Flavonolignans: One Step Further in the Broad-Spectrum Approach of Cancer

Background: The small chemical class of flavonolignans encompasses unique hybrid molecules with versatile biological activities. Their anticancer effects have received considerable attention, and a large body of supporting evidence has accumulated. Moreover, their ability to interact with proteins involved in drug resistance, and to enhance the effects of conventional chemotherapeutics in decreasing cell viability make them influential partners in addressing cancer. Objective: The review provides an outline of the various ways in which flavonolignans advance the combat against cancer. While the main focus falls on flavonolignans from milk thistle, attention is drawn to the yet, underexplored potential of less known flavonolignan subgroups derived from isoflavonoids and aurones. Methods: Proceeding from the presentation of natural flavonolignan subtypes and their occurrence, the present work reviews these compounds with regard to their molecular targets in cancer, anti-angiogenetic effects, synergistic efficacy in conjunction with anticancer agents, reversal of drug resistance, and importance in overcoming the side effects of anticancer therapy. Recent advances in the endeavor to improve flavonolignan bioavailability in cancer are also presented. Conclusions: Significant progress has been achieved in detailing the molecular mechanisms of silybin and its congeners in experimental models of cancer. The availability of novel formulations with improved bioavailability, and data from phase I clinical trials in cancer patients provide an encouraging basis for more extensive trials aimed at evaluating the benefits of Silybum flavonolignans in cancer management. On the other hand, further research on the antitumor efficacy of iso-flavonolignans and other subtypes of flavonolignans should be pursued.

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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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Molecular Mechanisms Underlying Cancer Preventive and Therapeutic Potential of Algal Polysaccharides

Current Pharmaceutical Design ◽

10.2174/1381612825666190425155126 ◽

2019 ◽

Vol 25 (11) ◽

pp. 1210-1235 ◽

Cited By ~ 3

Author(s):

Soraya Sajadimajd ◽

Saeideh Momtaz ◽

Pouya Haratipour ◽

Fardous F. El-Senduny ◽

Amin Iran Panah ◽

...

Keyword(s):

Signaling Pathways ◽

Anticancer Agents ◽

Recent Progress ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Sulfated Polysaccharides ◽

Cochrane Library ◽

Therapeutic Effects ◽

Cancer Management ◽

Algal Polysaccharides

Background: Algal polysaccharide and oligosaccharide derivatives have been shown to possess a variety of therapeutic potentials and drug delivery applications. Algal polysaccharides contain sulfated sugar monomers derived from seaweed including brown, red, and green microalgae. Here, in this review, the recent progress of algal polysaccharides’ therapeutic applications as anticancer agents, as well as underlying cellular and molecular mechanisms was investigated. Moreover, recent progress in the structural chemistry of important polysaccharides with anticancer activities were illustrated. Methods: Electronic databases including “Scopus”, “PubMed”, and “Cochrane library” were searched using the keywords “cancer”, or “tumor”, or “malignancy” in title/abstract, along with “algae”, or “algal” in the whole text until July 2018. Only English language papers were included. Results: The most common polysaccharides involved in cancer management were sulfated polysaccharides, Fucoidans, Carageenans, and Ulvan from different species of algae that have been recognized in vitro and in vivo. The underlying anticancer mechanisms of algal polysaccharides included induction of apoptosis, cell cycle arrest, modulation of transduction signaling pathways, suppression of migration and angiogenesis, as well as activation of immune responses and antioxidant system. VEGF/VEGFR2, TGFR/Smad/Snail, TLR4/ROS/ER, CXCL12/ CXCR4, TGFR/Smad7/Smurf2, PI3K/AKT/mTOR, PBK/TOPK, and β-catenin/Wnt are among the main cellular signaling pathways which have a key role in the preventive and therapeutic effects of algal polysaccharides against oncogenesis. Conclusion: Algal polysaccharides play a crucial role in the management of cancer and may be considered the next frontier in pharmaceutical research. Further well-designed clinical trials are mandatory to evaluate the efficacy and safety of algal polysaccharides in patients with cancer.

