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Synthesis of methotrexate α,γ‐bis(amides) and correlation of thermotropic and DPPC biomembrane interaction parameters with their anticancer activity
Author(s) -
Puglisi Giovanni,
Fresta Massimo,
Pignatello Rosario
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199806/07)44:2/3<62::aid-ddr3>3.0.co;2-8
Subject(s) - chemistry , thermotropic crystal , phospholipid , differential scanning calorimetry , biological membrane , membrane , amide , stereochemistry , lipid bilayer , biological activity , bilayer , organic chemistry , in vitro , biochemistry , liquid crystalline , physics , thermodynamics , phase (matter)
The interaction of MTX and some aliphatic bis(amide) derivatives with synthetic 1,2‐dipalmitoyl‐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 MTX‐bis(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. Drug Dev. Res. 44:62–69, 1998. © 1998 Wiley‐Liss, Inc.