36017-64-8Relevant academic research and scientific papers
Synergistic interaction of N-3-Br-benzyl-noscapine and docetaxel abrogates oncogenic potential of breast cancer cells
Dash, Shruti Gamya,Kantevari, Srinivas,Pandey, Swaroop Kumar,Naik, Pradeep Kumar
, p. 466 - 479 (2021)
Noscapine, an opium alkaloid, was discovered to bind tubulin, arrest dividing cells at mitosis, and selectively induce apoptosis to cancer cells. N-3-Br-Benzyl-Noscapine (Br-Bn-Nos), one of the derivatives of noscapine, was demonstrated to have improved anticancer potential compared with noscapine. We approached to evaluate the single and combined effect of Br-Bn-Nos and docetaxel (DOX) based on molecular modeling and cellular study. The individual predicted free energy of binding (?Gbind,pred) for Br-Bn-Nos and DOX with tubulin was found to be ?28.89 and ?36.07?kcal/mol based on molecular mechanics generalized Born solvation area (MM-GBSA) as well as ?26.21 and ?34.65?kcal/mol based on molecular mechanics Poisson Boltzmann solvation area (MM-PBSA), respectively. However, the ?Gbind,pred of Br-Bn-Nos was significantly reduced (?33.02 and ?30.24?kcal/mol using MM-GBSA and MM-PBSA) in the presence of DOX on its binding pocket. Parenthetically, the ?Gbind,pred of DOX was significantly reduced (?37.17 and ?32.80?kcal/mol using MM-GBSA and MM-PBSA) in the presence of Br-Bn-Nos on its binding pocket. The reduced ?Gbind,pred in the presence of Br-Bn-Nos and DOX together indicated a combination effect of both the ligands. The combined interaction of both the agents onto tubulin dimmer was also determined experimentally using purified tubulin, in which a?combination regimen of Br-Bn-Nos and DOX reduced the fluorescence intensity of tubulin to a higher value (68%) compared with the single regimen. Further, isobologram analysis revealed the synergistic effect of Br-Bn-Nos and DOX in antiproliferative activity using MCF-7 cell line at 48?hr (sum FIC?=?0.49) and at 72?hr (sum FIC?=?0.62). The combination dose regimen of Br-Bn-Nos and DOX blocks the cell cycle progression at the G2/M phase and induces apoptosis to cancer cells more effectively compared with the single regimen. Taken together, our study provides compelling evidence that the anticancer potential of noscapine derivatives may be substantially improved when it is used in a combined application with DOX for breast cancer.
N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study
Babanezhad Harikandei,Salehi, Peyman,Ebrahimi, Samad Nejad,Bararjanian, Morteza,Kaiser, Marcel,Khavasi, Hamid Reza,Al-Harrasi
, (2019)
Novel N-substituted noscapine derivatives were synthesized by a three-component Strecker reaction of cyclic ether of N-nornoscapine with varied aldehydes, in the presence of cyanide ion. Moreover, the corresponding amides were synthesized by the oxidation of cyanide moieties in good yields. The in vitro antiprotozoal activity of the products was also investigated. Interestingly, some analogues did put on display promising antiparasitic activity against Trypanosoma brucei rhodesiense with IC50 values between 2.5 and 10.0 μM and selectivity index (SI) ranged from 0.8 to 13.2. Eight compounds exhibited activity against Plasmodium falciparum K1 strain with IC50 ranging 1.7–6.4 μM, and SI values between 2.8 and 10.5 against L6 rat myoblast cell lines. Molecular docking was carried out on trypanothione reductase (TbTR, PDB ID: 2WOW) and UDP-galactose 4′ epimerase (TbUDPGE PDB: 1GY8) as targets for studying the envisaged mechanism of action. Compounds 6j2 and 6b2 displayed excellent docking scores with ?8.59 and ?8.86 kcal/mol for TbTR and TbUDPGE, respectively.
A convenient synthesis of aryl-substituted N-carbamoyl/N-thiocarbamoyl narcotine and related compounds
Aggarwal, Shefali,Ghosh, Narendra N.,Aneja, Ritu,Joshi, Harish,Chandra, Ramesh
, p. 2458 - 2462 (2002)
The reaction of nornarcotine and 5-bromonornarcotine, synthesized from noscapine, with suitable aromatic isocyanates or isothiocyanates provides a general method for the synthesis of aryl-substituted N-carbamoyl or N-thiocarbamoylnarcotine and related compounds. Similarly, 15a has been prepared via the reduction of the lactone ring moiety of noscapine. Also, an improved procedure, which utilizes narcotine N-oxide · HCl for generation of nornarcotine, is described.
Tubulin- and ROS-dependent antiproliferative mechanism of a potent analogue of noscapine, N-propargyl noscapine
Kantevari, Srinivas,Lopus, Manu,Nagireddy, Praveen Kumar Reddy,Nambiar, Nayana,Pedapati, Ravikumar
, (2020)
Aim: To rationally-design, synthesize, characterize, biologically evaluate, and to elucidate the anticancer mechanism of action of a novel analogue of noscapine, N-propargyl noscapine (NPN), as a potential drug candidate against triple-negative breast cancer (TNBC). Materials and methods: After the synthesis and IR, 1H, 13C NMR and mass spectral characterization of NPN, its antiproliferative efficacy against different cancer cell lines was investigated using Sulforhodamine B assay. Cell cycle progression was analysed using flow cytometry. The drug-tubulin interactions were studied using tryptophan-quenching assay, ANS-binding assay, and colchicine-binding assay. Immunofluorescence imaging was used to examine the effect of NPN on cellular microtubules. Levels of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and cell death were studied by staining the cells with DCFDA, Rhodamine 123, and acridine orange/ethidium bromide, respectively. Key findings: NPN strongly inhibited the viability (IC50, 1.35 ± 0.2 μM) and clonogenicity (IC50, 0.56 ± 0.06 μM) of the TNBC cell line, MDA-MB-231, with robust G2/M arrest. In vitro, the drug bound to tubulin and disrupted the latter's structural integrity and promoted colchicine binding to tubulin. NPN triggered an unusual form of microtubule disruption in cells, repressed recovery of cold-depolymerized cellular microtubules and suppressed their dynamicity. These effects on microtubules were facilitated by elevated levels of ROS and loss of MMP. Significance: NPN can be explored further as a chemotherapeutic agent against TNBC.
