Modified N,O-Nucleosides: Design, Synthesis, and Anti-tumour Activity

2014 ◽  
Vol 67 (4) ◽  
pp. 670 ◽  
Author(s):  
Loredana Maiuolo ◽  
Olga Bortolini ◽  
Antonio De Nino ◽  
Beatrice Russo ◽  
Riccardo Gavioli ◽  
...  
Keyword(s):  
Biological Activity ◽  
Partition Coefficient ◽  
Human Cancer ◽  
Aromatic Rings ◽  
Design Synthesis ◽  
Anti Tumour Activity ◽  
Tumour Activity

A preliminary library of modified N,O-nucleosides was prepared and tested on a selected number of human cancer lines that include SKOV3, SW480, and K562. Thymine, N-benzyl substituents, and aromatic rings contribute to an increase of the biological activity, up to 10–25 μM, that appeared also reliant on the calculated lipophilicity of the nucleosides, expressed as cLogP, where P represents the partition coefficient of a solute between n-octanol and water.

Targeting the oncogenic protein kinase Cι signalling pathway for the treatment of cancer

2007 ◽  
Vol 35 (5) ◽  
pp. 996-1000 ◽  
Author(s):  
A.P. Fields ◽  
L.A. Frederick ◽  
R.P. Regala
Keyword(s):  
Protein Kinase ◽  
Gene Amplification ◽  
Human Cancer ◽  
Signalling Pathway ◽  
Specific Gene ◽  
Phase I Clinical Trials ◽  
Effector Molecules ◽  
Anti Tumour Activity ◽  
Pb1 Domain ◽  
Tumour Activity

PKC (protein kinase C) isoenzymes are key signalling components involved in the regulation of normal cell proliferation, differentiation, polarity and survival. The aberrant regulation of PKC isoenzymes has been implicated in the development of many human diseases including cancer [Fields and Gustafson (2003) Methods Mol. Biol. 233, 519–537]. To date, however, only one PKC isoenzyme, the aPKC [atypical PKCι (protein kinase Cι)], has been identified as a human oncogene [Regala, Weems, Jamieson, Khoor, Edell, Lohse and Fields (2005) Cancer Res. 65, 8905–8911]. PKCι has also proven to be a useful prognostic marker and legitimate target for the development of novel pharmacological agents for the treatment of cancer. The PKCι gene resides at chromosome 3q26 and is a frequent target of tumour-specific gene amplification in multiple forms of human cancer. PKCι gene amplification in turn drives PKCι overexpression in these cancers. Genetic disruption of PKCι expression blocks multiple aspects of the transformed phenotype of human cancer cells including transformed growth in soft agar, invasion through Matrigel and growth of subcutaneous tumours in nude mice. Genetic dissection of oncogenic PKCι signalling mechanisms demonstrates that PKCι drives transformed growth by activating a PKCι → Rac1 → PAK (p21-activated kinase) → MEK [MAPK (mitogen-activated protein kinase) 1,2/ERK (extracellular-signal-regulated kinase) kinase] 1,2 signalling pathway [Regala, Weems, Jamieson, Copland, Thompson and Fields (2005) J. Biol. Chem. 280, 31109–31115]. The transforming activity of PKCι requires the N-terminal PB1 (Phox-Bem1) domain of PKCι, which serves to couple PKCι with downstream effector molecules. Hence, there exists a strong rationale for developing novel cancer therapeutics that target the PB1 domain of PKCι and thereby disrupt its interactions with effector molecules. Using a novel high-throughput drug screen, we identified compounds that can disrupt PB1–PB1 domain interactions between PKCι and the adaptor molecule Par6 [Stallings-Mann, Jamieson, Regala, Weems, Murray and Fields (2006) Cancer Res. 66, 1767–1774]. Our screen identified the gold compounds ATG (aurothioglucose) and ATM (aurothiomalate) as specific inhibitors of the PB1–PB1 domain interaction between PKCι and Par6 that exhibit anti-tumour activity against NSCLC (non-small-cell lung cancer) both in vitro and in vivo. Structural analysis, site-directed mutagenesis and modelling indicate that ATM specifically targets the PB1 domain of PKCι to mediate its anti-tumour activity [Erdogan, Lamark, Stallings-Mann, Lee, Pellechia, Thompson, Johansen and Fields (2006) J. Biol. Chem. 281, 28450–28459]. Taken together, our recent work demonstrates that PKCι signalling is required for transformed growth of human tumours and is an attractive target for development of mechanism-based cancer therapies. ATM is currently in Phase I clinical trials for the treatment of NSCLC.

