Novel organo-osmium(ii) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans

Abstract

This work reports the synthesis and characterization of some novel osmium(II) complexes with potential as anticancer drugs tested in vitro and in vivo. The complexes have a structure [(η⁶-p-cym)Os(C^N)(X)]^0/+, where the C^N ligand is deprotonated 2-phenylpyridine (ppy) or 4-(2-pyridin)benzaldehyde (ppy-CHO) and X is chloride, pyridine (py) or the pyridine derivative 4-NMe₂-py. The in vitro cytotoxic studies showed that complexes [(η⁶-p-cym)Os(C^N)(4-NMe₂-py)]⁺ (C^N = ppy 2a and ppy-CHO 5a) exerted effective antiproliferative activity towards both cisplatin-sensitive ovarian cancer cells (A2780) and cisplatin-resistant cells (A2780cis). The mechanism underlying the antiproliferative effects in vitro was studied showing a reduction of proteosynthesis up to 58% and an increase of apoptosis modulated by caspase-3. Model animal Caenorhabditis elegans was used to estimate the effects of 2a and 5a and the in-house 4-NMe₂-py Ru(II) analogue 5bin vivo. Compounds 2a, 5a and 5b were able to reduce tumor growth up 32.2%, 19% and 30%, respectively in the tumoral strain JK1466 and presented low toxicity in both tumoral and wild-type strains. The mechanistic study using reporter gene expression showed that 2a, 5a and 5b were able to maintain the reactive oxygen species (ROS) levels in the animals by increased expression of the mitochondrial superoxide dismutase 3 (SOD-3), an indication that they were able to regulate oxidative stress genes specifically. Interestingly the three complexes showed a similar mechanism of action, suggesting that the identity of the metal ion does not matter and the effect is more related to the whole structure of the complex. Worthy of note, cisplatin treatment produced elevated ROS levels in the animals and induced the expression of glutathione transferase 4 (GST-4) suggesting different mechanisms of action for the two complexes. Altogether the results showed that osmium(II) complexes can be potential candidates in the search for novel chemotherapeutic drugs.