Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity

Abstract

Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.

Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

“…PD0325901 analogue 7a was obtained in 68% yield (two steps) [15,18]. Derivation of the terminal amine group of 7awith succinic anhydride provided the hemisuccinate ester 8a in 85% yield [19]. The peptide conjugation reaction was initiated from the activation of 8a with PyBOP in the presence of DIPEA, followed by the addition of c(RGDyk) peptide, which afforded RGD-MEKI conjugate 9a in 45% yield.…”

“…Column chromatography was performed using 200-300 mesh silica with the proper solvent system according to TLC analysis using KMnO 4 stain and UV light to visualize the reaction components. Unless otherwise noted, 1 H-NMR (400 MHz), 19 F-NMR spectra (376 MHz) were recorded at ambient temperature using a BrukerAvance III400 MHz spectrometer (Bruker, Karlsruhecity, Germany). NMR data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet and bs = broad singlet), coupling constant in Hz and integration.…”

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

“…It has been previously demonstrated that esterification at 2′-OH or 7-OH abolished the microtubule binding affinity of the conjugates but not the total toxicity. 28 The DX conjugates as ester prodrugs are expected to be cleaved to release free DX and exert their antitumor toxicity after cleavage. However, in the present 48 hours in vitro cytotoxicity study, the hydrolysis rate may not be fast enough to release all the DX.…”

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

“…Prodrugs 3 and 4 were prepared starting by the reaction of the 2'-hydroxy function of PTX with 285 succinic anhydride according to the procedure of Deutsch (Deutsch et al, 1989). In order to facilitate the further PEGylation reaction, the carboxyl function of 2'-succinyl-paclitaxel was activated as N-hydroxysuccinimidil derivative (PTX-NHS, 2) using NHS and DCC.…”