Towards^99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study

Abstract

Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = (99m)Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the (99m)Tc compounds are prospective imaging agents.

Radioactive Transition Metals for Imaging and Therapy

“…Similarly, Alberto and co-workers functionalized Re­(CO) 3 with doxorubicin to potentiate its anticancer effects and observed organelle selectivity. , The corresponding 99m Tc analogue takes advantage of the emission of Auger electrons to impart additional cytotoxic activity (Figure ). Other Re/Tc-based small molecules developed for targeted applications include β-amyloid targeted small molecules by the groups of Donnelly and Pelecanou. , While the rhenium complex visualizes plaques in brain slices by fluorescence imaging, the corresponding 99m Tc complex has the potential to act as an in vivo SPECT tracer, although it exhibited only moderate brain uptake in rodents.…”

“…195 Similarly, Alberto and co-workers functionalized Re(CO) 3 with doxorubicin to potentiate its anticancer effects and observed organelle selectivity. 196,197 The corresponding 99m Tc analogue takes advantage of the emission of Auger electrons to impart additional cytotoxic activity (Figure 8). Other Re/Tcbased small molecules developed for targeted applications include β-amyloid targeted small molecules by the groups of Donnelly and Pelecanou.…”

“…Aalbersberg et al recently reported that irradiation of >96% isotopically enriched 194 Pt at the Petten High Flux Reactor produced 195m Pt with a specific activity of 33 MBq (890 μCi)/mg (6.4 GBq (170 mCi)/mmol). 293 Several radionuclides other than 195m Pt are also produced during the production of 195m Pt including 197 Pt, 191 Pt, 192 Ir, 194 Ir, 198 Au, and 199 Au, with 195m Pt only comprising 62% of the radioactivity at the end of irradiation. The half-lives of 197 Pt and 194 Ir are relatively short, so allowing 2 days of decay postirradiation increases 195m Pt to 77% of the total radioactivity.…”

“…293 Several radionuclides other than 195m Pt are also produced during the production of 195m Pt including 197 Pt, 191 Pt, 192 Ir, 194 Ir, 198 Au, and 199 Au, with 195m Pt only comprising 62% of the radioactivity at the end of irradiation. The half-lives of 197 Pt and 194 Ir are relatively short, so allowing 2 days of decay postirradiation increases 195m Pt to 77% of the total radioactivity. Higherspecific-activity 195m Pt can be prepared by the 192 Os(α,n) 195m Pt reaction using 18−24 MeV α particles or by the 197 Au-(γ,np) 195m Pt reaction.…”

Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2

“…Moreover, previously reported catalytic reductive alkylation systems have rarely been applied to amines bearing multiple carboxyl, hydroxyl, and/or additional amino groups. ,, Indeed, bioactive molecules often contain benzylamine or the corresponding heteroaromatic moieties together with carboxyl, hydroxyl, and/or amino groups (Figure ). , The development of a practical and environmentally benign reductive alkylation system that enables direct access to these multiply functionalized amines is thus of high interest . Herein, we report the reductive alkylation of primary amines with H 2 , which proceeds via a tandem reaction that consists of an organoborane-catalyzed formation of an imine, and a subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). ,− A variety of multiply substituted amines were efficiently functionalized using the present catalyst system, in which H 2 O was generated as the sole byproduct (Scheme ).…”