Abstract
Fluorescence properties of two new potential antitumoral tetracyclic thieno[3,2-b]pyridine derivatives were studied in solution and in liposomes of DPPC (dipalmitoyl phosphatidylcholine), egg lecithin (phosphatidylcholine from egg yolk; Egg-PC) and DODAB (dioctadecyldimethylammonium bromide). Compound 1, pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, exhibits reasonably high fluorescence quantum yields in all solvents studied (0.20 ≤ ΦF ≤ 0.30), while for compound 2, 3-[(p-methoxyphenyl)ethynyl]pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, the values are much lower (0.01 ≤ ΦF ≤ 0.05). The interaction of these compounds with salmon sperm DNA was studied using spectroscopic methods, allowing the determination of intrinsic binding constants, Ki = (8.7 ± 0.9) × 103 M-1 for compound 1 and Ki = (5.9 ± 0.6) × 103 M-1 for 2, and binding site sizes of n = 11 ± 3 and n = 7 ± 2 base pairs, respectively. Compound 2 is the most intercalative compound in salmon sperm DNA (35%), while for compound 1 only 11% of the molecules are intercalated. Studies of incorporation of both compounds in liposomes of DPPC, Egg-PC and DODAB revealed that compound 2 is mainly located in the hydrophobic region of the lipid bilayer, while compound 1 prefers a hydrated and fluid environment.
Highlights
Liposomes are among technological delivery developments for chemotherapeutic drugs in the treatment of cancer
Liposomes are closed spherical vesicles consisting of a lipid bilayer that encapsulates an aqueous phase in which hydrophilic drugs can be stored, while water insoluble compounds can be incorporated in the hydrophobic region of the lipid bilayer [4]
The higher hydrophobic character of compound 2, promoted by the functionalization of the pyridine with a triple bond linked to a p-methoxyphenyl group, may justify this behaviour. As both compounds 1 and 2 are neutral molecules, the high fa values indicate that the main type of interaction with the nucleic acid must be the binding to DNA grooves [28]. Fluorescence experiments of both compounds encapsulated in liposomes of Dipalmitoyl phosphatidylcholine (DPPC), dioctadecyldimethylammonium bromide (DODAB) and egg yolk phosphatidylcholine (Egg-PC) were carried out (Figure 8), in both gel and liquid-crystalline phases
Summary
Liposomes are among technological delivery developments for chemotherapeutic drugs in the treatment of cancer. Fluorescence quenching measurements using iodide ion showed that the usual Stern-Volmer plots (plots of the fluorescence intensity ratio in the absence, I0, and presence, I, of quencher vs quencher concentration) are not linear and exhibit a downward curvature (Figure 7A) This indicates that some compound molecules are not accessible to the anionic quencher, being intercalated between DNA base pairs. As both compounds 1 and 2 are neutral molecules (and electrostatic interaction with the negatively charged DNA molecule is not expected), the high fa values indicate that the main type of interaction with the nucleic acid must be the binding to DNA grooves [28] Fluorescence experiments of both compounds encapsulated in liposomes of DPPC, DODAB and Egg-PC were carried out (Figure 8), in both gel (below Tm) and liquid-crystalline (above Tm) phases. The encapsulation assays performed here may be important for future drug delivery applications of these potential antitumoral compounds using liposomes as drug carriers
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