Highly Water Soluble Taxol Derivatives: 7-Polyethylene Glycol Carbamates and Carbonates

Abstract

The first examples of highly water soluble taxol derivatives (0.1 mmol/mL) were prepared by the attachment of polyethylene glycol (molecular weight 2-5 kD) at the 7-position of taxol via a urethane or carbonate linkage. When lower molecular weight polyethylene glycols (350 and 750) were used, the solubilities were considerably lower (1.87 x mmob"L) but still substantially greater than taxol itself. Additional 7-substituted taxol derivatives were also prepared by utilizing small molecules consisting of sugars and ionic and multifunctional compounds. However, most of these derivatives had solubilities, calculated from HPLC retention times, that did not differ significantly from taxol itself. The use of methoxyacetate as a protecting group during these syntheses is discussed.Early difficulties in obtaining sufficient quantities of taxol for clinical studies to assess antitumor activity in ovarian, breast, and lung cancer have been overcome, but the associated problem of poor aqueous solubility still remains. Modification of both the 3' and 10 position has been achieved by French researchers1 to yield a 10deacetyl tert-butyl carbamate derivative (Taxotere) which produced a slightly more water soluble taxol analogue. Taxotere has also been reported to possess antitumor activity comparable to or greater than that of taxol itself.Considering the scope of interest manifested in taxol, few modifications of the 7 position and subsequent oncolytic activities have been reported. Most accounts to date have been concerned with esterifications of the hindered secondary alcohol moiety at the 7 position which could improve solubility while maintaining cytotoxic Polyethyleneglycol (PEG) is known to enhance water solubilitys8 and reduce immunogenicity of high molecular weight protein a d d u~t s~~-~ and therefore seemed like a n activity.2-43-10 @ Abstract published in Advance ACS Abstracts, January 1, 1995.(1) Commercon, A.; Bizard, D.; Bernard, F; Baurzat, J. D. Tetrahedron Lett. 1992, 33, 5785-5788 and references cited.

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

“…The results, reported in Table 2, show that PTX was very active and that the prodrugs 3 and 4 display a quite similar toxicity; these data are in accordance with the stability experiments that indicated that PTX was rapidly released from the conjugates 3 and 4. On the contrary, an important decrease in the 360 cytoxicity (from two to four orders) was observed in the PEG-carbamate prodrugs, in particular for the compounds obtained reacting the C7 position of PTX (14 and 15); a reduction in cytotoxic activity of C7 ester or carbamate derivatives was yet reported by other research groups (Greenwald et al, 1996;Greenwald et al, 1995).…”

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

“…It is very popular in protein PEGylation where lysine-, histidine-or cysteine-amino group of the bioactive protein is conjugated to PEG by replacing the hydroxyl end group (127). For instance PEGylation of bovine adenosine deaminase via amide bond (Adagen (127,(129)(130)(131)(132)(133). The pendant group systems consist of different types of polymers which may contain single reactive pendant group or specifically synthesized to control the number of reactive pendant groups along the polymer chain.…”

Synthesis and antimicrobial activity of ciprofloxacin and norfloxacin permanently bonded to polyethylene glycol by a thiourea linker

“…Norfloxacin was also attached to methacrylate polymers. 14 The goal of this work was to investigate the antimicrobial effect of the quinolonecarboxylic acid dimers prepared with a PEG linker, and to study the effect of PEGylation on the antibacterial activity.To investigate the separate effect of the PEGylation and dimerization of 1 and 2 on the antimicrobial effect, both the mono-and bifunctional PEG derivatives of the antimicrobial agents were prepared.Monomethoxy-PEG (MW average ¼1132 Da) and PEG (MW average ¼ 1382 Da) were converted 15 into the monoamino (3) and diamino (4) derivatives, whose treatment with thiophosgene gave the corresponding mono-and diisothiocyanates 5 and 6, respectively (Scheme 1).The reaction of 4 and 6 with ciprofloxacin and norfloxacin under mild conditions (Scheme 1) led to the PEG-conjugates (7,8,9,10), whose structures were proved by matrix-assisted laser desorption/ ionization (MALDI) mass spectrometry and NMR spectroscopy. (Figure 1 represents the MALDI-time of flight (TOF) mass spectrum of 6 and 9).…”

“…Monomethoxy-PEG (MW average ¼1132 Da) and PEG (MW average ¼ 1382 Da) were converted 15 into the monoamino (3) and diamino (4) derivatives, whose treatment with thiophosgene gave the corresponding mono-and diisothiocyanates 5 and 6, respectively (Scheme 1).The reaction of 4 and 6 with ciprofloxacin and norfloxacin under mild conditions (Scheme 1) led to the PEG-conjugates (7,8,9,10), whose structures were proved by matrix-assisted laser desorption/ ionization (MALDI) mass spectrometry and NMR spectroscopy. (Figure 1 represents the MALDI-time of flight (TOF) mass spectrum of 6 and 9).…”

“…There are few reports on permanently bonded drugs, but those compounds exhibit low biological activity. 10 Ciprofloxacin was encapsulated in PEG-coated, long-circulating sustained-release liposomes. 11,12 It is to be noted that Carraher et al 13 reported the synthesis and biological activity of ciprofloxacin covalently bonded to organotin polymers of 1 and 2.…”