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According to the mounting evidence in the literature, pro-inflammatory mediators/targets activate multiple signalling pathways to trigger illnesses that are ultimately responsible for acute pain, chronic inflammatory diseases, and several auto-immune disorders. Conventional drugs have been ruled out since proteolysis-targeting chimeras (PROTACs) are poised to overcome the limitations of traditional therapies. These heterobifunctional molecules help to degrade the targeted proteins of interest through ubiquitination. This review encompasses current and future aspects of PROTACs in inflammation-mediated and autoimmune targets. Different key points are highlighted and discussed, such as why PROTACs are preferred in this disease area, drawbacks and lessons learnt from the past, the role of linkers in establishing crucial degradation, in vitro findings, pharmacokinetics, in silico parameters, limitations of PROTACs in clinical settings, and future outcomes.
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Tumor progression depends on angiogenesis, which is stimulated by growth factors like VEGF, targeting VEGFR kinase with small molecules is an effective anti-angiogenic therapeutic approach. Sunitinib was rationally modified to spirocyclopropyloxindoline carboxamides and their in vitro cytotoxic profiling were evaluated. The molecular modelling studies enabled the screening of designed analogues and identified possible interactions within the type III allosteric inhibitor binding site of VEGFR-2. The biological screening of compounds 15a-y, revealed the ability of compound 15w to inhibit the cell growth in MCF-7 cells with IC50 value of 3.87 ± 0.19 µM and alongside inhibition of VEGFR-2 kinase at a IC50 concentration of 4.34 ± 0.13 µM was observed. VEGFR-2 inhibition was validated through HUVEC tube formation inhibition assay. 15w also inhibited cell migration in wound healing assay. The qualitative assessment of apoptosis induction by 15w in MCF-7 cells was evaluated through AO/EB and DAPI staining studies, whereas apoptotic quantification and cell cycle analysis were performed through FACS analysis. The current study strives to sequentially optimize the structural attributes of 3-alkenyl oxindole core to surpass the existing challenges of well-known VEGFR-2 inhibitors and compound 15w was identified to be a prominent lead towards the development of clinical drug candidates.
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Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.
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Antineoplásicos , Apoptosis , Proliferación Celular , Cromonas , Ensayos de Selección de Medicamentos Antitumorales , Tiazolidinedionas , Humanos , Apoptosis/efectos de los fármacos , Cromonas/farmacología , Cromonas/química , Cromonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tiazolidinedionas/farmacología , Tiazolidinedionas/química , Tiazolidinedionas/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Células HEK293 , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Línea Celular TumoralRESUMEN
An efficient Ru(II)-catalyzed C-H functionalization protocol for 2-arylbenzoazoles as the directing group and sulfoxonium ylide has been developed. Gratifyingly, concomitant annulation was observed when 3-(benzo[d]azol-2-yl) phenol was used, enabling the construction of benzofuran conjugates. Notably, the utilization of water as the solvent and an energy efficient approach makes the reaction greener, contributing to overall sustainability. This protocol exhibits excellent scalability up to the gram scale with a diverse array of substitutions. Furthermore, the mechanism was examined by ESI-MS, and photophysical studies were also performed.
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An efficient Rh(III)-catalysed C-H functionalization, tandem annulation of cis-stilbene acids using 2-diazo-1,3-diketones was devised. This protocol solely afforded 6,7-dihydrobenzofuran-4(5H)-ones using alicyclic diazocarbonyls via decarbonylation and α-pyrones with aliphatic diazo compounds. The chameleonic nature of cis-stilbene acid was observed with various diazo compounds by altering the additives. This synthetic method furnished good atom-economy and wide functional group tolerance, and also explained the use of carboxylic acids as a directing group. In addition, a mechanistic investigation of the catalysed reaction using ESI-MS, and the fluorescence properties of α-pyrones were well explored.
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A series of spirocyclopropyl oxindoles with benzimidazole substitutions was synthesized and tested for their cytotoxicity against selected human cancer cells. Most of the molecules exhibited significant antiproliferative activity with compound 12 p being the most potent. It exhibited significant cytotoxicity against MCF-7 breast cancer cells (IC50 value 3.14±0.50â µM), evidenced by the decrease in viable cells and increased apoptotic features during phase contrast microscopy, such as AO/EB, DAPI and DCFDA staining studies. Compound 12 p also inhibited cell migration in wound healing assay. Anticancer potential of 12 p was proved by the inhibition of tubulin polymerization with IC50 of 5.64±0.15â µM. These results imply the potential of benzimidazole substituted spirocyclopropyl oxindoles, notably 12 p, as cytotoxic agent for the treatment of breast cancer.
