Recent Development in Indole Derivatives as Anticancer Agents for Breast Cancer

Background:Breast Cancer (BC) is the second most common cause of cancer related deaths in women. Due to severe side effects and multidrug resistance, current therapies like hormonal therapy, surgery, radiotherapy and chemotherapy become ineffective. Also, the existing drugs for BC treatment are associated with several drawbacks such as poor oral bioavailability, non-selectivity and poor pharmacodynamics properties. Therefore, there is an urgent need for the development of more effective and safer anti BC agents.Objective:This article explored in detail the possibilities of indole-based heterocyclic compounds as anticancer agents with breast cancer as their major target.Methods:Recent literature related to indole derivatives endowed with encouraging anti BC potential is reviewed. With special focus on BC, this review offers a detailed account of multiple mechanisms of action of various indole derivatives: aromatase inhibitor, tubulin inhibitor, microtubule inhibitor, targeting estrogen receptor, DNA-binding mechanism, induction of apoptosis, inhibition of PI3K/AkT/NFkB/mTOR, and HDAC inhibitors, by which these derivatives have shown promising anticancer potential.Results:Exhaustive literature survey indicated that indole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Indoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogen-mediated activity. Furthermore, indole derivatives have been found to modulate critical targets such as topoisomerase and HDAC. These derivatives have shown significant activity against breast cancer cells.Conclusion:In BC, indole derivatives seem to be quite competent and act through various mechanisms that are well established in case of BC. This review has shown that indole derivatives can further be explored for the betterment of BC chemotherapy. A lot of potential is still hidden which demands to be discovered for upgrading BC chemotherapy.

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Indole based prostate cancer agents

Physical Sciences Reviews ◽

10.1515/psr-2021-0131 ◽

2022 ◽

Vol 0 (0) ◽

Author(s):

Sunil Kumar ◽

Madhuri T. Patil ◽

Deepak B. Salunke

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Lung Cancer ◽

Immune System ◽

Anticancer Agents ◽

Crucial Role ◽

Heterocyclic Compounds ◽

Indole Derivatives ◽

Cancer Chemotherapeutics ◽

Privileged Structure

Abstract Cancer weakens the immune system which fails to fight against the rapidly growing cells. Among the various types of cancers, prostate cancer (PCa) is causing greater number of deaths in men after lung cancer, demanding advancement to prevent, detect and treat PCa. Several small molecule heterocycles and few peptides are being used as oncological drugs targeting PCa. Heterocycles are playing crucial role in the development of novel cancer chemotherapeutics as well as immunotherapeutics. Indole skeleton, being a privileged structure has been extensively used for the discovery of novel anticancer agents and the application of indole derivatives against breast cancer is well documented. The present article highlights the usefulness of indole linked heterocyclic compounds as well as the fused indole derivatives against prostate cancer.

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Bestowal of Quinazoline Scaffold in Anticancer Drug Discovery

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200627205321 ◽

2020 ◽

Vol 20 ◽

Author(s):

Rina Das ◽

Dinesh K. Mehta ◽

Meenakshi Dhanawat

Keyword(s):

