Designing model imino bifunctional chelators for radiopharmaceuticals – in vitro antitumor activity, photoluminescence and structural analysis

Five imino salicylidene based bifunctional chelators were developed in order to act as a multipurpose ligand system. The chelators, namely 5-methyl-2-(1,2,4-triazol-3-yliminomethyl)phenol, 2-(9-ethylcarbazol-3-yliminomethyl)-5-methylphenol, 2-[(2-imidazol-4-yl)ethyliminomethyl]-5-methylphenol, 2-[(2-indol-3-yl-ethyl)iminomethyl]-5-methylphenol and 2-[2-(4-hydroxyphenyl)ethyliminomethyl]-5-methylphenol, all of which contain a biological directing functional group on the imine moiety, were investigated via crystallographic and DFT structural studies. Synthesis, in vitro cell testing and photoluminescence are reported indicating specific quantum yields and the respective suitability for radiopharmaceutical development.http://rsc.li/njc2019-04-07hj2019Pharmacolog

A cytotoxic bis(carbene)gold(I) complex of ferrocenyl complexes: Synthesis and structural characterisation

The N-heterocyclic carbene (NHC) precursors 1-[(E)-2-butenyl]-3-(4- ferrocenylphenyl)imidazolium bromide (2) and 1-[(E)-2-butenyl]-3-(4- ferrocenylphenyl)imidazolium tetrafluoroborate (3) were derived from 1-(4-ferrocenylphenyl)imidazole. Ferrocenyl complex 3 reacts with Ag 2O and chloro(dimethylsulfide)gold(i) in the presence of tetraethylammonium chloride to produce the mixed metal species bis{1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)-2H-imidazol-2-ylidene}gold(i) tetrafluoroborate (4). Single crystal X-ray structure analyses of 1, 3 and 4 indicate that the NCHN-hydrogen in 3 is hydrogen bonded to the BF 4- anion [C(H1)⋯F, 3.265(4) Å], as is also reflected in the position of its 1H NMR chemical shift. Cytotoxicity studies show that complex 4 is selective for cancer cells and active against the tumour cell lines Jurkat and MCF 7. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.The N-heterocyclic carbene (NHC) precursors 1-[(E)-2-butenyl]-3-(4- ferrocenylphenyl)imidazolium bromide (2) and 1-[(E)-2-butenyl]-3-(4- ferrocenylphenyl)imidazolium tetrafluoroborate (3) were derived from 1-(4-ferrocenylphenyl)imidazole. Ferrocenyl complex 3 reacts with Ag 2O and chloro(dimethylsulfide)gold(i) in the presence of tetraethylammonium chloride to produce the mixed metal species bis{1-[(E)-2-butenyl]-3-(4-ferrocenylphenyl)-2H-imidazol-2-ylidene}gold(i) tetrafluoroborate (4). Single crystal X-ray structure analyses of 1, 3 and 4 indicate that the NCHN-hydrogen in 3 is hydrogen bonded to the BF 4- anion [C(H1)⋯F, 3.265(4) Å], as is also reflected in the position of its 1H NMR chemical shift. Cytotoxicity studies show that complex 4 is selective for cancer cells and active against the tumour cell lines Jurkat and MCF 7. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.ArticleArticl

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist’s arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors’ laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10- to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs