British Journal of Pharmacology p. 2287 - 2301 (2017)
Update date:2022-08-03
Topics:
Ciaglia, Elena
Grimaldi, Manuela
Abate, Mario
Scrima, Mario
Rodriquez, Manuela
Laezza, Chiara
Ranieri, Roberta
Pisanti, Simona
Ciuffreda, Pierangela
Manera, Clementina
Gazzerro, Patrizia
D'Ursi, Anna Maria
Bifulco, Maurizio
Background and Purpose: N6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than i6A. Experimental Approach: We designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein. Key Results: CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors. Conclusion and Implications: The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.
View MoreKA-SHING Business Trade Macau Co., Ltd.
Contact:00853-28430045
Address:23rd Floor, Block 3 La Cite, Areia Preta, Macao
Qida Chemical Co., Ltd.(expird)
Contact:+86-25-8776 0031
Address:3-2001 Jiaye Int'l Town, 158 Lushan Road,Nanjing, 210019, China
Suzhou Jingye Medicine & Chemical Co., Ltd
website:http://www.jingyechem.cn
Contact:+86-512-66658588
Address:No. 88, Sanlian Street, Jinfeng Road, Suzhou New District, Jiangsu Province, P. R. China
Contact:0086 371 65711996
Address:Jalan 4/3, Kawasan Perindustrian Serendah, 48000 Rawang,
Hefei TNJ chemical industry co.,ltd
website:https://www.tnjchem.com
Contact:+86-551-65418695
Address:B911 Xincheng Business Center, Qianshan Road, Hefei Anhui China
Doi:10.1021/jo01190a007
(1943)Doi:10.1002/jlac.19707350111
(1970)Doi:10.3987/COM-05-S(T)65
(2006)Doi:10.3184/174751917X14873588907729
(2017)Doi:10.1021/acs.orglett.5b03268
(2015)Doi:10.1039/c8ob02330a
(2019)