Dna Repair ◽

Anticancer Activity ◽

Anticancer Drugs ◽

Anticancer Agents ◽

Chemotherapeutic Agents ◽

Special Focus ◽

Significant Activity ◽

Repair Enzyme ◽

Treatment Regimens ◽

Quinazoline Derivatives

Background: Cancer is one of the major causes of worldwide human mortality. A number of existing antineoplastic medications and treatment regimens are already working in the field and several new compounds are in different phases of clinical trials. An extensive series of anticancer drugs exists in the market, and studies suggest that these molecules are associated with different types of adverse side effects. Reduction of the cytotoxicity of drugs to the normal cells is a major problem in anticancer therapy. Therefore, researchers around the globe are involved in the development of more efficient and safer anticancer drugs. The output of extensive research is that the quinazoline scaffold and its various derivatives can be explored further as a novel class of cancer chemotherapeutic agents that has already shown promising activities against different tumours. Quinazoline derivatives have already occupied a crucial place in modern medicinal chemistry.Various research has been performed on quinazoline and their derivatives for anticancer activity and pharmacological importance of this scaffold has been well established. Objective: The aim of this review is to compile and highlight the developments concerning the anticancer activity of quinazoline derivatives as well as to suggest some new aspects on the expansion of anticancer activity of novel quinazoline derivatives as anticancer agents in the near future. Methods: Recent literature related to quinazoline derivatives endowed with encouraging anticancer potential is reviewed. With special focus on quinazoline moiety, this review offers a detailed account of multiple mechanisms of action of various quinazoline derivatives: inhibition of the DNA repair enzyme system, inhibition of EGFR, thymidylate enzyme inhibition and inhibitory effects for tubulin polymerization by which these derivatives have shown promising anticancer potential. Results: Exhaustive literature survey indicated that quinazoline derivatives are associated with properties of inhibiting EGFR and thymidylate enzyme. It was also found to be involved in disturbing tubulin assembly. Furthermore, quinazoline derivatives have been found to inhibit critical targets such as DNA repair enzyme. These derivatives have shown significant activity against cancer. Conclusion: In cancer therapy, Quinazoline derivatives seems to be quite promising and act through various mechanisms that are well established. This review has shown that quinazoline derivatives can further be explored for the betterment of chemotherapy. A lot of potential is still hidden which demands to be discovered for upgrading quinazoline derivatives efficacy.

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Recent Development in Indole Derivatives as Anticancer Agent: A Mechanistic Approach

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621999210104192644 ◽

2021 ◽

Vol 21 ◽

Author(s):

Neha Devi ◽

Kamalpreet Kaur ◽

Avadh Biharee ◽

Vikas Jaitak

Keyword(s):

Estrogen Receptor ◽

Tyrosine Kinase ◽

Kinase Inhibitor ◽

Multiple Drug Resistance ◽

Mtor Pathway ◽

Multiple Drug ◽

Significant Activity ◽

Indole Derivatives ◽

Tubulin Inhibitor ◽

Anti Cancer

Background: Cancer accounts for several deaths each year. There are multiple FDA approved drugs for cancer treatments. Due to the severe side effects and multiple drug resistance, the current drug therapies become ineffective. So, the newer moieties with fewer toxic effects are necessary for the development. Objective: The mechanism of indole derivatives as anti-cancer agents with their major target is explored in detail in this article. Methods: Recent advances and mechanism of indole derivatives as anti-cancer agents are reviewed. This review suggests a detailed explanation of multiple mechanisms of action of various indole derivatives: cell cycle arrest, aromatase inhibitor estrogen receptor regulator, tubulin inhibitor, a tyrosine kinase inhibitor, topoisomerase inhibitors, NFkB/PI3/Akt/mTOR pathway inhibitors, through which these derivatives have shown promising anti-cancer potential. Results: A full literature review showed that the indole derivatives are associated with the properties of inducing apoptosis, aromatase inhibition, regulation of estrogen receptor and inhibition of tyrosine kinase, tubulin assembly, NFkB/PI3/Akt/mTOR pathway, and HDACs. These derivatives have shown significant activity against cancer cell lines. Conclusion: Indole derivatives seem to be important in cancer via acting through various mechanisms. This review has shown that the indole derivatives can further be explored for the betterment of cancer treatment, and to discover the hidden potential of indole derivatives.

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Indole Derivatives as Anticancer Agents for Breast Cancer Therapy: A Review

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520615666150520144217 ◽

2015 ◽

Vol 16 (2) ◽

pp. 160-173 ◽

Cited By ~ 34

Author(s):

Jagpreet Singh Sidhu ◽

Ramit Singla ◽

Mayank ◽

Vikas Jaitak

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Anticancer Agents ◽

Indole Derivatives ◽

Breast Cancer Therapy

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Romidepsin (FK228), An Histone Deacetylase Inhibitor, and its Analogues in Cancer Chemotherapy.

Current Medicinal Chemistry ◽

10.2174/0929867327666200203113926 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Eftiola Pojani ◽

Daniela Barlocco

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

Synergistic Effects ◽

Hdac Inhibitors ◽

Covalent Modification ◽

Class I ◽

Significant Activity ◽

Dual Inhibitor ◽

Cancer Pathogenesis ◽

Pi3k Inhibition

Background: Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proven over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents. Objective: The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated. Materials and Methods: PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time. Results: HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoformrs are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structure-based optimization, several FK228 analogues [15 (FK-A5), 22, 23, 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC50 against p110α of 6.7 µM while for HDAC1 inhibitory activity IC50 was 0.64 nM). Conclusion: Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.