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Antineoplásicos , Apoptosis , Bencimidazoles , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Oxindoles , Polimerizacion , Moduladores de Tubulina , Tubulina (Proteína) , Humanos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Oxindoles/farmacología , Oxindoles/química , Oxindoles/síntesis química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Desarrollo de Medicamentos , Células MCF-7RESUMEN
A new class of benzimidazole derivatives as tubulin polymerization inhibitors has been designed and synthesized in this study. The in vitro anticancer profile of the developed molecules was reconnoitred on selected human cancer cells. The highest cytotoxicity was illustrated by compounds 7n and 7u with IC50 values ranging from 2.55 to 17.89 µM with specificity toward SK-Mel-28 cells. They displayed 5-fold less cytotoxicity towards normal rat kidney epithelial NRK52E cells, which implies that they are not harmful to normal, healthy cells. The cellular staining procedures like AO/EB, DCFDA, and DAPI were applied to comprehend the inherent mechanism of apoptosis which displayed nuclear and morphological alterations. The Annexin V binding and JC-1 studies were executed to evaluate the extent of apoptosis and the decline in mitochondrial transmembrane potential in SK-Mel-28 cell lines. Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC50 of 5.05±0.13 µM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively.
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Antineoplásicos , Moduladores de Tubulina , Ratas , Humanos , Animales , Relación Estructura-Actividad , Moduladores de Tubulina/química , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Antineoplásicos/química , Tubulina (Proteína)/metabolismo , Línea Celular Tumoral , Apoptosis , Bencimidazoles/farmacología , PolimerizacionRESUMEN
Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3-substituted-thiooxindole derivatives as anticancer agents. Among the new series, compounds 7d and 9c exhibited promising cytotoxic activity toward HCT-116 cells with IC50 values of 6.73 ± 0.36 and 6.64 ± 0.95 µM, respectively. Further, AO/EB, DCFDA, and DAPI staining studies were executed to establish the underlying apoptosis mechanism which displayed significant nuclear and morphological alterations. JC-1 staining and annexin V binding assay inferred the loss of mitochondrial membrane potential in HCT-116 cancer cells. Cell cycle analysis showed the treatment of 9c against HCT-116 cells, arrested the cell cycle in G2-M phase. In addition, tubulin binding assay revealed that compound 9c exhibited tubulin polymerase inhibition with IC50 value of 9.73 ± 0.18 µM. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.
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Antineoplásicos , Tubulina (Proteína) , Relación Estructura-Actividad , Polimerizacion , Tubulina (Proteína)/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Antineoplásicos/química , Apoptosis , Moduladores de Tubulina/química , Línea Celular TumoralRESUMEN
In the pursuit of potential and effective chemotherapeutic agents, a series of 2-((3-(indol-3-yl)-pyrazol-5-yl)imino)thiazolidin-4-ones was designed and synthesized, conjoining salient pharmacophoric properties for directing prominent cytotoxicity. The in vitro cytotoxicity evaluation revealed potent compounds with IC50 values <10 µM on tested human cancer cell lines. Compound 6c exhibited the highest cytotoxicity with an IC50 value of 3.46 µM against melanoma cancer cells (SK-MEL-28) and was highly cytospecific and selective towards cancer cells. The traditional apoptosis assays revealed morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented/blebbing nuclei, and the generation of ROS. Flow cytometric analysis revealed effective early-stage apoptosis induction and cell-cycle arrest in the G2/M phase. In addition, the enzyme-based effect of 6c on tubulin showed the inhibition of tubulin polymerization (about 60% inhibition, IC50 was <1.73 µM). Moreover, molecular modeling studies affirmed the constant accommodation of compound 6c at the active pocket of tubulin, establishing many electrostatic and hydrophobic interactions with the active pocket's residues. The tubulin-6c complex was stable during the MD simulation for 50 ns with the recommended range of RMSD value (2-4 Å) for each pose.
