Karen Ochoa Lara

Complexation Studies of Nucleotides by Tetrandrine Derivatives Bearing Anthraquinone and Acridine Groups

Water soluble dicationic cyclophane-type macrocycles bearing two anthraquinone (1) or two acridine groups (2) have been prepared by chemical modification of S,S-(+)-tetrandrine. Complexation of nucleotide anions (mono- di- and triphosphates) and D/L phenylalanine by tetrandrine derivatives has been studied by UV-Visible and fluorescence titrations in water. Association of nucleotides to semi-synthetic hosts 1 and 2 increases with increasing guest charge in the series AMP2 − < ADP3 − < ATP4 − . It was demonstrated for the 1- ATP and ADP complexes that association strength is increased in the absence of salt (NaCl). Besides, receptor 1 shows a slight preference for the complexation of UMP over nucleotides containing A (adenine), G (guanine), C (cytosine) or T (thymine) as bases. The major forces stabilizing the complexes result from ion pairing between the charged groups of host and guest and from stacking or hydrophobic interactions. Receptor 1 displayed chiral recognition towards D/L phenylalanine.

Recognition of α-amino acid derivatives by N,N′-dibenzylated S,S-(+)-tetrandrine

Complexation of free and N-acetylated α-amino acid anions (Gly, Ala, Phe) and some structurally related guests by a dicationic cyclophane-type N,N′-dibenzylated chiral derivative of a bisisoquinoline macrocyclic alkaloid S,S-(+)-tetrandrine (DBT) has been studied by 1H-NMR titrations in D2O. In contrast to other macrocyclic hosts like cyclodextrins and calixarenes, DBT shows highest affinity and large enantioselectivity (K(S)/K(R) ≥ 10) toward smaller N-acetylalanine and binds larger phenylalanine derivatives more weakly and non-selectively. With 1,2,3,4-tetrahydroisoquinoline-3-carboxylate, a rigid analog of phenylalanine, binding again becomes enantioselective with K(S)/K(R) = 3.8. The binding specificity of DBT is rationalized on the basis of molecular mechanics calculations.

Synthesis, spectroscopic, physicochemical and structural characterization of tetrandrine-based macrocycles functionalized with acridine and anthracene groups: DNA binding and anti-proliferative activity

In this work, we report on the synthesis of two new mono-alkylated tetrandrine derivatives with acridine and anthracene units, MAcT and MAnT. The compounds were fully characterized by physicochemical techniques and single-crystal X-ray diffraction analysis. In addition, both derivatives were studied as nucleotide receptors and double-stranded DNA binders in aqueous phosphate buffer at pH = 7.2 using UV-vis and fluorescence spectroscopy. According to the molecular recognition studies, MAcT and MAnT exhibit high affinity (K ∼ 105 M-1) and selectivity for ds-DNA, presumably in an intercalation mode. Finally, the anti-proliferative effects of the tetrandrine derivatives on different cancer cell lines were explored, revealing promising activities. Particularly, the mono-anthracene tetrandrine derivative MAnT showed an IC50 of 2.74 μg/mL on the HeLa cervical cancer cell line, representing a value 3.3 times smaller than that obtained for unsubstituted tetrandrine. Examination of the cytotoxic effects on the HeLa cell line by inverted microscopy suggests that the cell death mechanism consists basically in apoptosis. The molecular modelling of three ds-DNA-MAcT complexes, suggested that the macrocycles may use an intercalation binding mode towards DNA. MAcT is predicted to bind into the major groove of the ds-DNA providing non-covalent interactions such as electrostatic, van der Waals and hydrophobic interactions that lead to selectivity. Overall experimental data supports the mode of action of MAnT and MAcT as cytotoxic compounds against cancer cell lines via a DNA interaction mechanism.