- Heterofunctionalized amino acids for PET imaging
The synthesis of new heterofunctionalized amino acids with trifluoroborate or fluorosilane groups has been developed and provides modularity on the side chain and around boron or silicon atoms. These functional groups serve as fluoride traps for 18-fluoride radiolabeling for PET imaging. Radiolabeling led to B-18F and Si-18F amino acids with specific activities up to 400GBq/μmol. (Eur. J. Org. Chem. 2017: doi.org/10.1002/ejoc.201701170 ; J. Org. Chem. 2015: doi.10.1021/acs.joc.5b00246)
- Organometallic Theranostics
We are interested in the development of bimodal organometallic complexes that are able to gather the properties of metallodrugs and of imaging probes. We developed three kind of this trackable therapeutics: optical theranostics, radiotheranostics, and smart theranostics. Concerning optical theranostics, unprecedented BODIPY-phosphine ligands were synthetized and used as a valuable tool for imaging gold-, ruthenium- and osmium-complexes in vitro. This enabled to observe the accumulation site of these cytotoxic complexes in cancer cells by confocal fluorescence microscopy (Fig. 1a). The same philosophy was applied to obtain detectable coumarin-functionalized N-heterocyclic carbene (NHC) gold complexes (Fig. 1b). In parallel, phosphines were also grafted onto a porphyrin backbone to obtain cytotoxic theranostic palladium-gold complexes that display a part of their luminescence in the therapeutical window (near infrared) (Fig. 1c).
More recently, we developed a fluorescent platform enabling the easy synthesis of a large family of optical theranostics, and we designed water soluble and water stable Ti-based optical and radio-theranostics.
A family of radiotheranostic complexes, designed for SPECT detection, was also synthesized (Fig. 1d). Cold isotopes coordination was performed in our group for preliminary studies, while radiolabelling of these molecules and biological tests were performed through an international collaboration with the Technological and Nuclear Institute of Lisbon (P. Campello). These compounds appeared to be stable for days with an interesting cytotoxicity, and general toxicity and biodistribution were evaluated on healthy mice.
Following the achievement of these promising results, we decided to developed smart theranostics. More specifically, optical gold-based theranostics were obtained in the group using the coumarin scaffold as a synthetic platform. Through a local collaboration (A. Bettaïeb, C. Paul, EPHE, Dijon), their cytotoxicity and ability to trigger the production of reactive oxygen species (ROS) were evaluated. Their biodistribution was also studied in vitro using two-photon fluorescence microscopy and in vivo on healthy zebrafish larvae, revealing accumulation in the digestive system together with cytotoxicity on colon cancer cells (Fig. 1b). Very interestingly, the fluorescence being only observed when the coumarin-phophine is coordinated on the gold center, this "smartprobes" helped to demonstrate the stability of the organometallic complex in vivo. One of this smart theranostics was demonstrated to be non-toxic for healthy mice and show anticancer activity on tumor bearing mice.
Figure 1. Examples of Organometallic Theranostics developed in the group.
- Anticancer agents
Metal-based anticancer agents
Since our preliminary report in 2010 on bimetallic titanocene-phosphine based titanium-ruthenium complexes that exert higher cytotoxicity than their two independent metallic fragments (synergetic effect), we have implemented this family with the synthesis and study of even higher cytotoxic titanium-gold complexes (Fig. 3a). With the success of this early-late association, we also explored late-late metal bimetallic complexes. Gold-platinum derivatives were thus synthesized using a ditopic phosphine-bipyridylamine assembling ligand (Fig. 3b). Their cytotoxicity on cancer cells was found to be in the range of the one of cisplatin or higher, correlating well with their uptake in cells. Nonetheless, no DNA-adduct could be detected, thus suggesting a different mode of action than cisplatin. We have also developped the synthesis of a NHC ligand bearing an activatable ester that allows its linkage to other ligand-types like phosphines. Using this strategy, homobimetallic gold complexes and heterobimetallic gold-ruthenium and gold-copper complexes were obtained with in vitro antiproliferative properties up to 25 times higher than their monometallic counterpart (Fig. 9c). Taking advantage of our experience in the synthesis of NHC-complexes, we have also designed and studied cafeine- or more generally xanthine-derived NHC monometallic gold complexes (Fig. 9d). Although exhibiting moderate cytotoxicity on cancer cells, they nonetheless revealed a noteworthy high selectivity, with some of them being almost non toxic on healthy cells and ex vivo precision cut tissue slices (collaboration with the University of Groningen, A. Casini). In collaboration with the universities of Sassari (A. M. Cinellu) and Groningen (A. Casini), other carbon-gold bond containing complexes were studied (Fig. 3c). These cyclometallated compounds were found to inhibit the zinc finger enzyme PARP-1, involved in the DNA Damage Response (DDR), in the nM range.
Figure 2. Examples of potential anticancer agents developped in our group.
Synthesis and study of biological activities of trans-resveratrol derivatives
Background - The presence of trans-resveratrol in our daily diet is well-known. Although this natural polyphenol offers a broad range of biological activities, we focus on the synthesis of trans-resveratrol derivatives in the aim to better target and to improve some of these biological properties.
Results – Three series of 4-hydroxystilbenes were prepared and their biological activities were evaluated towards cancer colon cells SW480, hepatic tumor cells (HepG2) and two pathogen agents grapevine (Plasmora viticola and Botrytis cinerea).
In each series, several trans-resveratrol derivatives display a higher activity than the parent molecule towards tumor cells SW480 and HepG2 as well as pathogen agents grapevine.
People involved: C. Balan (AT uB), E. Bodio (MCF uB, HDR), R. Malacea-Kabbara (CR CNRS, HDR), M. Piquet (MCF uB), P. Le Gendre (PR uB), J. Roger (MCF uB), D. Vervandier-Fasseur (MCF uB, HDR)..