A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach
Journal
European Journal of Pharmaceutical Sciences
Journal Volume
91
Pages
50-63
Date Issued
2016
Author(s)
Marchetti P.
Pavan B.
Simoni D.
Baruchello R.
Rondanin R.
Mischiati C.
Feriotto G.
Ferraro L.
Lee R.M.
Dalpiaz A.
Abstract
We report the design, synthesis and biological characterisation of a novel hybrid drug by conjugation of two tubulin inhibitors, a hemiasterlin derivative A (H-Mpa-Tle-AHA-OH), obtained by condensation of three non-natural amino acids, and cis-3,4′,5-trimethoxy-3′aminostilbene (B). As we have previously demonstrated synergy between A and B, we used a monocarbonyl derivative of triethylene glycol as linker (L) to synthesise compounds A-L and A-L-B; via HPLC we analysed the release of its potential hydrolysis products A, A-L, B and B-L in physiological fluids: the hybrid A-L-B undergo hydrolysis in rat whole blood of the ester bond between A and L (half-life = 118.2 ± 9.5 min) but not the carbamate bond between B and L; the hydrolysis product B-L was further hydrolyzed, but with a slower rate (half-life = 288 ± 12 min). The compound A-L was the faster hydrolyzed conjugate (half-life = 25.4 ± 1.1 min). The inhibitory activity of the compounds against SKOV3 ovarian cancer cell growth was analysed. The IC 50 values were 7.48 ± 1.27 nM for A, 40.3 ± 6.28 nM for B, 738 ± 38.5 nM for A-L and 37.9 ± 2.11 nM for A-L-B. The anticancer effect of A-L-B was evidenced to be obtained via microtubule dynamics suppression. Finally, we stated the expression of the active efflux transporters P-gp (ABCB1) and MRP1 (ABCC1) in the human normal colon epithelial NCM460 cell line by reverse-transcription PCR. Via permeation studies across NCM460 monolayers we demonstrate the poor aptitude of A to interact with active efflux transporters (AET): indeed, the ratio between its permeability coefficients for the basolateral (B) → apical (A) and B → A transport was 1.5 ± 0.1, near to the ratio of taltobulin (1.12 ± 0.06), an hemiasterlin derivative able to elude AETs, and significantly different form the ratio of celiprolol (3.4 ± 0.2), an AET substrate. ? 2016 Elsevier B.V. All rights reserved.
Subjects
Hemiasterlin; Hybrid drug; Hydrolysis; NCM460 cells; Permeation; Stilbene
SDGs
Other Subjects
carbamic acid; celiprolol; taltobulin; ABCB1 protein, human; antineoplastic agent; cis-3,4',5-trimethoxy-3'-aminostilbene; hemiasterlin; multidrug resistance associated protein; multidrug resistance-associated protein 1; oligopeptide; stilbene derivative; tubulin modulator; antineoplastic activity; Article; cancer growth; colon mucosa; controlled study; drug design; drug half life; drug hydrolysis; drug synthesis; female; high performance liquid chromatography; human; human cell; microtubule; nonhuman; ovary cancer; priority journal; rat; reverse transcription polymerase chain reaction; RNA extraction; animal; cell cycle; cell line; chemistry; drug effect; drug stability; genetics; hydrolysis; liver; male; metabolism; solubility; tumor cell line; Wistar rat; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Cycle; Cell Line; Cell Line, Tumor; Drug Stability; Humans; Hydrolysis; Liver; Male; Multidrug Resistance-Associated Proteins; Oligopeptides; Rats, Wistar; Solubility; Stilbenes; Tubulin Modulators
Type
journal article