Tris and the ready production of drug‐fatty acyl conjugates

Wells, X; Bender, Veronika; Francis, Craig L.; He-Williams, Hua Ming; Manthey, Michael K.; Moghaddam, Minoo J.; Reilly, Wayne G.; Whittaker, Robert G.

doi:10.1002/(sici)1098-2299(199903/04)46:3/4<302::aid-ddr16>3.3.co;2-i

Cited by 5 publications

(10 citation statements)

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“…Increasing the lipophilicity of AZT by adding GTP1 and GTP2 groups caused increased cytotoxicity (greater than 50 fold) and this has previously been reported for other cell lines (Wells et al ., 1999). The strategy of increasing the lipophilicity is often used to increase the uptake and efficacy of a compound.…”

Section: Discussionsupporting

confidence: 94%

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The use of Tris‐Lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P‐glycoprotein or MRP1

Davey¹,

Davey²,

Cullen³

et al. 2002

British J Pharmacology

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1 Increasing the lipophilicity is a strategy often used to improve a compound's cellular uptake and retention but this may also convert it into a substrate for an ATP-dependent transporter such as Pglycoprotein or the multidrug resistance-associated protein (MRP1), which are involved in cellular e ux of drugs. Tris-Lipidation of compounds is a convenient way of modifying drug lipophilicity and generating an array of derivatives with diverse properties. 2 To determine the e ect of Tris-Lipidation on a drug's cytoxicity in multidrug resistant cells, various glycyl-Tris-mono-(GTP1), di-(GTP2) and tri-palmitate (GTP3) derivatives were prepared of the cancer chemotherapeutic drugs chlorambucil and methotrexate, and of the anti-HIV drug AZT. The cytotoxicity of these derivatives and their parent compounds was determined in the CEM/ VLB 100 cells with increased P-glycoprotein expression, the CEM/E1000 cells that overexpress MRP1 and the parent, drug-sensitive CCRF-CEM cells. 3 Increasing the lipophilicity of AZT increased its cytotoxicity in the sensitive CCRF-CEM parental cell line while decreased cytotoxicity was observed for the methotrexate derivatives. For the chlorambucil derivatives, both increased (GTP1) and decreased (GTP2) cytotoxicity occurred in the CCRF-CEM cells. With the exception of AZT-GTP1, all GTP1 and GTP2 derivatives of chlorambucil, methotrexate and AZT had decreased cytotoxicity in the P-glycoprotein-expressing CEM/VLB 100 cells while chlorambucil-GTP1, methotrexate-GTP2 and methotrexate-GTP3 were the only compounds with decreased cytotoxicity in the MRP1-overexpressing CEM/E1000 cells. 4 The number of palmitate residues, the position of derivatisation and the type of linkage all may a ect the P-glycoprotein and MRP1 substrate properties. 5 Tris-Lipidation may therefore provide a useful way of manipulating the pharmacokinetic properties of drugs.

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Section: Discussionsupporting

confidence: 94%

“…Modification of the γ‐carboxyl group would therefore reduce the cytotoxicity and our results are consistent with this as all methotrexate‐γ‐conjugates were less cytotoxic than the parent compound (Figure 2). This confirms the earlier observations of Wells et al . (1999).…”

Section: Discussionmentioning

confidence: 99%

The use of Tris‐Lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P‐glycoprotein or MRP1

Davey¹,

Davey²,

Cullen³

et al. 2002

British J Pharmacology

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“…Structure–activity relationship (SAR) studies of MTX derivatives have emphasized the importance of selective conjugation to the γ-carboxylic acid of the glutamate moiety to ensure high affinity binding to DHFR through interaction of this enzyme with the free α-carboxylic acid. [12] Hence, an objective of this study was to synthesize a versatile MTX-based building block and explore its use for easy and straightforward ligation to bait small molecules of interest.…”

Section: Introductionmentioning

confidence: 99%

A “Clickable” MTX Reagent as a Practical Tool for Profiling Small‐Molecule–Intracellular Target Interactions via MASPIT

et al. 2013

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We present a scalable synthesis of a versatile MTX reagent with an azide ligation handle that allows rapid γ-selective conjugation to yield MTX fusion compounds (MFCs) appropriate for MASPIT, a three-hybrid system that enables the identification of mammalian cytosolic proteins that interact with a small molecule of interest. We selected three structurally diverse pharmacologically active compounds (tamoxifen, reversine, and FK506) as model baits. After acetylene functionalization of these baits, MFCs were synthesized via a CuAAC reaction, demonstrating the general applicability of the MTX reagent. In analytical mode, MASPIT was able to give concentration-dependent reporter signals for the established target proteins. Furthermore, we demonstrate that the sensitivity obtained with the new MTX reagent was significantly stronger than that of a previously used non-regiomeric conjugate mixture. Finally, the FK506 MFC was explored in a cellular array screen for targets of FK506. Out of a pilot collection of nearly 2000 full-length human ORF preys, FKBP12, the established target of FK506, emerged as the prey protein that gave the highest increase in luciferase activity. This indicates that our newly developed synthetic strategy for the straightforward generation of MFCs is a promising asset to uncover new intracellular targets using MASPIT cellular array screening.

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“…Tris technology was used by Wells et al (8) to prepare fatty acid conjugates of the analgesic morphine, nonsteroidal antiinflammatory drug indomethacin, antiviral drug 3′-azido-3′-deoxythymidine (AZT), and antineoplastic drugs methotrexate and chlorambucil. In their studies they demonstrated that biological properties such as cellular uptake, delivery profiles, skin retention, and toxicity of these conjugates could be altered.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic Transmembrane-Peptide Lipid Conjugations Enhance Membrane Binding and Functional Activity in T-Cells

et al. 2005

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Application of different delivery methods for therapeutic peptides has gained much attention in recent years. In this paper we conjugated a transmembrane hydrophobic peptide (core peptide; CP) derived from the T-cell antigen receptor alpha-chain sequence with either one (LP1), two (LP2), or three (LP3) palmitic acids through a Tris linkage. The effect of these lipopeptides (LPs) were compared to CP's activity both in vitro and in model membrane binding experiments using surface plasmon resonance. The influence of charged amino acids, arginine and lysine, within the CP sequence was examined by synthesizing analogues where arginine and lysine were replaced by the neutral amino acid alanine and these analogues were subsequently Tris-lipid conjugated with either one (XP1), two (XP2), or three (XP3) palmitic acids through a Tris linkage. The results indicated that the amount of irreversible binding for LPs were all greater than that of the underivatized CP in model membranes. None of the LPs could be dissociated from the liposome membranes, even after prolonged washing. Binding results for the neutral conjugates showed that only the XP1 bound to model membranes. This binding was 20% as efficient compared to LP1. In biological assays it was found that LP1 and XP1 were toxic to cells. LP3 inhibited IL-2 production more effectively than CP. Control lipopeptides (XP2, XP3) did not inhibit IL-2 production. These results demonstrate that the number of lipids conjugated to peptide, and the charged amino acids of CP, are both essential factors for peptide function and activity that can be enhanced by lipidation.

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Tris and the ready production of drug‐fatty acyl conjugates

Cited by 5 publications

References 0 publications

The use of Tris‐Lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P‐glycoprotein or MRP1

The use of Tris‐Lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P‐glycoprotein or MRP1

A “Clickable” MTX Reagent as a Practical Tool for Profiling Small‐Molecule–Intracellular Target Interactions via MASPIT

Hydrophobic Transmembrane-Peptide Lipid Conjugations Enhance Membrane Binding and Functional Activity in T-Cells

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