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To scrutinize cis-stilbene based molecules with potential anticancer and tubulin polymerization inhibition activity, a new series of cis-stilbene-1,2,3-triazole congeners was designed and synthesized via a click chemistry protocol. The cytotoxicity of these compounds 9a-j and 10a-j was screened against lung, breast, skin and colorectal cancer cell lines. Based on the results of MTT assay, we further evaluated the selectivity index of the most active compound 9j (IC50 3.25 ± 1.04 µM on HCT-116) by comparing its IC50 value (72.24 ± 1.20 µM) to that of the normal human cell line. Further, to confirm apoptotic cell death, cell morphology and staining studies (AO/EB, DAPI and Annexin V/PI) were carried out. The outcomes of studies showed apoptotic features like change in cell shape, cornering of nuclei, micronuclei formation, fragmented, bright, horseshoe-shaped nuclei, etc. Moreover, active compound 9j displayed G2/M phase cell cycle arrest with significant tubulin polymerization inhibition activity with an IC50 value of 4.51 µM. Additionally, in silico ADMET, molecular docking and molecular dynamic studies of 9j with 3E22 protein proved the binding of the compound at the colchicine binding site of tubulin.
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A simple "click" protocol was employed in the quest of synthesizing 1,2,3-triazole-linked benzimidazoles as promising anticancer agents on various human cancer cell lines such as A549, HCT116, SK-Mel-28, HT-29, and MCF-7. Compound 12j demonstrated significant cytotoxic potential towards SK-Mel-28 cancer cells (IC50 : 4.17 ± 0.09 µM) and displayed no cytotoxicity (IC50 : > 100 µM) against normal human BEAS-2B cells inferring its safety towards normal healthy cells. Further to comprehend the underlying apoptosis mechanisms, AO/EB, dichlorodihydrofluorescein diacetate (DCFDA), and 4',6-diamidino-2-phenylindole (DAPI) staining were performed, which revealed the nuclear and morphological alterations. Compound 12j displayed impairment in cellular migration and inhibited colony formation. The annexin V binding assay and JC-1 were implemented to evaluate the scope of apoptosis and the loss of the mitochondrial transmembrane potential in SK-Mel-28 cells. Cell-cycle analysis revealed that compound 12j arrested the cells at the G2/M phase in a dose-dependent manner. Target-based assays established the inhibition of tubulin polymerization by 12j at an IC50 value of 5.65 ± 0.05 µM and its effective binding with circulating tumor DNA as a DNA intercalator. The detailed binding interactions of 12j with tubulin and DNA were examined by docking studies on PDB ID: 3E22 and DNA hexamer (PDB ID: 1NAB), respectively.
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Antineoplásicos , Moduladores de Tubulina , Humanos , Relación Estructura-Actividad , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Sustancias Intercalantes/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Apoptosis , ADN , Simulación del Acoplamiento Molecular , PolimerizacionRESUMEN
In a quest for effective cancer targeted drug therapy, a series of new ß-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC50 < 10 µM) on human cancer cell lines like HCT116, A549, SK-MEL-28, and MCF7. Precisely, compound 12x expressed the best cytotoxic potential against melanoma cancer cell line (SK-MEL-28) with an IC50 value of 4.37 µM. In addition, cytotoxicity evaluation against normal kidney cell line (NRK52E) entrenched the cytospecificity and selectivity index of 12x. The traditional apoptosis assays advised morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented nuclei, and generation of ROS. The flow cytometric analysis revealed significant early and slight late-stage induction of apoptosis. The target-based physiochemical assays indicated the ability of compound 12x to bind with DNA and inhibition of Topoisomerase II. Moreover, molecular modeling studies affirm the excellent DNA intercalation potential and stabilized interactions of 12x with DNA base pairs. In silico prediction of physicochemical parameters revealed the promising drug-like properties of the synthesized derivatives.