scholarly journals Anti-Tumour Effect of two Persicaria Species Seeds on Colon and Prostate Cancers

2018 ◽  
Vol 11 (2) ◽  
pp. 635-644
Author(s):  
Ahmed Mohamed Mohamed Youssef ◽  
Zeinab Ahmed Said El-Swaify
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Cell Lines ◽  
Human Cancer ◽  
Gas Chromatography Mass Spectrometry ◽  
Active Constituents ◽  
Aerial Parts ◽  
Anti Tumour Activity ◽  
Chromatography Mass Spectrometry ◽  
Tumour Activity

The active constituents present in Persicaria salicifolia and Persicaria senegalensis seeds may possess anti-tumour activity. Therefore, P. salicifolia and P. senegalensis seeds were extracted and analysed to identify their active constituents. Phytochemical compounds exist in 50 % methanol extracts of P. salicifolia and P. senegalensis seeds were identified through High-Performance Liquid Chromatography (HPLC), Liquid Chromatography/ Mass Spectrometry (LC/MS), and Gas Chromatography-Mass Spectrometry (GC/MS). MTT assay was utilized to analyse the anti-tumour activity of P. salicifolia and P. senegalensis seeds compared to their aerial parts against CaCo-2 and PC3 cell lines. The constituents of Persicaria species seeds have phenolic acids, flavonoid, and lipid compounds. The cytotoxicity of aerial parts of P. salicifolia showed half maximal inhibitory concentration (IC50) of 1.1 ± 0.15 µg/ml and 0.5 ± 0.0011 µg/ml and the seeds were 0.6 ± 0.0018 µg/ml and 1.0 ± 0.009 µg/ml against PC3 and CaCO-2 cell lines, respectively. While, the aerial parts of P. senegalensis showed IC50 of 2.3 ± 0.03 µg/ml and 2.0 ± 0.03 µg/ml, and the seeds were 3.5 ± 0.06 µg/ml and 1.5 ± 0.03 µg/ml against PC3 and Caco-2, respectively. The results showed that there was a potential cytotoxicity of two Persicaria species seeds against two human cancer cell lines comparing to their aerial parts that have antitumor activity as it is confirmed by the literature.

Design, synthesis and anti-tumour activity of new pyrimidine-pyrrole appended triazoles

2019 ◽  
Vol 60 ◽  
pp. 87-96 ◽  
Author(s):  
Arunkumar Thiriveedhi ◽  
Ratnakaram Venkata Nadh ◽  
Navuluri Srinivasu ◽  
Yamini Bobde ◽  
Balaram Ghosh ◽  
...  
Keyword(s):  
Design Synthesis ◽  
Anti Tumour Activity ◽  
Tumour Activity

Synthesis and Anti – Tumour Activity of Novel Camptothecin – Bile Acid Analogues

2011 ◽  
Vol 8 (8) ◽  
pp. 698-703 ◽  
Author(s):  
Q.-Y. Li ◽  
Y. Gao ◽  
W. Qiu ◽  
Y.-G. Zu ◽  
L. Su ◽  
...  
Keyword(s):  
Bile Acid ◽  
Anti Tumour Activity ◽  
Tumour Activity

Design, Synthesis and Biological Activity of Aromatic Diketone Derivatives as HIV-1 Integrase Inhibitors

