Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Pignatello, Rosario; Vicari, Luisa; Sorrenti, Valeria; Giacomo, Claudia Di; Spampinato, Giorgia; Puglisi, Giovanni; Tóth, István

doi:10.1002/ddr.1147

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…Pignatello et al have utilised Laas conjugated to a glucopyranosylamine moiety through an amide linkage to produce liposugar conjugates of methotrexate e.g. (8) [33]. Unfortunately these conjugates showed reduced in vitro activity against tumour cell growth compared to the Laa-MTX conjugates, possibly due to steric hindrances, however the synthetic strategy was successful and is generally applicable to many drug types.…”

Section: Liposaccharide Conjugationmentioning

confidence: 96%

Lipid, Sugar and Liposaccharide Based Delivery Systems 2

Blanchfield¹,

Tóth

2004

CMC

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The vast majority of biologically active compounds will never be considered as potential drugs due to inherently poor bioavailability. This review discusses the progress in the development of chemical systems to improve the metabolic stability, absorption and physicochemical properties of potential drugs. Delivery systems that involve the conjugation of lipid and/or sugar moieties are highlighted, as well as novel methods of conjugation of these groups to drugs. The use of sugar molecules to target drugs to particular organs or cells is also discussed, as is the use of lipids in the growing area of gene delivery. This is an update of a previous review.

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Section: Liposaccharide Conjugationmentioning

confidence: 96%

Lipid, Sugar and Liposaccharide Based Delivery Systems 2

Blanchfield¹,

Tóth

2004

CMC

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“…Linked to alkylating agents like chlorambucil, LAAs increased selectivity toward tumor cells [Wood et al, 1992]. Methotrexate-LAA conjugates showed an enhanced ability in penetrating resistant tumor cells by means of a passive internalization through the cell membrane [Pignatello et al, 1998[Pignatello et al, , 2000[Pignatello et al, , 2001[Pignatello et al, , 2004. Paclitaxel-LAA prodrugs have been shown to modify the onset of activity of the drug in vitro against a human ATC cell line (Aro cells), as well as to improve its passive uptake by these tumor cells [Pignatello et al, 2009].…”

Section: Introductionmentioning

confidence: 98%

Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine

Pignatello

Vicari²,

Pistarà

et al. 2010

Drug Development Research

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Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N 4 -acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM. Drug Dev Res 71: 294-302, 2010.

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“…For instance, methotrexate conjugates with LAA showed an enhanced ability in penetrating resistant tumour cells by means of a passive internalisation through the cell membrane [5][6][7]. LAA conjugation of high-affinity activator peptides of ryanodine receptor increased membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs [8].…”

Section: Introductionmentioning

confidence: 98%

Evaluation of Cell Tolerability of a Series of Lipoamino Acids Using Biological Membranes and a Biomembrane Model.

Pignatello

Noce²,

Campisi³

et al. 2007

CDD

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The interaction of a series of amphiphilic 2-alkyl aminoacids (lipoamino acids, LAAs) with different cell cultures and biomembrane models was investigated. LAAs can be useful promoieties to modify the physico-chemical properties of many drugs, and in particular their lipophilicity. Tests were performed in vitro on mammalian cells (murine astrocytes) and human red blood cells (haemolysis), and in vivo on rabbit eye as alternative models to assess the tolerability or the potential damaging effects of these compounds on different biological systems. The mode of interaction of LAAs with pure phospholipid multilamellar liposomes, taken as a biomembrane model, was also analysed by differential scanning calorimetry experiments. Different tolerability/toxicity patterns were obtained in the various models; in particular, the most lipophilic terms of the series, methyl 2-aminohexadecanoate (LAA16), displayed haemolytic activity and toxicity for mouse astrocyte cultures. A specific assay confirmed that LAA16 acted at level of cell membranes, while neither any damaging effects on nucleus or apoptotic induction were observed. The shorter-chain LAAs and the tetradecyl homologue (LAA14) showed the best compatibility with the various cell models.

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Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Cited by 13 publications

References 22 publications

Lipid, Sugar and Liposaccharide Based Delivery Systems 2

Lipid, Sugar and Liposaccharide Based Delivery Systems 2

Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine

Evaluation of Cell Tolerability of a Series of Lipoamino Acids Using Biological Membranes and a Biomembrane Model.

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