Lipid Nucleoside Conjugates for the Treatment of Cancer

Abstract

Phospholipid nucleoside conjugates and nucleosides with chemical additions to the hydroxyl and amino moieties have been used since the 1970s in order to increase the biological activity of the parent compound. Previous investigators have found that adding lipid moieties to ara-C or chemically linking ara-C to a phospholipid creates a prodrug that exhibits superior cytotoxic activity compared to ara-C alone when used in animal tumor models. The novel ara-C molecules reveal different pharmacological profiles from the parent compound such as decreased catabolism by cytidine deaminase, increased plasma half-life, and release of nucleoside monophosphate, a reaction that bypasses the rate limiting initial nucleoside phosphorylation. Additionally, these compounds were able to penetrate the blood-brain barrier and were active against tumor cells implanted i.c. The purpose of this review is to briefly cover the history and successes of previous investigators who have synthesized and tested these phospholipid ara-C conjugates, to discuss recent phospholipid ara-C and fludarabine conjugates, and to discuss the synthetic design and synthesis of a novel phospholipid gemcitabine conjugate. These phospholipid nucleoside conjugates possess the potential to have superior anti-neoplastic cytotoxicity profiles with fewer side effects than the parent nucleoside and merit further investigation.

Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

“…Chemical sites within gemcitabine that are potentially available for synthetic covalent bond reactions include the (C 4 ′)-NH2, (C 3 ′)-OH and (C 5 ′)-OH groups that can be reversibly protected utilizing di- tert -dibutyl dicarbonate [61] when non-selective organic chemistry reaction schemes are employed. Generation of a covalent bond at the C 5 - methylhydroxy group of gemcitabine represents one molecular approach to synthesizing covalent gemcitabine-immunochemotherapeutics or gemcitabine-ligand preparations [36,40,56-61,76]. A second and possibly more infrequently utilized organic chemistry reaction involves the creation of a covalent bond at the cytosine-like C 4 - amine group of gemcitabine either in the form of a direct link to a “targeting” platform for selectivey chemotherapeutic delivery or alternatively for the purpose of creating a gemcitabine reactive intermediate [21,59,61,77,78].…”

“…Gemcitabine has been covalently bound to biologically relevant ligands that inludes poly-L-glutamic acid (polypeptide configuration), [58] cardiolipin, [56,57] 1-dodecylthio-2-decyloxypropyl-3-phophatidic acid, [40,60] lipid-nucleosides, [76] N -(2-hydroxypropyl) methacrylamide polymer (HPMA), [21] benzodiazepine receptor ligand, [59,61] 4-( N )-valeroyl, 4-( N )-lauroyl, 4-( N )-stearoyl, [78] 1,1′,2-tris-noraqualenecarboxylic acid, [79] and the 4-fluoro [18F]-benzaldehyde derivative [77] for application as a positron-emitting radionuclide. Few if any published have described the molecular design, chemical synthesis and evaluation of the cytotoxic anti-neoplastic potency for gemcitabine immunochemotherapeutic created by generating a covalent bond at either the C 5 - methylhydroxy [36] or cytosine-like C 4 - amine groups of gemcitabine.…”

Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

“…However, only a few gemcitabine analogues with a phosphate moiety have been reported to address the problem. The first synthesized compound to address dCK deficiency was a gemcitabine derivative linked with a C-1 thioether, C-2 oxyether phospholipid (Alexander et al, 2003; Alexander et al, 2005; Alexander and Kucera 2005). Wu et al then introduced the gemcitabine phosphoramidate prodrug, which was shown to be 4 times more cytotoxic than gemcitabine in dCK deficient cell lines (Wu et al, 2007).…”

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

“…Conjugated agents have also been developed to improve the oral bioavailability of drugs [106]. Synthetic phospholipid conjugates of cytosine arabinoside (ara-C) and gemcitabine have been developed [107,108].…”