Abstract
Hydroxyurea (HU) has shown promise in breast cancer treatment, but its
hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids
could increase its liphophilicity and improve its cellular uptake, leading to
increased efficacy and reduced toxicity. The PI3K/Akt/mTOR
pathway is an attractive therapeutic target in cancer not only because it is the
second most frequently altered pathway after p53, but also because it serves as
a convergence point for many stimuli. The aim of this study is to design and
develop novel hydroxyurea lipid drug conjugates for breast cancer therapy
targeting the PI3K/Akt/mTOR pathway using in-silico and
in-vitro approaches. The conjugates are designed and docked with the
proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF),
mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME
studies and molecular dynamics. Stearic, lauric, palmitic, myristic and
linolenic acids have been used for the conjugation. The conjugates are
synthesized and characterized. The HLB calculation and partition coefficient are
carried out to find the improvement in liphophilicity of the conjugates compared
to hydroxyurea. Finally, the in-vitro cytotoxicity studies are performed
with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid)
with low IC50 is considered as the compound having good activity with
compound code. These conjugates have been shown to have improved drug solubility
and better cellular uptake compared to free hydroxyurea, which can increase drug
efficacy.
Key words
breast cancer - hydroxyurea - lipid conjugates - fatty acids - lipophilicity.
