Phenanthridine derivatives as promising new anticancer agents: synthesis, biological evaluation and binding studies

Aim: Phenanthridines are an essential class of nitrogenous heterocycles with extensive applications in medicinal chemistry. The development of efficient and eco-friendly methods for the preparation of chirally pure dihydropyrrolo[1,2- f]phenanthridines (5a–h), and their in vitro evaluation and modeling studies as potential anticancer, antioxidant and DNA cleavage agents is reported. Methodology & results: Compounds 5a–h were prepared through a facile one-pot synthesis and characterized by infrared, high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance. The molecules were subjected to virtual screening and docking analysis against selected human molecular targets. Compound 5g displayed good binding properties as well as significant anticancer and DNA cleavage activity. Conclusion: Compound 5g has been identified as a potential lead candidate for further testing against additional cancer cell lines and animal models in future.

Download Full-text

Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190308122734 ◽

2019 ◽

Vol 19 (10) ◽

pp. 1285-1292 ◽

Cited By ~ 2

Author(s):

Kuldip D. Upadhyay ◽

Anamik K. Shah

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

Biological Activities ◽

Cytotoxic Agents ◽

Tumor Growth Inhibition ◽

Mice Model ◽

One Pot ◽

Aryl Ring ◽

Hct 116

Background: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents. Objective: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity. Methods: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model. Results: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model. Conclusion: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

Download Full-text

Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents

Cells ◽

10.3390/cells7110216 ◽

2018 ◽

Vol 7 (11) ◽

pp. 216 ◽

Cited By ~ 8

Author(s):

Urszula Majcher ◽

Greta Klejborowska ◽

Magdalena Kaik ◽

Ewa Maj ◽

Joanna Wietrzyk ◽

...

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Binding Free Energy ◽

3D Structure ◽

Human Tumor ◽

Biological Evaluation ◽

Energy Estimates ◽

Colchicine Derivatives ◽

Mcf 7

Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.

Download Full-text

Synthesis and Biological Evaluation of Aminonaphthols Incorporated Indole Derivatives

International Journal of Medicinal Chemistry ◽

10.1155/2014/673206 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Saundane Anand Raghunath ◽

Kirankumar Nandibeoor Mathada

Keyword(s):

Radical Scavenging ◽

Antitubercular Activity ◽

Antimicrobial Activities ◽

Biological Evaluation ◽

Secondary Amines ◽

Anticancer Activities ◽

One Pot ◽

Antioxidant Power ◽

Mic Value

An efficient one pot condensation of naphthols (1), 2,5-disubstituted indole-3-carboxaldehydes (2), and secondary amines (3) has been achieved using dichloromethane as a solvent, stirring at room temperature. Some of the new [(disubstituted amino)(5-substituted 2-phenyl-1H-indol-3-yl)methyl]naphthalene-ols (4) derivatives were prepared in good yields. The significant features of this method are simple work-up procedure, inexpensive nontoxic solvent, shorter reaction times, and excellent product yields. The structures of newly synthesized compounds (4a–r) are confirmed by their elemental analysis, FTIR, 1H and 13C NMR, and mass spectral data. These compounds were screened for their in vitro antioxidant, antimicrobial, antitubercular, and anticancer activities. Among the synthesized compounds (4a–r), the compound 4e exhibited highest activity for radical scavenging and ferric ions reducing antioxidant power activities; compounds 4b, 4h, and 4k showed good metal chelating activity. Compounds 4n and 4q showed excellent antimicrobial activities with MIC value 08 µg/mL against tested strains. Compounds 4h, 4k, 4n, and 4q exhibited promising antitubercular activity with MIC value 12.5 µg/mL. Compounds 4k and 4q exhibited 100% cell lysis at concentration 10 µg/mL against MDA-MB-231 (human adenocarcinoma mammary gland) cell lines.

