Hydrolyzable hydrophobic taxanes: synthesis and anti-cancer activities

Abstract

A series of taxane prodrugs with 2-bromoacyl chains attached at the 2'-position of the paclitaxel side chain, varying from six, eight, 12, 14 to 16 carbons in length, were synthesized, characterized and evaluated against human breast MCF-7 cancer cell line for their growth inhibitory (GI50) activities. The GI50 is the drug concentration required to inhibit cell growth by 50%. For comparison, hydrophobic taxanes varying in acyl chain lengths from six to 16 carbons were also synthesized and compared for their G050s with taxanes having equivalent bromoacyl chain lengths. The bromoacyl taxanes bearing six, eight and 12 carbon acyl chain lengths had GI50 values very similar to parent paclitaxel. The GI50 was 3 nM for three taxanes versus 1 nM for paclitaxel on the MCF-7 cell line. Increasing the acyl chain length to 14 or 16 carbons resulted in a significant decrease in cytotoxicity and an increase in the GI50 to 20 or 70 nM, respectively. In general, the GI50 values were directly related to the bromoacyl chain lengths in cultured tumor cells. Unlike bromoacyl taxanes, the taxanes lacking bromine in their acyl chain composition were 50- to 250-fold less active, suggesting that the heteroatom facilitated the hydrolysis of acyl chains to yield free paclitaxel. These differences in growth inhibitory activities may indirectly reflect differences in the susceptibility of the acyl chain to bromine-induced hydrolysis after association of the derivative with cell membranes. Liposome formulations of 2-bromoacyl taxanes bearing six, eight, 12 and 16 carbons were prepared and tested in SCID mice against a xenografted human ovcar-3 ovarian tumor. In vivo results showed that bromoacyl taxanes with a longer chain were therapeutically more efficacious than those with a short chain, presumably due to slow hydrolysis of the prodrug followed by sustained delivery of paclitaxel to the tumor.

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

“…Many studies have reported the reduction of PX or DX activity by conjugating fatty acid chains to 2′-OH. 21,23,24 This study is consistent with previous reports that in general, all three DX-lipid conjugates were less potent than DX against DU-145 cells, and increasing the lipid chain length decreased the cell growth inhibitory activity in vitro. 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.…”

“…21 It has been previously reported that the conjugation of fatty acids to DX and PX occurs preferentially on 2′-OH. 21,23,24 By controlling the molar ratio of the fatty acid chloride to DX carefully, 2′-mono substituted DX conjugates were obtained with minimal formation of 2′,7-di substituted byproducts and unreacted DX. In the case of C22-DX, only the 2′-OH ester derivative was obtained after washing with 5% HCl and brine as determined by thin layer chromatography and nuclear magnetic resonance, without further chromatography required.…”

“…Another study showed that the 2′-(2-bromo)-hexadecanoyl DX with lowest in vitro cytotoxicity in its kind was most effective in vivo, showing 100% survival at day 300 for OVCAR-3-bearing SCID mice. 24 The DHA-PX on clinical trial III prepared by linking PX to docosahexaenoic acid (DHA) was less toxic than PX in vitro but cured 10/10 M109 tumor-bearing mice, whereas PX cured 0/10. 29 Our pharmacokinetic results provided the basis for enhanced in vivo efficacy.…”

2'-(2-bromohexadecanoyl)-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model

“…9 Briefly, PX was conjugated with 2-bromohexadecanoic acid via a one-step esterification reaction with DMAP (SigmaAldrich Co.) as the catalyst. The product was purified by preparative thin layer chromatography.…”

“…Previously Ali et al synthesized a series of lipophilic PX conjugates bearing 6, 8, 12, 14, or 16-carbon chains at the 2′-position. 9 The PX conjugate with a long 16-carbon chain exhibited decreased cytotoxicity compared to conjugates with shorter chain lengths, but was therapeutically more efficacious when loaded into liposomes for the treatment of mouse ovarian cancer. Moreover, the incorporation of an electron-withdrawing bromine (Br) atom was evaluated in the PX conjugates.…”