ~ 18

Author(s):

Jerald J. Nair ◽

Jaume Bastida ◽

Francesc Viladomat ◽

Johannes van Staden

Keyword(s):

Drug Discovery ◽

Anticancer Agents ◽

Structural Similarity ◽

Biological Properties ◽

Cytotoxic Agents ◽

Motor Neuron Diseases ◽

Amaryllidaceae Alkaloids ◽

Drug Candidates ◽

Sar Studies ◽

The Family

In the alkaloid galanthamine, the plant family Amaryllidaceae has endowed the pharmaceutical community with a potent and selective inhibitor of the enzyme acetylcholinestersae (AChE), of prominence in the chemotherapeutic approach towards motor neuron diseases. Following on the commercial success of this prescription drug in the treatment of Alzheimer's disease, it is anticipated that other drug candidates will in future emerge from the family. In this regard, the phenanthridones, exemplified by narciclasine and pancratistatin, of the lycorine series of Amaryllidaceae alkaloids have shown much promise as remarkably potent and selective anticancer agents, with a drug target of the series destined for the clinical market within the next decade. Given these interesting biological properties and their natural abundance, plants of the Amaryllidaceae have provided a diverse and accessible platform for phytochemical-based drug discovery. The crinane series of Amaryllidaceae alkaloids are also enriched with a significant array of biological properties. As a consequence of their close structural similarity to the anticancer agents of the lycorine series, the cytotoxic potential of crinane alkaloids has been realized through structure-activity relationship (SAR) studies involving targets of both semi-synthetic and natural origin, which has identified several members as leads with promising antiproliferative profiles. As the first of its kind, this review seeks to collate such information from the past few decades in advancing the crinane group as a viable platform for anticancer drug discovery.

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Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells.

Acta Biochimica Polonica ◽

10.18388/abp.2016_1264 ◽

1970 ◽

Vol 64 (1) ◽

Cited By ~ 1

Author(s):

Angelika Długosz ◽

Katarzyna Gach ◽

Jacek Szymański ◽

Jakub Modranka ◽

Tomasz Janecki ◽

...

Keyword(s):

Anticancer Activity ◽

Phosphonic Acid ◽

Anticancer Agents ◽

Hepg2 Cells ◽

Acid Moiety ◽

Drug Candidates ◽

Hybrid Molecules ◽

Ic50 Values ◽

Apoptosis Inducer ◽

Molecular Hybrids

Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.

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Cytotoxic Agents of the Crinane Series of Amaryllidaceae Alkaloids

Natural Product Communications ◽

10.1177/1934578x1300800501 ◽

2013 ◽

Vol 8 (5) ◽

pp. 1934578X1300800 ◽

Cited By ~ 2

Author(s):

Jerald J. Nair ◽

Jaume Bastida ◽

Francesc Viladomat ◽

Johannes van Staden

Keyword(s):

Drug Discovery ◽

Anticancer Agents ◽

Structural Similarity ◽

Biological Properties ◽

Cytotoxic Agents ◽

Motor Neuron Diseases ◽

Amaryllidaceae Alkaloids ◽

Drug Candidates ◽

Sar Studies ◽

The Family

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Arylhydrazono/Aryldiazenyl Pyrazoles: Green One-Pot Solvent-Free Synthesis and Anticancer Evaluation

Letters in Organic Chemistry ◽

10.2174/1570178617666200320104923 ◽

2020 ◽

Vol 17 (10) ◽

pp. 772-778

Author(s):

Abdulrhman Alsayari ◽

Abdullatif Bin Muhsinah ◽

Yahya I. Asiri ◽

Jaber Abdullah Alshehri ◽

Yahia N. Mabkhot ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Anticancer Agents ◽