Download Full-text

Steroidal glycoalkaloids fromSolanum nigrumtarget cytoskeletal proteins: anin silicoanalysis

PeerJ ◽

10.7717/peerj.6012 ◽

2019 ◽

Vol 7 ◽

pp. e6012 ◽

Cited By ~ 2

Author(s):

Rumana Ahmad

Keyword(s):

Binding Affinity ◽

Anticancer Agents ◽

Principal Component ◽

Cytoskeletal Proteins ◽

Hydroxyl Group ◽

Docking Analysis ◽

Drug Candidates ◽

Division Cell

BackgroundSolanum nigrum(black nightshade;S. nigrum), a member of family Solanaceae, has been endowed with a heterogeneous array of secondary metabolites of which the steroidal glycoalkaloids (SGAs) and steroidal saponins (SS) have vast potential to serve as anticancer agents. Since there has been much controversy regarding safety of use of glycoalkaloids as anticancer agents, this area has remained more or less unexplored. Cytoskeletal proteins like actin play an important role in maintaining cell shape, synchronizing cell division, cell motility, etc. and along with their accessory proteins may also serve as important therapeutic targets for potential anticancer candidates. In the present study, glycoalkaloids and saponins fromS. nigrumwere screened for their interaction and binding affinity to cytoskeletal proteins, using molecular docking.MethodsBioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis were performed using softwares Molinspiration and Osiris Data Explorer respectively, to assess the feasibility of selected phytoconstituents as potential drug candidates. The results were compared with two standard reference drugs doxorubicin hydrochloride (anticancer) and tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA).ResultsDocking analysis revealed that the binding affinities of the phytoconstituents towards the target cytoskeletal proteins decreased in the order coronin>villin>ezrin>vimentin>gelsolin>thymosin>cofilin. Glycoalkaloid solasonine displayed the greatest binding affinity towards the target proteins followed by alpha-solanine whereas amongst the saponins, nigrumnin-I showed maximum binding affinity. PASS Analysis of the selected phytoconstituents revealed 1 to 3 violations of Lipinski’s parameters indicating the need for modification of their structure-activity relationship (SAR) for improvement of their bioactivity and bioavailability. Glycoalkaloids and saponins all had bioactivity scores between −5.0 and 0.0 with respect to various receptor proteins and target enzymes. Solanidine, solasodine and solamargine had positive values of druglikeness which indicated that these compounds have the potential for development into future anticancer drugs. Toxicity potential evaluation revealed that glycoalkaloids and saponins had no toxicity, tumorigenicity or irritant effect(s). SAR analysis revealed that the number, type and location of sugar or the substitution of hydroxyl group on alkaloid backbone had an effect on the activity and that the presence of α-L-rhamnopyranose sugar at C-2 was critical for a compound to exhibit anticancer activity.ConclusionThe present study revealed some cytoskeletal target(s) forS. nigrumphytoconstituents by docking analysis that have not been previously reported and thus warrant further investigations bothin vitroandin vivo.

Download Full-text

Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2019.01.049 ◽

2019 ◽

Vol 166 ◽

pp. 514-530 ◽

Cited By ~ 2

Author(s):

Rita Morigi ◽

Alessandra Locatelli ◽

Alberto Leoni ◽

Mirella Rambaldi ◽

Roberta Bortolozzi ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Evaluation

Download Full-text

A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids

Molecules ◽

10.3390/molecules25235581 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5581

Author(s):

Raju Suresh Kumar ◽

Dhaifallah M. Al-thamili ◽

Abdulrahman I. Almansour ◽

Natarajan Arumugam ◽

Faruq Mohammad

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

One Pot ◽

Major Pathway ◽

Molecular Scaffold ◽

Highly Active ◽

Ft Ir ◽

Derivatives Of ◽

Unique Mechanism

With an aim to develop more effective and affordable anticancer agents possessing a unique mechanism of action, we designed and synthesized derivatives of spirooxindole-pyrrolidine heterocyclic hybrids in good yields through a one-pot three-component (3+2) cycloaddition strategy. The synthesized compounds were characterized thoroughly for the physicochemical properties by making use of FT-IR, NMR spectroscopy, and mass spectrometry. Further, these compounds have been evaluated for the influence of anticancer activity against HepG2 cells up to 200 µg/mL concentration. The highly active molecular scaffold was tested for the in-depth mechanistic studies, and it was found that the major pathway of cell death is apoptosis which occurs through the induction of reactive oxygen species followed by the involvement of caspases.

