Abstract
The binding sites of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with tRNA were located, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Different binding sites are involved in drug-tRNA adducts with DOX located in the vicinity of A-29, A-31, A-38, C-25, C-27, C-28, G-30 and U-41, while FDOX bindings involved A-23, A-44, C-25, C-27, G-24, G-42, G-53, G-45 and U-41 with similar free binding energy (-4.44 for DOX and -4.41 kcal/mol for FDOX adducts). Spectroscopic results showed that both hydrophilic and hydrophobic contacts are involved in drug-tRNA complexation and FDOX forms more stable complexes than DOX with K DOX-tRNA = 4.7 (±0.5)×104 M−1 and K FDOX-tRNA = 6.3 (±0.7)×104 M−1. The number of drug molecules bound per tRNA (n) was 0.6 for DOX and 0.4 for FDOX. No major alterations of tRNA structure were observed and tRNA remained in A-family conformation, while biopolymer aggregation and particle formation occurred at high drug concentrations.
Highlights
Anthracycline antibiotics such as doxorubicin and its derivatives (Fig. 1) are extensively used as chemotherapeutic agents for the treatment of several types of cancers including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers [1]
We report the structural analysis of tRNA complexes with DOX and FDOX by FTIR, CD, fluorescence spectroscopic methods and molecular modeling
Materials Doxorubicin hydrochloride was generously provided by Pharmacia/Farmitalia Carlos Erba, Italy and N-(trifluoroacetyl) doxorubicin was synthesized according to the published methods [14,15]
Summary
Anthracycline antibiotics such as doxorubicin and its derivatives (Fig. 1) are extensively used as chemotherapeutic agents for the treatment of several types of cancers including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers [1]. While doxorubicin intercalation with DNA duplex is well investigated [4], less is known about the effect of this antitumor drug on RNA structure. A comparative study of polynucleotides, DNA, RNA and nucleosomes with anthracycline antibiotics has been reported [5] and the effect of antibiotics on RNA synthesis and cell growth is investigated [6,7,8]. Even though much is known about the interaction of anthracyclines with DNA [2], the binding sites of antibiotics with RNA are not well characterized. It was of interest to locate the binding sites of doxorubicin with tRNA and the effect of drug complexation on RNA structure and dynamic. This comprehensive structural analysis of doxorubicin-tRNA adducts could have major biological and biochemical implications
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