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Antineoplásicos , Neoplasias , Humanos , Estructura Molecular , Relación Estructura-Actividad , ADN/química , Antineoplásicos/química , Carbolinas/farmacología , Carbolinas/química , Simulación por Computador , ADN-Topoisomerasas de Tipo II/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Apoptosis , Línea Celular TumoralRESUMEN
A protocol for carbene insertion into the inert C(sp2)-H bond has been established wherein ß-carbolines and isoquinolines are explored as intrinsic directing groups. The Ru(II)-catalyzed strategy employing sulfoxonium ylides as the carbene precursor offers an effective and atom-economical functionalization of substrates of biological interest with only DMSO as the sole by-product. The strategy is scalable to gram scale, and it also showcases a wide range of functional group tolerance. ESI-MS studies assisted in the identification of intermediates and consolidation of a probable mechanistic pathway. Furthermore, investigations revealed that the functionalized molecules not only displayed selective inhibition against cancer cell lines, but also demonstrated promising photophysical properties.
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Carbolinas , Isoquinolinas , Catálisis , Metano/análogos & derivados , Estructura MolecularRESUMEN
With the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 µM against A549 and 3.02-10.91 µM in the other tested cancer cell lines. Gratifyingly, 11g displayed 43-fold higher selectivity towards A549 cancer cells as compared to the non-cancer cells. Subsequently, conjugate 12g also demonstrated significant cytotoxicity against SK-MEL-28 cells. Basing the in vitro cytotoxicity results, SAR was established. Later, the conjugates 11g and 12g were further evaluated for their apoptosis-inducing ability, which was quantified by flow cytometric analysis, DNA-binding, Topo I inhibitory activity and IC50 value calculation. Molecular modeling studies provided profound insights about the binding nature of these compounds with DNA-Topo I complex. In silico ADME/T and prediction studies corroborated the drug-likeness of the two investigated compounds. TOPKAT toxicity profiling studies demonstrated the compounds' safety in many animal models with a minimal toxicological profile. Encouraging results obtained from in vitro and in silico studies could put this series of conjugates at the forefront of cancer drug discovery.
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Antineoplásicos , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Azepinas , Línea Celular Tumoral , Proliferación Celular , ADN/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Pirroles , Relación Estructura-Actividad , Tiazolidinas , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
The design and synthesis of a new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids was accomplished. The in vitro cytotoxic potential of these new compounds was evaluated against lung cancer (A549), prostate cancer (PC-3, DU-145) and human embryonic kidney (HEK) cell lines. Compound 9p showed the highest potency on A549 cells with an IC50 value of 3.8 ± 0.02 µM. Moreover, 9p was found to be 25-fold more selective towards cancer cell lines than the non-cancerous (HEK) cell line. The target-based assay revealed the inhibition of the topoisomerase II enzyme by compound 9p. UV-visible spectroscopy, fluorescence, circular dichroism (CD), and viscosity studies inferred the intercalative property and effective binding of compound 9p with CT-DNA. Apoptosis induced by the compound 9p was observed by various morphological staining assays, i.e, DAPI, EtBr/AO. Further, the molecular modeling studies revealed the binding of compound 9p at the active site of the DNA-topoisomerase II complex while the physicochemical properties were in the recommended range. Finally, mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives can be considered as a promising scaffold for development as effective anticancer agents and topoisomerase II inhibitors.
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Antineoplásicos , Inhibidores de Topoisomerasa II , Antineoplásicos/química , Apoptosis , Proliferación Celular , ADN/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxadiazoles , Pirimidinas , Relación Estructura-ActividadRESUMEN
A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their antiproliferative activity against a panel of selected human cancer cell lines including A549 (lung cancer), HCT116 (colon cancer), MCF7 (breast cancer), and SK-MEL-28 (melanoma). Among the synthesized molecules (14a-m and 15a-d), compound 14d displayed remarkable activity against A549, HCT116 and SK-MEL-28 cells with IC50 values < 4 µM with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC50 value of 2.33 µM) over the normal rat kidney cells (NRK). Further, 14d-mediated apoptosis affected the cellular and nuclear morphology of the cancer cells in a dose-dependent manner. Wound healing and clonogenic assays inferred the inhibition of cell growth and migration. Target-based studies of compound 14d corroborated its DNA-intercalative capability and Topo I inhibitory activity which have been fortified by molecular modeling studies. Finally, the drug-likeness of the potent compound was determined by performing in silico ADME/T prediction studies.
