Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via transcobalamin-mediated uptake

Abstract

Herein we report the synthesis of new water-soluble vitamin B 12 prodrugs bearing metal complexes at the β-upper side of the cobalt center. A total of three derivatives with the general design {Co-CuC-bpy-M}, where M represents a cytotoxic metal complex, were prepared and tested for their cytotoxicity against MCF-7 breast cancer cells. The choice of the metal was oriented on the eminent Pt and promising Ru and Re species to demonstrate the general applicability of the approach. The recognition of the derivatives by transcobalamin was demonstrated by competitive displacement assays using rhodamine labeled B 12 .This compound further served to prepare a dual luminescent probe by orthogonal synthesis with M = ((HCCbpy)Ru(bpy) 2 )Cl 2 and to perform in vitro assays. Cellular imaging experiments allowed us to observe the different compartmentalization of both dyes and thus prove that the species follow the natural cobalamin uptake as well as the self-triggered release of the β-upper complex.

Synthetic Approaches toward Vitamin B12 Conjugates

“…The aforementioned approach was successfully applied by Zobi et al. for the synthesis of water‐soluble cobalamin derivatives with cytotoxic metal complexes 11 a – c (Scheme ) …”

“…(CN)Cbl ( 1 a ) was reacted with bipyridyl Pt, Re, and Ru complexes bearing a terminal alkyne moiety in the presence of CuOAc and DBU giving conjugates 12 a , 12 b , and 12 c in 61%, 78%, and 73% yield, respectively. These were found to be active against MCF‐breast cancer cells and the metal complexes were entirely released under reductive conditions …”

Antivitamin B12 Inhibition of the Human B12‐Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate

“…[22] Studies of B 12 antivitamins and related Cbls as anticancer agents have also raised interest. [5,8,23] Indeed, 3 is apromising, light-stable alternative to the antivitamin B 12 1, [6,10] and might also be av ery versatile biomedical tool. Long-term experiments with animals in close to natural habitats [6] may be feasible with 3,a nd will specifically help in expanding our knowledge of the physiological effects of B 12 deficiency, and in reducing the gap in understanding its downstream pathophysiological effects in humans.…”

Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release

“…This approach seemed to be reasonable because small variations in the coordination sphere of rhenium complexes have profound consequences on the electrochemistry, water stability and CO releasing properties of the dicarbonyl core. 17 B 12 appeared to be attractive as ligand for the rhenium-based CORM entity mainly because of two reasons: (a) its cellular uptake properties can be exploited to deliver therapeutic agents specifically at disease sites; [18][19][20] (b) the electronic properties at the cobalt center can be selectively modified by introducing structural modifications at the corrin-p-system. [21][22][23][24] Having the general design of the B 12 -ReCORMs derivatives in mind (Scheme 1), we synthesized and studied first a series of six cobalamins for coordinating them later to 1 (Scheme 2A).…”