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Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

Cell Death Discovery ◽

10.1038/s41420-021-00635-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ser Yue Loo ◽

Nicholas L. Syn ◽

Angele Pei-Fern Koh ◽

Janet Cheng-Fei Teng ◽

Amudha Deivasigamani ◽

...

Keyword(s):

Breast Cancer ◽

Anticancer Agents ◽

Triple Negative ◽

De Novo ◽

Hdac Inhibitors ◽

Peroxisome Proliferator ◽

Concomitant Treatment ◽

Cancer Subtypes ◽

Pparγ Agonist ◽

Pparγ Agonists

AbstractClinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

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Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207319666160801154415 ◽

2016 ◽

Vol 19 (9) ◽

pp. 735-751 ◽

Cited By ~ 9

Author(s):

Preeti Patel ◽

Avineesh Singh ◽

Vijay Patel ◽

Deepak Jain ◽

Ravichandran Veerasamy ◽

...

Keyword(s):

Virtual Screening ◽

Anticancer Agents ◽

Hdac Inhibitors ◽

3D Qsar ◽

Docking Studies

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Synthesis, In-vitro and Docking Analysis of C-3 substituted Coumarin Analogues as Anticancer Agents C-3 Substituted Coumarins as Anticancer Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200120114641 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anuradha Thakur ◽

Kamalpreet Kaur ◽

Praveen Sharma ◽

Ramit Singla ◽

Sandeep Singh ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Anticancer Agents ◽

Proliferative Activity ◽

Binding Interaction ◽

Diverse Range ◽

Mcf 7 ◽

Substituted Coumarins

Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effect along with multi-drug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking. Method: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues 12 and 13 show good antiproliferative activity with IC50 values 1and 1.3 µM respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit dock score of -4.10 kcal/mol and -4.38 kcal/mol respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

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The Anti-Proliferative Activity of Anisosciadone: A New Guaiane Sesquiterpene from Anisosciadium lanatum

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190308112732 ◽

2019 ◽

Vol 19 (9) ◽

pp. 1114-1119 ◽

Cited By ~ 2

Author(s):

Ahmed A. Mahmoud ◽

Wael M. El-Sayed

Keyword(s):

Anticancer Agents ◽

Antiproliferative Activity ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Chemical Constituents ◽

Spectroscopic Techniques ◽

Significant Activity ◽

Caspase 9 ◽

P53 Expression ◽

Expression And Activity

Background: The increase in cancer rate and the development of resistant tumors require a continuous search for new anticancer agents. Aims: This study aimed to analyze and identify the chemical constituents of Anisosciadium lanatum, and to investigate the antiproliferative activity of the identified constituents against various human cell lines (HepG2, MCF7, HT29, A549, and PC3) along with the possible molecular mechanisms involved. Methods: The structure of the isolated compounds was determined by spectroscopic techniques including HRFABMS, GC-MS, IR, and 400 MHz 1D and 2D NMR analyses (1H, 13C NMR, DEPT, 1H-1H COSY, HMQC, HMBC and NOESY). The antiproliferative activity and IC50 value of the isolated compounds were measured and compared to doxorubicin. Results: A new guaiane sesquiterpene containing a rare epoxide structural element, 10β,11β−epoxy−1α,4β,5β,7αΗ- guaiane-9-one, anisosciadone (1), and stigmasterol (2) have been isolated from the plant. Anisosciadone (1) showed a significant antiproliferative activity against liver, colon, and lung cells only, while stigmasterol (2) had a significant activity against liver, colon, and breast cells. Both 1 and 2 caused no cytotoxicity to normal fibroblasts. Anisosciadone elevated the expression and activity of Caspase 3 as well as p53 expression without affecting Caspase 9 in HepG2 cells. It also caused ~ 50% downregulation in cdk1 expression. Conclusion: Taken together, anisosciadone was specific in action against cancer cells and induced apoptosis in liver cells. It also has a unique feature by elevating the expression and activity of Caspase 3 without affecting the initiator Caspase 9. Therefore, anisosciadone deserves more investigation as a targeted therapy for cancer.

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