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Antineoplásicos , Animales , Apoptosis , Azepinas , Línea Celular Tumoral , Proliferación Celular , ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxindoles/farmacología , Pirroles , Ratas , Relación Estructura-ActividadRESUMEN
Knoevenagel condensation is an entrenched, prevailing, prominent arsenal following greener principles in the generation of α, ß-unsaturated ketones/carboxylic acids by involving carbonyl functionalities and active methylenes. This reaction has proved to be a major driving force in many multicomponent reactions indicating the prolific utility toward the development of biologically fascinating molecules. This eminent reaction was acclimatised on different pharmacophoric aldehydes (benzimidazole, ß-carboline, phenanthrene, indole, imidazothiadiazole, pyrazole etc.) and active methylenes (oxindole, barbituric acid, Meldrum's acid, thiazolidinedione etc.) to generate the library of chemical compounds. Their potential was also explicit to understand the significance of functionalities involved, which thereby evoke further developments in drug discovery. Furthermore, most of these reaction products exhibited remarkable anticancer activity in nanomolar to micromolar ranges by targeting different cancer targets like DNA, microtubules, Topo-I/II, and kinases (PIM, PARP, NMP, p300/CBP) etc. This review underscores the efficiency of the Knoevenagel condensation explored in the past six-year to generate molecules of pharmacological interest, predominantly toward cancer. The present review also provides the aspects of structure-activity relationships, mode of action and docking study with possible interaction with the target protein.
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Antineoplásicos , Aldehídos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Cetonas , Relación Estructura-ActividadRESUMEN
A Ru(II)-catalyzed regioselective direct ortho-amidation of 2-aryl benzo[d]thiazoles employing acyl azides as a nitrogen source has been accomplished. This approach utilizes the efficiency of benzothiazole as a directing group and the role of acyl azide as an effective amidating agent toward C-N bond formation, thereby evading the general Curtius rearrangement. The protocol highlights significant functional group tolerance, single-step, and external oxidant-free conditions, with the release of only innocuous molecular nitrogen as the byproduct. The reaction mechanism and the intermediates associated with this selective Ru-catalyzed reaction have been investigated using ESI-MS. The protocol also aided in the construction of ortho-amidated ß-carbolines, unveiling another class of fluorescent molecules.
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Triple-negative breast cancer (TNBC) is a particularly lethal subtype of breast cancer owing to its heterogeneity, high drug resistance, poor prognosis and lack of therapeutic targets. Recent insights into the complexity of TNBC have been explained by epigenetic regulation and its ability to modulate certain oncogenes and tumour suppressor genes. This has opened an emerging area in anti-cancer therapy using epigenetic modulating drugs, highlighting the epigenetic reprogramming during tumorigenesis and tumour development. Histone methylation and demethylation are such dynamic epigenetic mechanisms mediated by histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively. The interplay between HMTs and HDMs in histone methylation extrapolates their viability as druggable epigenetic targets in TNBC. In this review, we aim to summarize recent progress in the field of epigenetics focusing on HMTs and HDMs in TNBC development and their potential use in targeted therapy for TNBC management.
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Histona Demetilasas/fisiología , Histona Metiltransferasas/fisiología , Neoplasias de la Mama Triple Negativas/metabolismo , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , OncogenesRESUMEN
Cancer is a silent killer and remains to pose major health problems globally. Amongst the several biological targets, DNA is one of the most striking targets in cancer chemotherapy. Owing to its planar structure, phenanthrene and its derivatives exhibit potential cytotoxicity by intercalating between the DNA base pairs and by inhibiting the enzymes that are involved in the synthesis of DNA. However, due to the off-target effects and resistance, the development of novel chemotherapeutic agents would be meritorious. In this regard, we present a detailed review on the development of phenanthrene-based derivatives reported in the last quinquennial. This review mainly focuses on the synthetic aspects and strategies to procure the fused phenanthrene derivatives such as (i) phenanthroindolizidines, phenanthroquinolizidine, phenanthroimidazoles, podophyllotoxin-based phenanthrenes, and dihydrophenanthrodioxine derivatives, (ii) phenanthrene conjugates with other pharmacologically significant pharmacophores, and (iii) phenanthrene-metal complexes. This review also edifies their potential in vitro cytotoxicity evaluation against various carcinoma cell lines in submicromolar to nanomolar ranges. Additionally, computational studies and structure-activity relationships (SARs) have also been presented to highlight the essential features of the designed congeners. Thus, this review would aid in the development of novel derivatives in future as potential cytotoxic agents in the field of medicinal chemistry.