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Progress and development of C-3, C-6, and N-9 position substituted carbazole integrated molecular hybrid molecules as potential anticancer agents

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210521221808 ◽

2021 ◽

Vol 21 ◽

Author(s):

Pratibha Mehta Luthra ◽

Nitin Kumar

Keyword(s):

Biological Activity ◽

Side Effects ◽

Anticancer Agents ◽

Biological Activities ◽

Structural Motif ◽

Hybrid Compounds ◽

Hybrid Molecules ◽

Anticancer Mechanism ◽

Pharmacologically Active

Abstract: The carbazole skeleton, a key structural motif occurring naturally or chemically synthesized, have shown various biological activities. Molecular hybridization based on the combination of two or more bioactive pharmacophores has been an important tool to convert the potent structural leads to form new hybrid compounds with improved biological activity. In recent years, modifications/substitutions of the carbazole motif at C3, C6, N9 position have been carried to develop novel carbazole based potential anticancer agents in the cancer therapy. In the last fifteen years, several compounds based on carbazole core integrated to pharmacologically active molecular hybrid having active pharmacophore such as 1,3,4-thiadiazole, thiazole, guanidine, sulfonamides, glyoxamides, imidazole, phenanthrene, rhodamine, chalcones, imidazopyridine, platinum 2H-chromen-2-one, hydrazones, piperazine, Isoxazole-thiadiazole, pyrazole etc. have been synthesized showing anticancer profile at sub-micromolar to nano-molar concentrations. We have thoroughly reviewed the design, progress and development of C-3, C-6, and N-9 position substituted carbazole derivatives integrated with various medicinally active pharmacophore as potential anticancer agents evaluated against various cancer cell lines. Additionally, the anticancer mechanism and in vivo activity of the reported compounds have been discussed. This study will support in designing of a new pharmacophore that can be linked to carbazole motif for development for new, potent and target specific anticancer drugs with improved pharmacokinetics and minimal side effects.

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Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

Radiology and Oncology ◽

10.2478/raon-2019-0018 ◽

2019 ◽

Vol 53 (2) ◽

pp. 148-158 ◽

Cited By ~ 46

Author(s):

Tomaz Makovec

Keyword(s):

Drug Resistance ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Large Body ◽

Chemical Properties ◽

Platinum Complexes ◽

Platinum Drugs ◽

Metal Compounds ◽

Development Of Resistance ◽

Covalent Adducts

AbstractBackgroundPlatinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients’ responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity.ConclusionsCisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

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Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269

Molecules ◽

10.3390/molecules26237329 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7329

Author(s):

Roman G. Zenkov ◽

Olga A. Vlasova ◽

Varvara P. Maksimova ◽

Timur I. Fetisov ◽

Natalia Y. Karpechenko ◽

...

Keyword(s):

Anticancer Activity ◽

Chromatin Remodeling ◽

Anticancer Agents ◽

Molecular Mechanisms ◽

Target Genes ◽

Biological Activities ◽

Binding Constants ◽

Histone H1 ◽

Immortalized Cells

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed–the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated—LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.

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Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Phytochemistry Reviews ◽

10.1007/s11101-021-09761-5 ◽

2021 ◽

Author(s):

Harald Greger

Keyword(s):

Cinnamic Acid ◽

Anticancer Agents ◽

Insecticidal Activity ◽

Molecular Mechanisms ◽

Biological Activities ◽

Building Blocks ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Cyclopentane Ring ◽

The Impact

AbstractFlavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure–activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

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Anticancer mechanisms of cannabinoids

Current Oncology ◽

10.3747/co.23.3080 ◽

2016 ◽

Vol 23 ◽

pp. 23 ◽

Cited By ~ 71

Author(s):

G. Velasco ◽

C. Sánchez ◽

M. Guzmán

Keyword(s):

Anticancer Agents ◽

Molecular Mechanisms ◽

Cell Signalling ◽

Large Body ◽

Resistance Mechanisms ◽

Laboratory Animals ◽

Cancer Cell Proliferation ◽

Antitumour Agents ◽

Potential Clinical Benefit ◽

Do So

In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. They do so by modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. In this review, we discuss the current understanding of cannabinoids as antitumour agents, focusing on recent discoveries about their molecular mechanisms of action, including resistance mechanisms and opportunities for their use in combination therapy. Those observations have already contributed to the foundation for the development of the first clinical studies that will analyze the safety and potential clinical benefit of cannabinoids as anticancer agents.

