Synthesis of methotrexate α,γ-bis(amides) and correlation of thermotropic and DPPC biomembrane interaction parameters with their anticancer activity
✍ Scribed by Giovanni Puglisi; Massimo Fresta; Rosario Pignatello
- Book ID
- 101265643
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 170 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
The interaction of MTX and some aliphatic bis(amide) derivatives with synthetic 1,2dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) biomembranes was investigated. The drug-membrane model interaction was carried out by differential scanning calorimetry. Anticancer activity of MTX bis(amides) was evaluated on cultures of a human leukemic cell line (CCRF-CEM) in comparison with MTX. Compounds were tested at a concentration ranging between 10 nM and 1 µM. The MTX is able to interact with the outer part of the phospholipid bilayers due to its polar nature. Results showed that the amide derivatives of MTX, presenting a marked lipophilic character, are able to interact with the hydrophobic core of the DPPC bilayers, thus perturbing the packing order of the phospholipid bilayers. Particularly, a reduction of the enthalpy values linked to the transition from the gel state to the liquid crystal state of DPPC membranes was observed. This effect is a function of the type and molar fraction of the various compounds. The in vitro antitumor activity on leukemic CCRF-CEM cells was higher for MTXbis(tetradecylamide) than for the other derivatives. The biological effectiveness of the various MTX derivatives correlates very well with the enthalpy of the transition of drug-loaded DPPC biomembranes.