Discovery of noscapine derivatives as potential β-tubulin inhibitors
Bararjanian, Morteza,Bifulco, Giuseppe,Bruno, Ines,Hadian, Nasim,Lauro, Gianluigi,Mohebbi, Maryam,Nemati, Faezeh,Ruggiero, Dafne,Salehi, Peyman,Terracciano, Stefania
, (2020)
Twenty novel 1,2,3-triazole noscapine derivatives were synthesized starting from noscapine by consecutive N-demethylation, reduction of lactone ring, N-propargylation and Huisgen 1,3-dipolar cycloaddition reaction. In order to select the most promising molecules to subject to further biophysical and biological evaluation, a molecular docking analysis round was performed using noscapine as reference compound. The molecules featuring docking predicted binding affinity better than that of noscapine were then subjected to MTT assay against MCF7 cell line. The obtained results disclosed that all the selected triazole derivatives exhibited a remarkably lower cell viability compared to noscapine in the range of 20 μM in 48 h. In an attempt to correlate the biological activity with the ability to bind tubulin, the surface plasmon resonance (SPR) assay was employed. Compounds 8a, 8h, 9c, 9f and 9j were able to bind tubulin with affinity constant values in the nanomolar range and higher if compared to noscapine. Integrating computational predictions and experimental evaluation, two promising compounds (8h and 9c) were identified, whose relevant cytotoxicity was supposed to be correlated with tubulin binding affinity. These findings shed lights onto structural modifications of noscapine toward the identification of more potent cytotoxic agents targeting tubulin.
A Novel Class of N-Sulfonyl and N-Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells
Yong, Cassandra,Devine, Shane M.,Gao, Xuexin,Yan, Angelina,Callaghan, Richard,Capuano, Ben,Scammells, Peter J.
, p. 1968 - 1981 (2019)
Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N-methyl group in the 6′-position with a range of substituents, where N-ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N-sulfonyl and N-sulfamoyl noscapine derivatives. A number of these sulfonyl-containing noscapinoids demonstrated improved activities compared to noscapine. ((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline) (14 q) displayed sub-micromolar activities of 560, 980, 271 and 443 nM against MCF-7, PANC-1, MDA-MB-435 and SK-MEL-5 cells, respectively. This antiproliferative effect was also maintained against drug-resistant NCI/AdrRES cells despite high expression of the multidrug efflux pump, P-glycoprotein.
1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure
Yong, Cassandra,Devine, Shane M.,Abel, Anne-Catherine,Tomlins, Stefan D.,Muthiah, Divya,Gao, Xuexin,Callaghan, Richard,Steinmetz, Michel O.,Prota, Andrea E.,Capuano, Ben,Scammells, Peter J.
, p. 2882 - 2894 (2021/07/19)
Since the revelation of noscapine's weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6′, and 9′-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multi-functionalised noscapine derivatives that also possessed modifications previously shown to promote anti-proliferative activity in the 1-, 6′- and 9′-positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino-containing analogue 20 as potent cytotoxic agents with EC50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF-7) cells. Compound 20 also exhibited EC50 values of ADR/RES). We also conducted X-ray crystallography studies that yielded the high-resolution structure of 14 e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.
Identification of novel anti-cancer agents by the synthesis and cellular screening of a noscapine-based library
Nemati, Faezeh,Bischoff-Kont, Iris,Salehi, Peyman,Nejad-Ebrahimi, Samad,Mohebbi, Maryam,Bararjanian, Morteza,Hadian, Nasim,Hassanpour, Zahra,Jung, Yvonne,Schaerlaekens, Sofie,Lucena-Agell, Daniel,Oliva, María A.,Fürst, Robert,Nasiri, Hamid R.
, (2021/07/26)
Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z’ > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 μM and 1.5 μM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 μM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine.
An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine
Li, Jihui,Liu, Yongxiang,Song, Xinjing,Wu, Tianxiao,Meng, Jiaxin,Zheng, Yang,Qin, Qiaohua,Zhao, Dongmei,Cheng, Maosheng
, p. 7149 - 7153 (2019/09/30)
An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.
Synthesis, in-vitro antiprotozoal activity and molecular docking study of isothiocyanate derivatives
Al-Harrasi, Ahmed,Babanezhad Harikandei, Kosar,Bararjanian, Morteza,Ebrahimi, Samad Nejad,Kaiser, Marcel,Salehi, Peyman
, (2019/12/09)
Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC50 values between 0.4 and 1.0 μM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC50 = 0.7 μM). Compound 7h demonstrated the best antileishmanial activity with an IC50 value of 0.4 μM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC50s below 2.0 μM and SI between 2.7 and 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC50s in the range of 1.1–2.7 μM and SI values between 1.1 and 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC50 value of 1.9 μM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.
