Abstract
An efficient method of thiol group introduction to the structure of common natural products and synthetic active compounds with recognized biological efficacy such genistein (1), 5,11-dimethyl-5H-indolo[2,3-b]quinolin (2), capecitabine (3), diosgenin (4), tigogenin (5), flumethasone (6), fluticasone propionate (7), ursolic acid methyl ester (8), and β-sitosterol (9) was developed. In most cases, the desired compounds were obtained easily via two-step processes involving esterification reaction employing S-trityl protected thioacetic acid and the corresponding hydoxy-derivative, followed by removal of the trityl-protecting group to obtain the final compounds. The results of our preliminary experiments forced us to change the strategy in the case of genistein (1), and the derivatization of diosgenin (4), tigogenin (5), and capecitabine (3) resulted in obtaining different compounds from those designed. Nevertheless, in all above cases we were able to obtain thiol-containing derivatives of selected biological active compounds. Moreover, a modelling study for the two-step thiolation of genistein and some of its derivatives was accomplished using the density functional theory (B3LP). A hypothesis on a possible reason for the unsuccessful deprotection of the thiolated genistein is also presented based on the semiempirical (PM7) calculations. The developed methodology gives access to new sulphur derivatives, which might find a potential therapeutic benefit.
Highlights
The sulfur atoms are important structural motifs presented in a number of biologically active natural β-lactam-antibiotics such as penicillin and fusaperazine as well as synthetic drugs, like amoxicillin, cefoxitin, and thienamicin for treatment in bacterial infections [1]
In present work we focused on developing a methodology to attach a thiomethylcarbonyl linker via ester or amide bonds in order to synthesize the thiol-containing derivatives of compounds 1–9 as promising substrates for a AuNPs-based drug delivery system
The treatment of 22 with this three-component cocktail led only to a decomposition of the starting material. We examined another mild detritylation method using p-toluenesulfonic acid, but the results were unsatisfactory again
Summary
The sulfur atoms are important structural motifs presented in a number of biologically active natural β-lactam-antibiotics such as penicillin and fusaperazine as well as synthetic drugs, like amoxicillin, cefoxitin, and thienamicin for treatment in bacterial infections [1]. The use of the thiol groups to link biologically active compounds to gold nanoparticles is well known and established [5,6]. It is known, that such conjugates may improve therapeutic efficacy of many drugs by: (i) transporting the drug directly to the target/receptor, (ii) increasing solubility in water, (iii) stability, (iv) bioavailability, and Molecules 2020, 25, 3470; doi:10.3390/molecules25153470 www.mdpi.com/journal/molecules (v) by increasing the cell membrane permeability [7].
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