|CHELLAN, PRINESSA - University Of Warwick|
|AVERY, VICKY - Griffiths University|
|DUFFY, SANDRA - Griffiths University|
|LAND, KIKWOOD - Pacific University|
|Kim, Jong Heon|
|ROMERO-CANELÓN, ISOLDA - University Of Warwick|
|SADLER, PETER - University Of Warwick|
Submitted to: Inorganic Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/21/2021
Publication Date: 4/4/2021
Citation: Chellan, P., Avery, V.M., Duffy, S., Land, K., Tam, C.C., Kim, J., Cheng, L.W., Romero-Canelón, I., Sadler, P.J. 2021. Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin. Inorganic Biochemistry. 219. Article 111408. https://doi.org/10.1016/j.jinorgbio.2021.111408.
Interpretive Summary: Artemisinin (ART) is a natural product extracted from the Chinese herb plant. The first report of its potential as an antimalarial agent was in 1979, and ART is still in use today as part of the World Health Organisation’s (WHO) recommended ART combination therapy group of drugs used for treatment of uncomplicated malaria. ART can readily be derivatized, allowing generation of numerous compound libraries with antitumoral and/or anti-parasitic activity. Many reports demonstrate the potential of organometallic ART complexes as new therapeutics. In this study, we have investigated the activity of metallic and ART complexes towards various human cancer cell lines and parasite strains. The obtained anti-parasitic complexes inhibited parasite growth at very low (nanomolar) concentrations and display higher or comparable anticancer activity to the clinical drug cisplatin.
Technical Abstract: Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new artemisinin ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1 – 6) containing cyclopentadienyl, (Cp*), tetramethylphenylcyclo-pentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated ’bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the 3D7 (asexual chloroquine sensitive), Dd2 (asexual chloroquine resistant) strains and late stage gametocytes (LSGNF54) parasite strains, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin, however no selectivity for the resistant Pf strain was observed. As anticancer agents, several of the complexes showed high inhibitory effects. Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 with the tetramethylbiphenylcyclopentadienyl ligand emerged as the most promising candidate for future studies.