“Click and go”: simple and fast folic acid conjugation

Abstract

Folic acid targeting by functionalization of the terminal γ-carboxylic acid is one of the most important strategies to selectively deliver chemotherapeutics and dyes to cancer cells which overexpress folate receptors. However, conjugation of folic acid is limited by its unique solubility and by selectivity issues imposing the need for expensive preparative reverse-phase chromatographic purification to isolate γ-folate conjugates. Herein is provided a novel synthetic tool for the synthesis of new folic acid conjugates with excellent γ-purity based on strain-promoted alkyne-azide cycloadditions with a γ-folate-cyclooctyne conjugate 3. To demonstrate the potential of this methodology several new folate conjugates were synthesized with high γ-purity and without using any type of chromatographic purification by reacting conjugate 3 with several fluorescent probes, polymers and siliceous materials bearing azide. In addition, the cycloaddition reaction between conjugate 3 and an azido-derived fluorescent dye was successfully performed in cellular media leading to an increase of fluorescence in the cells which overexpress folate receptors (NCI-H460).

Towards potent but less toxic nanopharmaceuticals – lipoic acid bioconjugates of ultrasmall gold nanoparticles with an anticancer drug and addressing unit

“…The preparation of LAFA (Scheme 1) starts from regioselective coupling of g-carboxylic function of FA with N-Bocethylenediamine in conditions described by Trindade and coworkers. 21 Next, Boc-group deprotection followed by the coupling of the resulting amine with N-hydroxysuccinimidyl liponate (LA-NHS) leads to a good yield of LAFA. The LA-NHS was obtained by the reaction of LA with N,N-disuccinimidyl carbonate (NHS) and N,N-diisopropylethylamine in deoxygenated acetone.…”

One Scaffold, Many Possibilities – Copper(I)‐Catalyzed Azide–Alkyne Cycloadditions, Strain‐Promoted Azide–Alkyne Cycloadditions, and Maleimide–Thiol Coupling of Ruthenium(II) Polypyridyl Complexes

“…The use of the strain‐activated cyclooctyne motif promotes “click” chemistry without the need for a catalyst; hence, SPAAC is a valuable bioorthogonal alternative. Commercially available cyclooctyne derivatives can be employed for the functionalization of biomolecules . Therefore, we focused our efforts on the development of ruthenium photosensitizers with stable pendant azide groups to undergo SPAAC, and these compounds also provide the photophysical properties for potential PDT applications.…”

Modular Assembly of Reversible Multivalent Cancer‐Cell‐Targeting Drug Conjugates

“…[9] Next, we addressed the preparation of the remaining components of the boronated core.F ollowing reported methodologies,t he hydroxyacetophenone and the aminophenol components were modified to incorporate asmall Peg chain (compound 6)and an azide function (compound 7)for postfunctionalization with folate and cyclooctyne units (see structure 9 with af olic acid moiety attached;S cheme 3). [10] Thea ssembly reaction was attempted with the components Btz, 6,and 7,but the desired product was never formed. We reasoned that this lack of reactivity might be due to ac ombination of steric constraints imposed by the Btz structure and the Peg chain in 6 (see the Supporting Information).…”