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Anticancer Activity of Natural and Synthetic Chalcones

International Journal of Molecular Sciences ◽

10.3390/ijms222111306 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11306

Author(s):

Teodora Constantinescu ◽

Claudiu N. Lungu

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Biological Activities ◽

Basic Structure ◽

Anticancer Therapy ◽

Huge Number ◽

Current Standard ◽

Aromatic Residues ◽

Diaryl Ether ◽

Hybrid Molecules

Cancer is a condition caused by many mechanisms (genetic, immune, oxidation, and inflammatory). Anticancer therapy aims to destroy or stop the growth of cancer cells. Resistance to treatment is theleading cause of the inefficiency of current standard therapies. Targeted therapies are the most effective due to the low number of side effects and low resistance. Among the small molecule natural compounds, flavonoids are of particular interest for theidentification of new anticancer agents. Chalcones are precursors to all flavonoids and have many biological activities. The anticancer activity of chalcones is due to the ability of these compounds to act on many targets. Natural chalcones, such as licochalcones, xanthohumol (XN), panduretin (PA), and loncocarpine, have been extensively studied and modulated. Modification of the basic structure of chalcones in order to obtain compounds with superior cytotoxic properties has been performed by modulating the aromatic residues, replacing aromatic residues with heterocycles, and obtaining hybrid molecules. A huge number of chalcone derivatives with residues such as diaryl ether, sulfonamide, and amine have been obtained, their presence being favorable for anticancer activity. Modification of the amino group in the structure of aminochalconesis always favorable for antitumor activity. This is why hybrid molecules of chalcones with different nitrogen hetercycles in the molecule have been obtained. From these, azoles (imidazole, oxazoles, tetrazoles, thiazoles, 1,2,3-triazoles, and 1,2,4-triazoles) are of particular importance for the identification of new anticancer agents.

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Recent Progress of Benzimidazole Hybrids for Anticancer Potential

Current Medicinal Chemistry ◽

10.2174/0929867326666190808122929 ◽

2020 ◽

Vol 27 (35) ◽

pp. 5970-6014 ◽

Cited By ~ 3

Author(s):

Md. Jawaid Akhtar ◽

Mohammad Shahar Yar ◽

Vinod Kumar Sharma ◽

Ahsan Ahmed Khan ◽

Zulphikar Ali ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Alkylating Agents ◽

American Chemical Society ◽

Chemical Society ◽

Benzimidazole Derivatives ◽

Progressive Development ◽

Anticancer Properties ◽

Naturally Occurring ◽

Nitrogenous Base

This review presents the detailed account of factors leading to cancer and design strategy for the synthesis of benzimidazole derivatives as anticancer agents. The recent survey for cancer treatment in Cancer facts and figures 2017 American Chemical Society has shown progressive development in fighting cancer. Researchers all over the world in both developed and developing countries are in a continuous effort to tackle this serious concern. Benzimidazole and its derivatives showed a broad range of biological activities due to their resemblance with naturally occurring nitrogenous base i.e. purine. The review discussed benzimidazole derivatives showing anticancer properties through a different mechanism viz. intercalation, alkylating agents, topoisomerases, DHFR enzymes, and tubulin inhibitors. Benzimidazole derivatives act through a different mechanism and the substituents reported from the earlier and recent research articles are prerequisites for the synthesis of targeted based benzimidazole derivatives as anticancer agents. The review focuses on an easy comparison of the substituent essential for potency and selectivity through SAR presented in figures. This will further provide a better outlook or fulfills the challenges faced in the development of novel benzimidazole derivatives as anticancer.

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E6 and E7 oncoproteins: Potential targets of cervical cancer

Current Medicinal Chemistry ◽

10.2174/0929867327666201111145546 ◽

2020 ◽

Vol 27 ◽

Author(s):

Ramarao Malla ◽

Mohammad Amjad Kamal

Keyword(s):

Cervical Cancer ◽

Drug Resistance ◽

Host Cell ◽

Molecular Mechanisms ◽

Immune Therapy ◽

Cervical Lesions ◽

Diagnostic Strategies ◽

E6 And E7 Oncoproteins ◽

E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

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