Binding Mode ◽

Docking Studies ◽

Solvent Free ◽

Pyrazole Derivatives ◽

One Pot ◽

Solvent Free Conditions ◽

Hybrid Molecules

The aim of this study was to synthesize and evaluate the biological activity of pyrazole derivatives, in particular, to perform a “greener” one-pot synthesis using a solvent-free method as an alternative strategy for synthesizing hydrazono/diazenyl-pyridine-pyrazole hybrid molecules with potential anticancer activity. Effective treatment for all types of cancers is still a long way in the future due to the severe adverse drug reactions and drug resistance associated with current drugs. Therefore, there is a pressing need to develop safer and more effective anticancer agents. In this context, some hybrid analogues containing the bioactive pharmacophores viz. pyrazole, pyridine, and diazo scaffolds were synthesized by one-pot method. Herein, we describe the expedient synthesis of pyrazoles by a onepot three-component condensation of ethyl acetoacetate/acetylacetone, isoniazid, and arenediazonium salts under solvent-free conditions, and the evaluation of their cytotoxicity using a sulforhodamine B assay on three cancer cell lines. Molecular docking studies employing tyrosine kinase were also carried out to evaluate the binding mode of the pyrazole derivatives under study. 1-(4-Pyridinylcarbonyl)-3- methyl-4-(2-arylhydrazono)-2-pyrazolin-5-ones and [4-(2-aryldiazenyl)-3,5-dimethyl-1H-pyrazol-1- yl]-4-pyridinylmethanones, previously described, were prepared using an improved procedure. Among these ten products, 1-isonicotinoyl-3-methyl-4-[2-(4-nitrophenyl)hydrazono]-2-pyrazolin-5-one (1f) displayed promising anticancer activity against the MCF-7, HepG2 and HCT-116 cell lines, with an IC50 value in the range of 0.2-3.4 μM. In summary, our findings suggest that pyrazoles containing hydrazono/ diazenyl and pyridine pharmacophores constitute promising scaffolds for the development of new anticancer agents.

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Bile Acid Conjugates with Anticancer Activity: Most Recent Research

Molecules ◽

10.3390/molecules26010025 ◽

2020 ◽

Vol 26 (1) ◽

pp. 25

Author(s):

Maria Luisa Navacchia ◽

Elena Marchesi ◽

Daniela Perrone

Keyword(s):

Bile Acid ◽

Cancer Therapy ◽

Anticancer Activity ◽

Bile Acids ◽

Treatment Modality ◽

Biological Properties ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

Hybrid Functional ◽

Hybrid Molecules

The advantages of a treatment modality that combines two or more therapeutic agents in cancer therapy encourages the study of hybrid functional compounds for pharmacological applications. In light of this, we reviewed recent works on hybrid molecules based on bile acids. Due to their biological properties, as well as their different chemical/biochemical reactive moieties, bile acids can be considered very interesting starting molecules for conjugation with natural or synthetic bioactive molecules.

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Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds

International Journal of Molecular Sciences ◽

10.3390/ijms21228692 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8692

Author(s):

Alessandra Benassi ◽

Filippo Doria ◽

Valentina Pirota

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Biological Properties ◽

Aromatic Rings ◽

Antitumor Effects ◽

Comprehensive Overview ◽

Biological Targets ◽

Structural Modifications ◽

Starting Point ◽

Oxadiazole Derivatives

Nowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles—five-membered aromatic rings—emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially on 1,2,4 and 1,3,4 regioisomers. In the last years, an increasing number of oxadiazole derivatives, with remarkable cytotoxicity for several tumor lines, were identified. Structural modifications, that ensure higher cytotoxicity towards malignant cells, represent a solid starting point in the development of novel oxadiazole-based drugs. To increase the specificity of this strategy, outstanding oxadiazole scaffolds have been designed to selectively interact with biological targets, including enzymes, globular proteins, and nucleic acids, showing more promising antitumor effects. In the present work, we aim to provide a comprehensive overview of the anticancer activity of these heterocycles, describing their effect on different targets and highlighting how their structural versatility has been exploited to modulate their biological properties.

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Hybrid cis-stilbene Molecules: Novel Anticancer Agents

International Journal of Molecular Sciences ◽

10.3390/ijms20061300 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1300 ◽

Cited By ~ 4

Author(s):

Natalia Piekuś-Słomka ◽

Renata Mikstacka ◽

Joanna Ronowicz ◽

Stanisław Sobiak

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Distinct Group ◽

Design Synthesis ◽

Drug Candidates ◽

Structure Activity ◽

Polymerization Inhibitor ◽

Hybrid Molecules ◽

Tubulin Polymerization Inhibitor ◽

Pharmacologically Active

The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design, synthesis and bioevaluation. Many novel multi-target-directed drug candidates were synthesized, and their biological activities were evaluated. For the design of anticancer hybrid compounds, the molecules of stilbenes, aromatic quinones, and heterocycles (benzimidazole, imidazole, pyrimidine, pyridine, pyrazole, quinoline, quinazoline) were applied. A distinct group of hybrids comprises the molecules built with natural compounds: Resveratrol, curcumin, coumarin, and oleanolic acid. In this review, we present the studies on bioactive hybrid molecules of a well-known tubulin polymerization inhibitor, combretastatin A-4 and its analogs with other pharmacologically active entities. The mechanism of anticancer activity of selected hybrids is discussed considering the structure-activity relationship.

