| dc.description.abstract | One of the biggest problems of the global public health is the increase number of
cancer cases. In Poland every year the cancer is diagnosed in 155000 of people. Since the
causes of some of the cancers have not been sufficiently well acknowledged, the most
important task is to find an effective cancer treatment. A significant role may play the
drug carriers which are able to form stable complexes with drugs and can change their
bioavailability. In 2014 the research team from the Department of Organic and Applied
Chemistry, University of Lodz synthesized two new molecules: 1,10-N,N’-bis-(β-Dureidoglucopyranosyl)-
4,7,13-trioxa-1,10-diazacyclopentadecane (molecule L1) and
1,10-N,N’-bis-(β-D-ureidocellobiosyl)-4,7,13-trioxa-1,10-diazacyclopentadecane
(molecule L2). These molecules contain the sugar substituents which are linked by the
urea bridges with the diaza-crown ether. It is known that, sugar units possess abilities to
recognize the target tissue, while diaza-crown ethers are characterized by very good
complexation abilities to the alkaline ions as well as to the neutral molecules.
Additionally, they are characterized by the good solubility, high molecular weight and
were experimentally proved to be non-toxic. Due to these properties the molecules L1 and
L2 are considered as potential drug carriers. In the work [1], the authors show that L1 and
L2 are able to form stable complexes with the drugs such as aspirin and paracetamol,
which are very popular, analgesic, antipyretic and cheap medicines. However, they are
characterized by the low water solubility, and the latter causes their low gastrointestinal
absorption.
The aim of my doctoral thesis was to investigate the structural and energetic
properties of L1 and L2 and their complexes with aspirin, paracetamol and busulfan
(anticancer drug which is characterized the high toxicity and is used in the chemioteraphy
against the leukemia) using theoretical methods. The dissertation is focused on finding
structures which have the lowest energy as well as on the studies of intermolecular
interactions between L1, L2 and the drugs in the complexes. For this purpose,
configurational analysis of the molecules and their complexes was performed with the use
of the approximate methods such as: molecular mechanics, semiempirical methods,
computer simulation, followed by the more advanced calculations at the density
functional theory (DFT) level. The calculated NMR chemical shifts are compared with
the experimental data.
The results of my studies show that molecules L1 and L2 are characterized by
very compact geometric structure which is mainly determined by formation of hydrogen
bonds between the sugar units. The orbital analysis indicate that in both molecules the
HOMO and LUMO orbitals are localized on the diaza-crown ether and sugar units, while
the Natural Bond Analysis reveals that the most stabilizing interaction is localized in the
area of urea.
It i also shown that, according to the B3LYP-GD2 results, the ligands L1 and L2
prefer to create the non-inclusion complexes with aspirin, paracetamol and busulfan.
However, L2 can form the stable inclusion complexes, but only with the paracetamol
molecule, and they are not energetically preferable. The supramolecular analysis indicates
that molecules L1 and L2 form the most stable complexes with aspirin, despite the fact
that the strongest interactions occur in the complexes with paracetamol. It is shown that
complexation process is exothermic and spontaneous. | pl_PL |