2015 ◽  
Vol 11 (2) ◽  
pp. 180-187 ◽  
Author(s):  
Liming Hu ◽  
Zhipeng Li ◽  
Zhanyang Wang ◽  
Gengxin Liu ◽  
Xianzhuo He ◽  
...  
Keyword(s):  
Biological Activity ◽  
Integrase Inhibitors ◽  
Design Synthesis ◽  
Hiv 1

Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety

2020 ◽  
Vol 16 (7) ◽  
pp. 958-968
Author(s):  
Yunrui Cai ◽  
Tong Chen ◽  
Huajian Zhu ◽  
Hongbin Zou
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Human Cancer ◽  
The Body ◽  
Human Breast ◽  
Design Synthesis ◽  
Human Carcinoma ◽  
Xenograft Models ◽  
New Compounds ◽  
Mcf 7

Background: The development of novel antineoplastic agents remains highly desirable. Objective: This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Methods: Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). Results: A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients. Conclusion: In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

scholarly journals Photochemical Reactivity of Naphthol-Naphthalimide Conjugates and Their Biological Activity

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3355
Author(s):  
Matija Sambol ◽  
Patricia Benčić ◽  
Antonija Erben ◽  
Marija Matković ◽  
Branka Mihaljević ◽  
...  
Keyword(s):  
Biological Activity ◽  
Rational Design ◽  
Human Cancer ◽  
Photophysical Properties ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Quinone Methide ◽  
Quantum Yields ◽  
Photochemical Reactivity ◽  
Human Cancer Cell Lines

Quinone methide precursors 1a–e, with different alkyl linkers between the naphthol and the naphthalimide chromophore, were synthesized. Their photophysical properties and photochemical reactivity were investigated and connected with biological activity. Upon excitation of the naphthol, Förster resonance energy transfer (FRET) to the naphthalimide takes place and the quantum yields of fluorescence are low (ΦF ≈ 10−2). Due to FRET, photodehydration of naphthols to QMs takes place inefficiently (ΦR ≈ 10−5). However, the formation of QMs can also be initiated upon excitation of naphthalimide, the lower energy chromophore, in a process that involves photoinduced electron transfer (PET) from the naphthol to the naphthalimide. Fluorescence titrations revealed that 1a and 1e form complexes with ct-DNA with moderate association constants Ka ≈ 105–106 M−1, as well as with bovine serum albumin (BSA) Ka ≈ 105 M−1 (1:1 complex). The irradiation of the complex 1e@BSA resulted in the alkylation of the protein, probably via QM. The antiproliferative activity of 1a–e against two human cancer cell lines (H460 and MCF 7) was investigated with the cells kept in the dark or irradiated at 350 nm, whereupon cytotoxicity increased, particularly for 1e (>100 times). Although the enhancement of this activity upon UV irradiation has no imminent therapeutic application, the results presented have importance in the rational design of new generations of anticancer phototherapeutics that absorb visible light.

scholarly journals Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates

MedChemComm ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 1905-1909 ◽  
Author(s):  
Faustine d'Orchymont ◽  
Jeannine Hess ◽  
Gordana Panic ◽  
Marta Jakubaszek ◽  
Lea Gemperle ◽  
...  
Keyword(s):  
Biological Activity ◽  
Antimalarial Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Derivatives Of

The design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the antimalarial mefloquine is described.

scholarly journals Potent anti‐angiogenesis and anti‐tumour activity of pegaptanib‐loaded tetrahedral DNA nanostructure

2019 ◽  
Vol 52 (5) ◽  
Author(s):  
Xueping Xie ◽  
Yuxin Zhang ◽  
Wenjuan Ma ◽  
Xiaoru Shao ◽  
Yuxi Zhan ◽  
...  
Keyword(s):  
Dna Nanostructure ◽  
Anti Tumour Activity ◽  
Tumour Activity
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