Download Full-text

Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING)

Molecules ◽

10.3390/molecules25225285 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5285

Author(s):

Xin Xie ◽

Junyi Liu ◽

Xiaowei Wang

Keyword(s):

Transmembrane Protein ◽

Biological Evaluation ◽

Type I ◽

Vaccine Adjuvants ◽

One Pot ◽

Design Synthesis ◽

Cellular Assays ◽

Type I Ifns ◽

Sting Pathway

Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3′-5′ and 2′-5′ phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2′3′-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound 8d (KD = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (KD = 0.543 μM). Cellular assays confirmed that 8d could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. 8d also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings provide guidelines for the design and structural optimization of CDNs as STING agonists.

Download Full-text

DIPEAc promoted one-pot synthesis of dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives as potent tyrosinase inhibitors and anticancer agents: in vitro screening, molecular docking and ADMET predictions

New Journal of Chemistry ◽

10.1039/c8nj04622k ◽

2018 ◽

Vol 42 (23) ◽

pp. 18621-18632 ◽

Cited By ~ 11

Author(s):

Manisha R. Bhosle ◽

Lalit D. Khillare ◽

Jyotirling R. Mali ◽

Aniket P. Sarkate ◽

Deepak K. Lokwani ◽

...

Keyword(s):

Molecular Docking ◽

Anticancer Activity ◽

Anticancer Agents ◽

Oral Drug ◽

In Vitro Screening ◽

Pyrimidine Derivatives ◽

Rapid Synthesis ◽

One Pot ◽

Tyrosinase Inhibitors

Efficient and rapid synthesis of 18 tyrosinase inhibitors with good to moderate anticancer activity and good oral drug like properties.

Download Full-text

Fragmentation Study, Dual Anti-Bactericidal and Anti-Viral Effects and Molecular Docking of Cobalt(III) Complexes

International Journal of Molecular Sciences ◽

10.3390/ijms21218355 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8355

Author(s):

Laísa de P. Fernandes ◽

Júlia M. B. Silva ◽

Daniel O. S. Martins ◽

Mariana B. Santiago ◽

Carlos H. G. Martins ◽

...

Keyword(s):

Molecular Docking ◽

High Resolution Mass Spectrometry ◽

Biological Activities ◽

Therapeutic Application ◽

Chikv Infection ◽

Docking Analysis ◽

Future Studies ◽

Relative Binding ◽

Good Potential

Considering our previous findings on the remarkable activity exhibited by cobalt(III) with 2-acetylpyridine-N(4)-R-thiosemicarbazone (Hatc-R) compounds against Mycobacterium tuberculosis, the present study aimed to explored new structure features of the complexes of the type [Co(atc--R)2]Cl, where R = methyl (Me, 1) or phenyl (Ph, 2) (13C NMR, high-resolution mass spectrometry, LC–MS/MS, fragmentation study) together with its antibacterial and antiviral biological activities. The minimal inhibitory and minimal bactericidal concentrations (MIC and MBC) were determined, as well as the antiviral potential of the complexes on chikungunya virus (CHIKV) infection in vitro and cell viability. [Co(atc-Ph)2]Cl revealed promising MIC and MBC values which ranged from 0.39 to 0.78 µg/mL in two strains tested and presented high potential against CHIKV by reducing viral replication by up to 80%. The results showed that the biological activity is strongly influenced by the peripheral substituent groups at the N(4) position of the atc-R1− ligands. In addition, molecular docking analysis was performed. The relative binding energy of the docked compound with five bacteria strains was found in the range of −3.45 and −9.55 kcal/mol. Thus, this work highlights the good potential of cobalt(III) complexes and provide support for future studies on this molecule aiming at its antibacterial and antiviral therapeutic application.

Download Full-text