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

Herein we report the synthesis of new water-soluble vitamin B12 prodrugs bearing metal complexes at the β-upper side of the cobalt center. A total of three derivatives with the general design {Co–C[triple bond, length as m-dash]C-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 B12. This compound further served to prepare a dual luminescent probe by orthogonal synthesis with M = ((HCCbpy)Ru(bpy)2)Cl2 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

Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS) Plasmodium falciparum strains

Evaluation of the potential of cobalamin derivatives bearing ru(ii) polypyridyl complexes as photosensitizers for photodynamic therapy

The current photosensitizers (PSs) for photodynamic therapy (PDT) lack selectivity for cancer cells. To tackle this drawback, in view of selective cancer delivery, we envisioned conjugating two ruthenium polypyridyl complexes to vitamin B12 (Cobalamin, Cbl) to take advantage of the solubility and active uptake of the latter. Ultimately, our results showed that the transcobalamin pathway is unlikely involved for the delivery of these ruthenium‐based PDT PSs, emphasizing the difficulty in successfully delivering metal complexes to cancer cells

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

This communication describes the anti-platelet effects of a new class of cis-rhenium(II)- dicarbonyl-vitamin B12 complexes (B12-ReCORMs) with tuneable CO releasing properties

Antiplasmodial activity and in vivo bio-distribution of chloroquine molecules released with a 4-(4-ethynylphenyl)-triazole moiety from organometallo-cobalamins

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide- functionalized drugs which, after coupling to the vitamin, are released with a 4-(4- ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine- sensitive (CQS) Plasmodium falciparum strains

Cytotoxicity of Mn-Based photoCORMs of Ethynyl-α-Diimine Ligands Against Different Cancer Cell Lines: The Key Role of CO-Depleted Metal Fragments

A series of fac-[Mn(CO)3]+ complexes bearing 4-ethynyl-2,2\u27-bipyridine and 5-ethynyl-1,10-phenanthroline α-diimine ligands were synthetized, characterized and conjugated to vitamin B12, previously used as a vector for drug delivery, to take advantage of its water solubility and specificity toward cancer cells. The compounds act as photoactivatable carbon monoxide-releasing molecules (photoCORMs) rapidly liberating on average ca. 2.3 equivalents of CO upon photo-irradiation. Complexes and conjugates were tested for their anticancer effects, both in the dark and following photo-activation, against breast cancer MCF-7, lung carcinoma A549 and colon adenocarcinoma HT29 cell lines as well as immortalized human bronchial epithelial cells 16HBE14o- as the non-carcinogenic control. Our results indicate that the light-induced cytotoxicity these photoCORMs can be attributed to both their released CO and to their CO-depleted metal fragments (i-photoCORMs) including liberated ligands.<br /

Cytotoxicity of Mn-based photoCORMs of ethynyl-α-diimine ligands against different cancer cell lines: The key role of CO-depleted metal fragments

A series of tricarbonyl manganese complexes bearing 4-ethynyl-2,2′-bipyridine and 5- ethynyl-1,10-phenanthroline α-diimine ligands were synthetized, characterized and conjugated to vitamin B12, previously used as a vector for drug delivery, to take advantage of its water solubility and specificity toward cancer cells. The compounds act as photoactivatable carbon monoxide-releasing molecules rapidly liberating on average ca. 2.3 equivalents of CO upon photo-irradiation. Complexes and conjugates were tested for their anticancer effects, both in the dark and following photo-activation, against breast cancer MCF-7, lung carcinoma A549 and colon adenocarcinoma HT29 cell lines as well as immortalized human bronchial epithelial cells 16HBE14o- as the non-carcinogenic control. Our results indicate that the light-induced cytotoxicity these molecules can be attributed to both their released CO and to their CO-depleted metal fragments including liberated ligands

Evaluation of the Potential of Cobalamin Derivatives Bearing Ru(II) Polypyridyl Complexes as Photosensitisers for Photodynamic Therapy

International audienceThe current photosensitizers (PSs) for photodynamic therapy (PDT) lack selectivity for cancer cells. To tackle this drawback, in view of selective cancer delivery, we envisioned conjugating two ruthenium polypyridyl complexes to vitamin B12 (Cobalamin, Cbl) to take advantage of the solubility and active uptake of the latter. Ultimately, our results showed that the transcobalamin pathway is unlikely involved for the delivery of these ruthenium-based PDT PSs, emphasizing the difficulty in successfully delivering metal complexes to cancer cells

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

This communication describes the anti-platelet effects of a new class of cis-rhenium(II)-dicarbonyl-vitamin B12 complexes (B12-ReCORMs) with tuneable CO releasing properties

Antiplasmodial activity and in vivo bio-distribution of chloroquine molecules released with a 4-(4-ethynylphenyl)-triazole moiety from organometallo-cobalamins

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS) Plasmodium falciparum strains