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Synthetic Strategies and Biological Potential of Coumarin-Chalcone Hybrids: A New Dimension to Drug Design

Current Organic Chemistry ◽

10.2174/1385272824666200219091830 ◽

2020 ◽

Vol 24 (4) ◽

pp. 402-438

Author(s):

Sharda Pasricha ◽

Pragya Gahlot

Keyword(s):

Drug Discovery ◽

Chemical Potential ◽

Wide Spectrum ◽

Biological Properties ◽

Sar Studies ◽

Discovery Research ◽

Biological Potential ◽

Drug Discovery Research ◽

Hybrid Molecules ◽

Agent Development

Privileged scaffolds are ubiquitous as effective templates in drug discovery regime. Natural and synthetically derived hybrid molecules are one such attractive scaffold for therapeutic agent development due to their dual or multiple modes of action, minimum or no side effects, favourable pharmacokinetics and other advantages. Coumarins and chalcone are two important classes of natural products affording diverse pharmacological activities which make them ideal templates for building coumarin-chalcone hybrids as effective biological scaffold for drug discovery research. Provoked by the promising medicinal application of hybrid molecules as well as those of coumarins and chalcones, the medicinal chemists have used molecular hybridisation strategy to report dozens of coumarin- chalcone hybrids with a wide spectrum of biological properties including anticancer, antimicrobial, antimalarial, antioxidant, anti-tubercular and so on. The present review provides a systematic summary on synthetic strategies, biological or chemical potential, SAR studies, some mechanisms of action and some plausible molecular targets of synthetic coumarin-chalcone hybrids published from 2001 till date. The review is expected to assist medicinal chemists in the effective and successful development of coumarin- chalcone hybrid based drug discovery regime.

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Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520999200824103803 ◽

2020 ◽

Vol 20 ◽

Cited By ~ 1

Author(s):

Nitesh Sanghai ◽

Kashfia Shafiq ◽

Geoffrey K. Tranmer

Keyword(s):

Drug Discovery ◽

Drug Repurposing ◽

Compassionate Use ◽

Drug Candidates ◽

Working Day ◽

Novel Coronavirus ◽

Approved Drugs ◽

Day By Day ◽

Potential Use

: Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).

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New Uracil Analogs with Exocyclic Methylidene Group as Potential Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666191211104128 ◽

2020 ◽

Vol 20 (3) ◽

pp. 359-368 ◽

Cited By ~ 2

Author(s):

Angelika Długosz-Pokorska ◽

Joanna Drogosz ◽

Marlena Pięta ◽

Tomasz Janecki ◽

Urszula Krajewska ◽

...

Keyword(s):

Dna Damage ◽

Cell Line ◽

Cell Lines ◽

Anticancer Agents ◽

Elisa Test ◽

Pcr Analysis ◽

Cytotoxic Activities ◽

Drug Candidates ◽

Hybrid Molecules ◽

M Phase

Background: Hybrid molecules combining uracil skeleton with methylidene exo-cyclic group were designed in the search for novel anticancer drug candidates. Objective: Two series of racemic 5-methylidenedihydrouracils, either 1,3-disubstituted or 1,3,6-trisubstituted were synthesized and tested for their possible cytotoxic activity against two cancer cell lines (HL-60 and MCF-7) and two healthy cell lines (HUVEC and MCF-10A). The most cytotoxic analogs were re-synthesized as pure enantiomers. The analog designated as U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], which had a very low IC50 value in HL-60 cell line (0.77μM) and was the most selective towards cancer cells was chosen for further experiments on HL-60 cell line, in order to determine the possible mechanism involved in its antineoplastic action. Methods: Cytotoxic activities of compound was assessed by the MTT assay. In order to explore the mechanism of U-332 activity, we performed quantitative real-time PCR analysis of p53 and p21 genes. Apoptosis, cell proliferation and DNA damage in HL-60 cells were determined using the flow cytometry. The ability of U-332 to determine GADD45ɑ protein level in HL-60 cells incubated with U-332 was analyzed by ELISA test. Results: U-332 was shown to generate excessive DNA damage (70% of the cell population), leading to p53 activation, resulting in p21 down-regulation and a significant increase of GADD45α protein, responsible for the cell cycle arrest in G2/M phase. Conclusion: U-332 can be used as a potential lead compound in the further development of novel uracil analogs as anticancer agents.

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